Dermatologic and ocular manifestations of inflammatory bowel disease

INTRODUCTION — There are several extraintestinal manifestations of inflammatory bowel disease (IBD). These manifestations vary in severity and can be more debilitating than the underlying IBD. While some extraintestinal manifestations parallel the disease activity of IBD (eg, erythema nodosum, episcleritis, and Sweet syndrome), the course of others (eg, pyoderma gangrenosum, uveitis) is independent of intestinal inflammation.

This topic will review the skin and eye manifestations of IBD. The clinical manifestations, diagnosis, and management of ulcerative colitis and Crohn disease are discussed separately. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Medical management of low-risk adult patients with mild to moderate ulcerative colitis" and "Management of the hospitalized adult patient with severe ulcerative colitis" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Overview of the medical management of mild (low risk) Crohn disease in adults" and "Medical management of moderate to severe Crohn disease in adults".)

EPIDEMIOLOGY — The prevalence of extraintestinal manifestations in patients with IBD has not been extensively studied. However, data suggest that 6 to 40 percent of patients with IBD have one or more extraintestinal manifestation [1-3]. Up to 15 percent of patients have a cutaneous manifestation of IBD [4,5]. Ocular manifestations of IBD occur in 4 to 10 percent of patients and may be more likely to occur in patients with Crohn disease as compared with ulcerative colitis [6,7].

PATHOGENESIS — The pathogenesis of extraintestinal manifestations in patients with IBD is incompletely understood. However, it is hypothesized that the diseased gastrointestinal mucosa may trigger an immune response at the extraintestinal site due to shared epitopes [8]. Triggers of the immune response in certain organs may be influenced by genetic factors. Associations of extraintestinal manifestations of IBD with major histocompatibility complex loci have also been demonstrated [9]. As an example, HLA-B27 and HLA-B58 are associated with ocular inflammation in patients with IBD.

DERMATOLOGIC DISEASE

Erythema nodosum — Erythema nodosum is the most common dermatologic manifestation of inflammatory bowel disease (IBD), occurring in up to 3 percent of patients with ulcerative colitis and up to 8 percent of patients with Crohn disease [10-12]. Lesions typically consist of raised, tender, red or violet subcutaneous nodules that are 1 to 5 cm in diameter (picture 1). The nodules are most commonly located on the extensor surfaces of the extremities, particularly over the anterior tibial area. Biopsy of these lesions shows focal panniculitis. However, the diagnosis is most often clinical, and biopsy is required only in atypical cases (eg, patients with no lesions on the legs, persistence beyond six to eight weeks, or the development of ulceration).

The appearance of erythema nodosum usually parallels intestinal disease activity, and treatment directed at the underlying IBD usually results in resolution of the lesions. Skin lesions rarely precede the onset of IBD, or occur during quiescent phases of IBD; in these settings, therapy with other treatments, including prednisone, may be required. The management of erythema nodosum is discussed separately.

Pyoderma gangrenosum — Pyoderma gangrenosum is the second most common dermatologic manifestation of IBD. However, the proportion of patients with IBD who develop pyoderma gangrenosum appears to be small [10,13]. In one cohort study that included 2402 patients with IBD, pyoderma gangrenosum was detected in only 0.75 percent of patients [10].

The lesions initially appear as single or multiple erythematous papules or pustules that are often preceded by trauma to the skin (picture 2). They occur most commonly on the legs, but can develop in any area of the body, including the abdominal wall adjacent to the stoma after colectomy or surgical scars [14]. Subsequent necrosis of the dermis leads to the development of deep ulcerations that contain purulent material that is usually sterile on culture (picture 3). Biopsy reveals nonspecific findings consistent with a sterile abscess (picture 4). (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

Pyoderma gangrenosum lesions usually do not parallel IBD activity [15]. In patients with active IBD and pyoderma gangrenosum, therapy with systemic glucocorticoids usually results in healing. Pyoderma gangrenosum is also responsive to tumor necrosis factor (TNF) antagonists [16]. The clinical manifestations, diagnosis, and management of pyoderma gangrenosum are discussed in detail, separately. (See "Pyoderma gangrenosum: Treatment and prognosis", section on 'Treatment principles' and "Overview of the medical management of mild (low risk) Crohn disease in adults" and "Medical management of moderate to severe Crohn disease in adults".)

