Cutaneous manifestations of inflammatory bowel disease

Skin lesions are associated with inflammatory bowel disease in up to one third of patients with ulcerative colitis and ≤50% of patients with Crohn's disease (1). This article reviews several of the cutaneous manifestations of inflammatory bowel disease including pyoderma gangrenosum and pustular eruptions, erythema nodosum, aphthous stomatitis, disorders of coagulation, metastatic Crohn's disease, and perianal and peristomal lesions. Pyoderma gangrenosum is a chronic cutaneous ulcerating condition reported in 1-10% of patients with ulcerative colitis and 0.5-20% of patients with Crohn's disease (1,–4). It also has been found in association with chronic active hepatitis (5), rheumatoid arthritis (6), acute myeloid leukemia (7), chronic myeloid leukemia, polycythemia vera (8), multiple myeloma (9), hypogammaglobulinemia (10), and monoclonal immunoglobulin A (IgA) gammopathy (11). Clinically, pyoderma gangrenosum begins with a pustule or erythematous papule or nodule that quickly breaks down to form an ulcer with violaceous undermined borders. The ulcers arc frequently covered with pus or necrotic debris, and they contain fistulous tracts of pus that can be demonstrated if a liquid medication such as triamcinolone acetonide is injected into the ulcer. The medication often follows the fistulous tract and can be seen dripping from a part of the ulcer remote from the site of injection. Pus can be squeezed out of the fistulous tracts underneath the surface of the ulcer by applying pressure to the area. The fistulous tracts open into very characteristic crater-like holes (Fig. 1) that, when healed, leave a typical pattern of cribriform scarring. The fistulous tracts, holes, and cribriform scarring are so characteristic that they were even noted in the original descriptions of pyoderma gangrenosum by Brunsting et al. in 1930 (12). Pyoderma gangrenosum: Note the characteristic crater-like holes. The ulcers of pyoderma gangrenosum can be solitary or multiple, unilateral or bilateral, and range in size from a few centimeters to an entire limb. The legs are by far the most common site of involvement, although peristomal pyoderma gangrenosum probably occurs more frequently than is generally appreciated (13). Involvement of other sites, including the trunk or even the face, has been reported. A variant of pyoderma gangrenosum, known as malignant pyoderma, occurs when multiple ulcers of pyoderma gangrenosum develop over a short time on the face, trunk, and extremities (14a). A characteristic feature of pyoderma gangrenosum is the development of pathergy (14b). Simply stated, the phenomenon of pathergy means that patients develop large ulcers in response to minor trauma. Pathergy occurs in only two conditions, Behcet's syndrome and pyoderma gangrenosum, and its finding is therefore quite specific for these two disorders. Patients will often develop pyoderma gangrenosum after trauma or surgical procedures on the legs or even after simple needle sticks for venipuncture on the legs. The differential diagnosis of pyoderma gangrenosum includes bacterial pyoderma, iododerma or bromoderma, deep fungal infection, necrotizing vasculitis, lymphoma cutis, or factitial ulcer. Definitive diagnosis of pyoderma gangrenosum depends on the exclusion of these conditions. Fungal and bacterial cultures of pyoderma gangrenosum are frequently sterile. Histopathology is frequently nonspecific but is helpful in excluding a diagnosis of lymphoma cutis in patients in whom that condition is a possibility. Fungal and bacterial etiologies may be detected with appropriate stains as well. Early in the course of pyoderma gangrenosum, there is a dense dermal infiltrate of lymphocytes with invasion of blood vessel walls with histologic features reminiscent of cell-mediated hypersensitivity reactions (15). Dermal necrosis and epidermal ulceration are accompanied by the infiltration of neutrophils that is characteristically seen in later stages of pyoderma gangrenosum. In view of the phenomenon of pathergy that accompanies pyoderma gangrenosum, the question of whether or not to perform biopsies of ulcers thought to represent pyoderma gangrenosum is quite relevant. The histology of this disease is often nonspecific and therefore not helpful, but biopsy should be considered if a diagnosis of lymphoma cutis is seriously entertained. A number of clinical features assist in establishing the diagnosis of pyoderma gangrenosum. Pyoderma gangrenosum should certainly be considered when ulcers begin as pustules on the legs or in peristomal sites. The association of leg ulcers with inflammatory bowel disease should raise the physician's suspicion of pyoderma gangrenosum. It should be pointed out, however, that in some instances, the bowel disease may be occult. Moreover, in many cases of pyoderma gangrenosum, there is no apparent underlying etiology. The