Hidradenitis suppurativa — Hidradenitis suppurativa (HS) is a chronic follicular occlusive disease involving the follicular portion of the folliculopilosebaceous units (FPSUs) (picture 5). Data have suggested an association between HS and IBD, particularly in patients with Crohn disease [17,18]. The diagnosis and management of HS are discussed separately. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis" and "Hidradenitis suppurativa: Management".)

Rare dermatologic diseases

Neutrophilic dermatoses

●Sweet syndrome – Sweet syndrome is an acute inflammatory dermatitis characterized by tender papules, plaques, and nodules distributed on the face, arms, and trunk (picture 6). Skin lesions are most commonly seen on the head, neck, and upper extremities. Episcleritis is a frequent ocular finding. Sweet syndrome is usually associated with active IBD, but may precede the onset of intestinal symptoms in approximately 20 percent of patients [19]. Biopsy of the lesion reveals an intense neutrophilic infiltrate without evidence of vasculitis. The lesions of Sweet syndrome usually respond quickly to oral glucocorticoids [20]. The clinical manifestations, diagnosis, and management of Sweet syndrome are discussed in detail, separately. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis" and "Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis".)

●Aseptic abscess syndrome – In rare cases, patients with IBD may present with aseptic abscess syndrome. The typical presentation includes fever, weight loss, abdominal pain, and leukocytosis [21]. Patients characteristically have aseptic sterile collections with a neutrophil predominant infiltrate. These sterile abscesses are usually located in the spleen, but approximately 20 percent of patients have cutaneous abscesses. Both systemic glucocorticoids and TNF antagonists have been effective in treating aseptic abscess syndrome in small observational studies [22]. However, the disease frequently follows a relapsing course.

●Bowel-associated dermatosis-arthritis syndrome – Patients with bowel-associated dermatosis-arthritis syndrome present with a serum sickness-like syndrome characterized by fever, chills, malaise, arthralgia, arthritis, and myalgia, which frequently precede the skin eruption [23]. Patients may have associated diarrhea due to active inflammation from underlying IBD. The aseptic non-erosive polyarthritis is asymmetric, episodic, and affects both small and large joints. The most characteristic cutaneous skin lesions are erythematous macules up to 1 cm in diameter that develop a central papulovesicle or pustule (picture 7). The eruption most often occurs on the upper extremities and trunk. Treatment consists of management of the underlying IBD with glucocorticoids. In refractory cases, other immunosuppressive agents, such as azathioprine or TNF antagonists, may be required. The clinical manifestations, diagnosis, and management of bowel-associated dermatosis-arthritis syndrome are discussed in detail, separately. (See "Neutrophilic dermatoses", section on 'Bowel-associated dermatosis-arthritis syndrome'.)

Cutaneous vasculitis — Cutaneous small vessel vasculitis and cutaneous polyarteritis nodosa (PAN) are associated with IBD [24,25]. The major clinical findings in patients with cutaneous vasculitis include nonblanching palpable purpura and/or petechiae (picture 8). Sometimes these lesions coalesce, ulcerate, or are surrounded by hemorrhagic bullae. Skin manifestations of PAN may include tender erythematous nodules, purpura, livedo reticularis, ulcers, and bullous or vesicular eruption. The clinical manifestations, diagnosis, and management of cutaneous vasculitis are discussed separately. (See "Overview of cutaneous small vessel vasculitis", section on 'Treatment'.)

Metastatic Crohn disease — Metastatic Crohn disease is characterized by cutaneous ulcerating nodules and violaceous plaques that demonstrate histologic similarity to the underlying Crohn disease and have noncaseating granulomas on biopsy (picture 9). These lesions can occur anywhere on the body, but most often occur on the anterior abdominal wall in the submammary area, intertriginous skin, and on the extremities [26,27]. Observational studies suggest that lesions respond to treatment of the underlying Crohn disease [28,29]. The management of Crohn disease is discussed in detail, separately. (See "Overview of the medical management of mild (low risk) Crohn disease in adults" and "Medical management of moderate to severe Crohn disease in adults".)

Epidermolysis bullosa acquisita — Epidermolysis bullosa acquisita is a rare subepithelial blistering disorder that has been associated with Crohn disease [30,31]. Classical epidermolysis bullosa acquisita presents as a mechanobullous disorder associated with skin fragility and noninflammatory tense bullae, with a predilection for acral areas (picture 10). The onset of the gastrointestinal symptoms generally precedes or occurs simultaneously with the skin lesions [30]. The clinical manifestations, diagnosis, and management of epidermolysis bullosa acquisita are discussed in detail, separately. (See "Epidermolysis bullosa acquisita".)

Associated conditions and complications — Patients may also have other dermatologic diseases associated with the underlying IBD or that develop as a consequence of therapy. Dermatologic complications of TNF antagonists and glucocorticoids are discussed separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Cutaneous reactions' and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy", section on 'Skin cancer risk' and "Major adverse effects of systemic glucocorticoids".)

Psoriasis — Psoriasis is the most frequently associated dermatologic disease in patients with IBD [32,33]. In one study, for example, psoriasis was present in 13 of 136 (9.6 percent) patients with Crohn disease as compared with 3 of 136 (2 percent) controls [33]. In addition, patients with Crohn disease were more likely to have a first-degree relative with psoriasis (10 versus 3 percent). Chronic plaque psoriasis, the most common presentation of psoriasis, most commonly presents with sharply defined erythematous plaques with overlying silvery scales (picture 11A-E). The scalp, extensor elbows, knees, and back are common locations for plaque psoriasis. The onset of psoriasis usually precedes IBD, and the course of psoriasis is independent of the disease activity of IBD. [33,34]. The clinical manifestations, diagnosis, and management of psoriasis are discussed in detail, separately. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Treatment of psoriasis in adults".)

Skin cancer — Patients with IBD are at an increased risk for melanoma [35]. In a meta-analysis of 12 cohort studies, patients with IBD were at an increased risk of melanoma as compared with the general population (relative risk [RR] 1.37, 95% CI 1.10-1.70), with a pooled crude incidence rate of melanoma of 27.5 cases/100,000 person-years (95% CI 19.9-37.0) [36]. The risk was increased among patients with Crohn disease and ulcerative colitis (RR 1.80; 95% CI 1.17-2.75 and 1.23; 95% CI 1.01-1.50, respectively). This risk appeared to be independent of biologic use, which may also increase the risk of melanoma [37]. The risk of skin cancer associated with TNF antagonists is discussed in detail, separately. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy", section on 'Skin cancer risk'.)

Among patients with IBD, the use of thiopurines has been associated with nonmelanoma skin cancer (NMSC) [38]. In a meta-analysis of eight studies that included 60,351 patients with IBD, the risk of NMSC was increased twofold with the use of thiopurines (hazard ratio 2.28, 95% CI 1.5-3.5) [39]. However, there was significant heterogeneity between studies included in the meta-analysis, and the risk of NMSC may be overestimated due to ascertainment bias. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Malignancy'.)

OCULAR DISEASE

Indications for urgent evaluation — Several ocular diseases may be associated with inflammatory bowel disease (IBD), some of which require urgent evaluation by an ophthalmologist. (See "The red eye: Evaluation and management".)

Warning signs that should prompt urgent evaluation by an ophthalmologist include:

●Reduction of visual acuity (concerns about keratitis, uveitis, angle-closure glaucoma).

●Severe foreign body sensation that prevents the patient from keeping the eye open (concerns about keratitis).

●Fixed pupil (concerns about angle-closure glaucoma).

●Severe headache with nausea (concerns about angle-closure glaucoma).

●Corneal opacity (concerns about keratitis).