presence of crater-like holes described or the development of pathergy are both so characteristic that they may leave little doubt about the diagnosis. Treatment of pyoderma gangrenosum depends on the extent of involvement. In localized limited disease, intralesional corticosteroids such as triamcinolone acetonide, 10-40 mg/ml, can be injected as often as once per week. Injections are administered at the advancing border of the ulcer but can also be administered into the ulcer center (16). Topical application of anesthetics such as a eutectic mixture of local anesthetics applied before injection may diminish the pain associated with this treatment. Topical corticosteroids and topical application of sodium cromoglycate spray also have been advocated for pyoderma gangrenosum (17), but these are much less effective than intralesional corticosteroids. In more extensive disease, systemic corticosteroids have been the first treatment of choice with daily doses of ≥60 mg of prednisone. Other immunosuppressive agents such as cyclophosphamide (18) or azathioprine (19) also have been administered successfully for the treatment of pyoderma gangrenosum. Other drugs reported to be effective for this condition include oral minocycline (20), cyproheptadine (21), sulfasalazine (22), and dapsone (23), although these are less reliably effective. Clofazimine has been beneficial in refractory cases (24) and can be administered with other drugs to help reduce the dosage of systemic corticosteroids or immunosuppressive agents. Thalidomide, which was removed from the market several decades ago because of its role in the development of birth defects, is reemerging as a treatment for oral aphthous stomatitis and also has proven to be effective in some refractory cases of pyoderma gangrenosum (25). It is associated with a number of side effects such as peripheral neuropathy and fatigue, and patients taking thalidomide must be monitored carefully by neurologists and dermatologists. In the past decade, cyclosporine has been used in the treatment of pyoderma gangrenosum (26). Few treatments have resulted in as dramatic or rapid remissions as has this drug. The purulent exudate associated with pyoderma gangrenosum dries up in a matter of hours after intravenous administration of cyclosporine. Most patients are treated orally at doses of 5 mg/kg per day. The main limiting side effect is nephrotoxicity. Intralesional cyclosporine also has been effective in some patients, but the injections are quite painful (27). Painful pustular eruptions have been described on the skin and mucous membranes of patients with ulcerative colitis (28). Those lesions have typically developed during flares of disease activity and resolved as gastrointestinal symptoms improved. Some of the pustular lesions have developed into necrotic plaques or ulcers whose descriptions resemble that of pyoderma gangrenosum. The question must be raised whether these lesions in fact represented pyoderma gangrenosum, and at least one author suggested that the pustular reactions of ulcerative colitis are forme frustes of pyoderma gangrenosum (29). Perhaps the inflammatory response is simply inadequate to induce necrosis and ulcer formation that is typical of pyoderma gangrenosum. Pyoderma vegetans is a rare, pustular eruption that affects flexural areas but can occur on the trunk, extremities, and even the mouth, oral mucosa, and palpebral conjunctivae (30). Lesions begin as pustules, which quickly erode, leaving a bleeding, red, oozing base. The elevated, eroded, vegetating red plaque can be surrounded by pustules at its periphery. Plaques can become extensive, covering large areas of the trunk or extremities, but eventually dry, leaving hyperpigmented scars after months or years. Occasionally lesions relapse in the same sites. The majority of reported cases are associated with ulcerative colitis that precedes skin lesions by several years. Treatment of the underlying bowel disease may result in resolution of skin lesions of pyoderma vegetans. Many of the pustular lesions associated with ulcerative colitis should be considered as variants of pyoderma gangrenosum and can be treated accordingly. Erythema nodosum is an inflammation of subcutaneous fat that affects 3-10% of patients with ulcerative colitis and 4-15% of patients with Crohn's disease (1). The disease is primarily a disorder of women between the ages of 25 and 40 years. Children can be affected, and the disorder seldom occurs after the age of 50 years. Women are affected several times more commonly than men. Erythema nodosum has been associated with a number of conditions other than inflammatory bowel disease. At one time, tuberculosis was one of the most common causes of erythema nodosum (31). The disorder has been reported in association with numerous infections, including coccidioidomycosis, histoplasmosis, North American blastomycosis, and others (32). Streptococcal infection is a common cause of erythema nodosum in the 1990s (33). Yersinia infection is commonly associated with erythema nodosum (34). Behcet's syndrome and sarcoid also are common underlying disorders in patients with erythema nodosum (33,35). In both Crohn's disease and sarcoidosis, erythema nodosum is associated with acute flares of the underlying disease and frequently resolves when the bowel or pulmonary disease subsides. Medications associated with the development of erythema nodosum include sulphonamides, iodides, bromides, and estrogens (35,36). Erythema nodosum is also frequently seen during pregnancy (37), and we have observed patients with recurrent erythema nodosum that occurred only during repeated pregnancies, including a patient who was not taking any oral medications or vitamin supplements. Clinically the lesions are seen as deep, tender nodules most commonly occurring on the shins. Occasionally the skin overlying these deep nodules appears bruised or erythematous (Fig. 2), but the lesions are frequently more palpable than visible, with overlying skin changes being subtle. Although legs are the most frequent site of involvement, erythema nodosum can occur in subcutaneous fat anywhere on the body including the arms and trunk. Erythema nodosum: deep, tender, erythematous nodules on the lower legs are characteristic. Lesions may be more easily palpated than seen. Individual lesions frequently resolve spontaneously in 3-6 weeks, but new lesions may develop over months. Lesions heal without any scars. In some patients, skin lesions are accompanied by high fevers and chills. Increased white blood count, with a preponderance of neutrophils and bands, can occur. Arthralgia or arthritis occurs in ≤70% of patients and can last from days to months. In some patients, arthritis precedes erythema nodosum by several weeks (38). Joint involvement is uncommon in children with erythema nodosum. Diagnosis of erythema nodosum depends on histologic verification of septal panniculitis. Inflammation of vessels in the fibrous septa of subcutaneous fat is characteristic, and infiltration of the septa with neutrophils frequently occurs. Hemorrhage into the septa may account for the bruise-like appearance seen in some patients. Inflammatory bowel disease should be suspected in any patient with erythema nodosum. In patients in whom the underlying disorder is not apparent, chest radiograph, ASO titer, throat culture, Yersinia titer, and other appropriate skin tests, such as purified protein derivative (PPD), should be considered. Treatment involves bedrest and oral nonsteroidal antiinflammatory drugs such as aspirin, indomethacin, ibuprofen, or others (39). Intralesional corticosteroids may be rapidly effective in isolated lesions. Oral corticosteroids are quite effective, but only temporarily improve erythema nodosum (40). Oral saturated solution of potassium iodide is beneficial in patients refractory to oral nonsteroidal antiinflammatory drugs (41). Oral colchicine has been anecdotally helpful in selected patients (42). Treatment of the underlying disorder may result in resolution of the lesions of erythema nodosum. Aphthous ulcers are common in patients with both ulcerative colitis and Crohn's disease (1). In patients with ulcerative colitis, they often occur during flares of the underlying gastrointestinal disease. They are clinically indistinguishable from the oral ulcerations that are called canker sores or idiopathic aphthous stomatitis. In patients with Crohn's disease, aphthous ulcers may develop on the buccal mucosa and lips. Histologic examination often reveals noncaseating granulomas and granulomatous inflammation similar to that seen in the bowel wall (43). Symptomatic treatment, including topical anesthetics such as viscous xylocaine, can be helpful in alleviating the pain of aphthous ulcers. Topical antibiotics, topical corticosteroids, and destructive modalities such as topical application of silver nitrate offer limited benefit. Intralesional corticosteroids and topical cyclosporine have been anecdotally successful. Oral thalidomide has been reported to be beneficial for aphthous stomatitis related to human immunodeficiency virus (HIV) infection and has been used for other conditions associated with oral aphthae (44). Its use should certainly be considered in aphthous stomatitis associated with inflammatory bowel disease. A hypercoagulable state has been described in both ulcerative colitis and Crohn's disease. Thrombophlebitis has been reported in ≤10% of patients with ulcerative colitis, but on autopsy, venous thromboses are found in >30% of patients (45). Phlebitis is slightly less common in patients with Crohn's disease. Increased factor VIII activity was found by at least one investigator who studied 16 patients with active ulcerative colitis (46). Thrombocytosis, with platelet counts ranging from 500,000 to >1 million, was