●Ciliary flush: a pattern of injection in which the redness is most pronounced in a ring at the limbus (the limbus is the transition zone between the cornea and the sclera) (concerns about keratitis, anterior uveitis, angle closure glaucoma).

Episcleritis — Episcleritis, inflammation of the episclera, the layer directly beneath the conjunctiva, is the most common ocular manifestation of IBD, occurring in 2 to 5 percent of patients [40]. Episcleritis characteristically flares during increases of intestinal IBD activity.

Episcleritis should be suspected in patients with IBD who present with acute redness of one or both eyes and complaints of irritation, itching, or burning. Pain or tenderness to palpation is common. Injection of the ciliary vessels and inflammation of the episcleral tissues are the prominent features on physical examination; episcleral nodules may also be present (picture 12A-B).

Episcleritis does not produce significant ocular complications and does not impair vision. Management consists of topical therapy to provide symptomatic relief and treatment of the underlying IBD. The clinical manifestations, diagnosis, and management of episcleritis are discussed in detail, separately. (See "Episcleritis".)

Scleritis — Scleritis is a severe ocular disorder that can impair vision. Scleritis is usually associated with a severe, constant, boring pain that worsens at night or in the early morning hours and radiates to the face and periorbital region. The extraocular muscles insert into the sclera, which explains why ocular movements exacerbate the pain associated with scleral inflammation. The pain generally limits activity and often prevents sleep. Additional symptoms include headache, watering of the eye, ocular redness, and photophobia. Diffuse anterior scleritis is associated with widespread ocular erythema and scleral edema (picture 13). When posterior scleritis occurs in isolation, the eye is white. However, inflammation of parts of the posterior sclera can be seen at extremes of the patient's gaze. Scleritis does not parallel the disease activity of IBD and may precede or follow the diagnosis of IBD [40]. The clinical manifestations, diagnosis, and management of scleritis are discussed in detail, separately. (See "Clinical manifestations and diagnosis of scleritis" and "Treatment of scleritis".)

Uveitis — Uveitis occurs in 0.5 to 3 percent of patients with IBD. Uveitis may precede diagnosis of IBD and may be associated with an axial and/or peripheral arthritis. It is four times more common in females as compared with males. It is insidious in onset and can recur in the contralateral eye [41].

Anterior uveitis may produce pain and redness; posterior or intermediate uveitis is more likely to be painless, but is often associated with floaters and/or some degree of visual loss. The uveitis in patients with IBD more commonly involves the posterior uveal tract. The diagnosis requires slit-lamp examination and a dilated fundus examination to detect inflammation of the uveal tract. Corneal clouding and conjunctival injection may also be seen (picture 14). (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Diagnosis and referral'.)

The course of uveitis usually does not parallel the activity of IBD. Prompt diagnosis and therapy with topical or systemic glucocorticoids is required. An acute episode may be followed by iris atrophy, lens deposits, and synechiae. Secondary glaucoma and rarely blindness may occur if management is delayed. (See "Uveitis: Treatment" and "Angle-closure glaucoma".)

Rare ocular diseases — Other eye conditions may also be seen in patients with IBD. Ocular side effects of medications used to treat IBD are discussed separately. (See "Major side effects of low-dose methotrexate", section on 'Others' and "Major adverse effects of systemic glucocorticoids".)

Keratopathy — Corneal disease (keratopathy) is a rare manifestation of IBD [42,43]. Patients present with eye pain or foreign body sensation. Lesions may be seen as an opacity in the peripheral cornea and can potentially thin or perforate the cornea and affect vision. Topical glucocorticoids should be avoided as they can contribute to corneal thinning. Treatment usually involves oral glucocorticoids or immunosuppressive agents.