reported in six patients with ulcerative colitis or Crohn's disease (47a). Platelet counts decreased to normal levels in three patients whose bowel disease responded to treatment. Cryoglobulinemia and cutaneous gangrene have been reported in several patients with Crohn's disease (47b,47c). One patient with ulcerative colitis who developed cryofibrinogenemia and fibrin split products infarcted the skin on the medial aspect of one of his knees (48). Histologic examination revealed thrombosed vessels, and the entire picture was suggestive of a syndrome simulating disseminated intravascular coagulation. Arterial thromboses of the digits and penis have been reported (48,49). We have seen an individual who infarcted his arm and distal foot, resulting in amputations of portions of both limbs. Fortunately, arterial thromboses requiring amputation are rare in patients with inflammatory bowel disease. Granulomatous inflammation with noncaseating granulomas is a hallmark of Crohn's disease of the bowel and has been found in perianal and peristomal sites, as well as in the oral mucosa. When similar histologic findings develop remote from the gastrointestinal tract in patients with Crohn's disease, the term metastatic Crohn's disease has been applied. It should be pointed out that the disease is not considered contagious nor is it capable of metastases in the manner we associate with malignancies. Although metastatic Crohn's disease is considered rare, it is undoubtedly underreported. Patients can have a wide array of skin lesions, and unless skin biopsy is taken, the diagnosis is missed. Lesions can occur anywhere on the body. We have observed patients with superficial ulcers (50). A patient has been reported whose only manifestation was angioedema-like swelling of the malar area (50). Erythematous macules and nodules have been reported. Flexural and intertriginous sites are frequently affected, including the groin and skin under the breasts. Any body site can be affected, however, including the genital area and the retroauricular folds. Other cases of metastatic Crohn's disease have been misdiagnosed as seborrheic dermatitis, acne, factitial dermatitis, intertrigo, hidradenitis suppurativa, cellulitis, and erythema nodosum. This disorder, like many other cutaneous manifestations of Crohn's disease, is more commonly seen in patients with involvement of the colon or rectum rather than the terminal ileum alone. Treatment of the underlying gastrointestinal disease has resulted in improvement of skin lesions in some patients, but not all. A variety of topical therapies have been used with limited success. Perianal lesions characteristically occur in patients with Crohn's colitis and differentiate the disease from ulcerative colitis (1). They are much less common in patients whose Crohn's disease is limited to the terminal ileum. Up to 60% of patients develop perianal abscesses, draining sinus tracts (Fig. 3), anal fistulae, or anal fissures. Fistulae from bowel disease may precede gastrointestinal symptoms by several years. Enlarged, inflamed perianal tags result from swelling and inflammation of anal Morgagni's crypts. Perianal abscesses may follow. Large ulcerations of the perianal, perineal, and genital skin can result. Skin biopsy taken from affected areas may reveal granulomatis inflammation with noncaseating granulomas. A draining sinus tract is shown on the thigh of a patient with Crohn's disease. As with other extraintestinal manifestations of Crohn's disease, treatment of the underlying bowel disease may result in improvement of these symptoms. Topical and intralesional corticosteroids may be of some benefit. More than 80,000 patients undergo colostomies or ileostomies each year. Complications include irritant or allergic contact dermatitis and peristomal ulceration. The latter condition can be caused by pressure from a poorly fitting device, fistulae to the anterior abdominal wall, peristomal pyoderma gangrenosum, or infected hematomas (51). Irritating adhesives and solvents used to remove them, combined with occlusion by the ostomy device, lead to irritation and maceration. Leakage of intestinal contents can lead to irritation and infection. Use of topical and intralesionally injected corticosteroids, protective tapes, pastes, lotions, powders, sprays, ointments, and use of mild nonirritating soap substitutes can be helpful. Swelling of genital skin has been reported in both male and female patients with Crohn's disease (52). Nontender, edematous swelling of the vulva (Fig. 4), scrotum, or penis can occur. The precise mechanism by which this happens has not been identified, but some patients are found to have noncaseating granulomas on skin biopsy. Vulvar swelling in a patient with Crohn's disease. An association has also been reported between psoriasis and Crohn's disease. Further documentation of the extent of this association is needed (53).