Retinopathy — Retinal vascular disease with central vein occlusion as well as retinal vasculitis involving the retinal arteries have rarely been reported in Crohn disease [44]. Central serous chorioretinopathy with bullous retinal detachment has been associated with ulcerative colitis [45].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults" and "Society guideline links: Crohn disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Erythema nodosum (The Basics)")

●Beyond the Basics topics (see "Patient education: Crohn disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Approximately 6 to 40 percent of patients with inflammatory bowel disease (IBD) have one or more extraintestinal manifestation. Up to 8 percent of patients have a cutaneous manifestation of IBD. Ocular manifestations of IBD occur in 4 to 10 percent of patients with IBD, occurring more often in Crohn disease as compared with ulcerative colitis. While some extraintestinal manifestations parallel the disease activity of IBD (eg, erythema nodosum, episcleritis, and Sweet syndrome), the course of others (eg, pyoderma gangrenosum, uveitis) is independent of intestinal inflammation. (See 'Introduction' above and 'Epidemiology' above.)

●The pathogenesis of extraintestinal manifestations is incompletely understood. However, it is hypothesized that the diseased gastrointestinal mucosa may trigger an immune response at the extraintestinal site due to shared epitopes. (See 'Pathogenesis' above.)

●Erythema nodosum and pyoderma gangrenosum are the most common dermatologic manifestations of IBD (picture 1 and picture 2 and picture 3). Patients with IBD also appear to be at an increased risk for melanoma. (See 'Dermatologic disease' above.)

●Erythema nodosum typically appears as raised, tender, red or violet subcutaneous nodules on the extensor surfaces of extremities (picture 1). As erythema nodosum usually parallels intestinal disease activity, treatment is directed at the underlying IBD. (See 'Erythema nodosum' above and "Erythema nodosum".)

●Pyoderma gangrenosum lesions may appear as erythematous papules or pustules that are often preceded by trauma to the skin (picture 2). Subsequent necrosis of the dermis leads to the development of deep ulcers. Therapy directed at the underlying IBD usually results in healing. (See 'Pyoderma gangrenosum' above and "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis" and "Pyoderma gangrenosum: Treatment and prognosis".)

●Several ocular diseases may be associated with IBD, some of which require urgent evaluation by an ophthalmologist. Warning signs that should prompt urgent evaluation by an ophthalmologist include (see 'Ocular disease' above):

•Reduction of visual acuity

●Severe foreign body sensation that prevents the patient from keeping the eye open

•Fixed pupil

•Severe headache with nausea

●Corneal opacity

•Ciliary flush: a pattern of injection in which the redness is most pronounced in a ring at the limbus (the limbus is the transition zone between the cornea and the sclera)

●Episcleritis should be suspected in patients with IBD who present with acute redness of one or both eyes and complaints of irritation, itching, or burning. Pain or tenderness to palpation is common. Injection of the ciliary vessels and inflammation of the episcleral tissues are the prominent features on physical examination; episcleral nodules may also be present (picture 12A and picture 12B). Management consists of topical therapy to provide symptomatic relief and treatment of the underlying IBD. (See 'Episcleritis' above and "Episcleritis".)

●Scleritis is usually associated with a severe, constant, boring pain that worsens at night or in the early morning hours and radiates to the face and periorbital region. Diffuse anterior scleritis is associated with widespread ocular erythema and scleral edema. When posterior scleritis occurs in isolation, the eye is white. However, inflammation of parts of the posterior sclera can be seen only at extremes of the patient's gaze. Scleritis does not parallel IBD disease activity and may precede or follow the diagnosis of IBD. Scleritis is a severe ocular disorder that can impair vision and requires prompt diagnosis and treatment by an ophthalmologist. (See 'Scleritis' above and "Clinical manifestations and diagnosis of scleritis" and "Treatment of scleritis".)

●Anterior uveitis may produce pain and redness; posterior or intermediate uveitis is more likely to be painless, but is often associated with floaters and/or some degree of visual loss (picture 14). Prompt diagnosis and therapy with topical or systemic glucocorticoids is required. An acute episode may be followed by iris atrophy, lens deposits, and synechiae. Secondary glaucoma and rarely blindness may occur if management is delayed. (See 'Uveitis' above and "Uveitis: Etiology, clinical manifestations, and diagnosis" and "Uveitis: Treatment".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Rutgeerts, MD (deceased), who contributed as a section editor for UpToDate in Gastroenterology.