40 Cutaneous manifestations of inflammatory bowel disease
SCOTT W. BINDER
Introduction Table 1. Cutaneous manifestations of Inflammatory bowel disease Cutaneous manifestations are common in inflamma Specific lesions tory bowel disease (IBD). In one study, the incidence Fissures and fistulas was reported to be as high as 34%. [1] However, some Oral manifestations (Crohn's disease) of the early studies included non-specific inflamma Metastatic Crohn's disease tory conditions such as urticaria, various maculo- papular eruptions, and pigmentary abnormalities, Reactive lesions Erythema nodosum some or all of which may be unrelated to the bowel Pyoderma gangrenosum disease. Other rigorous studies provide a more Aphthous ulcers reasonable estimate of cutaneous involvement in Vesiculopustular eruption patients with ulcerative colitis (UC) and Crohn's Pyoderma vegetans Necrotizing vasculitis disease (CD) (9-19%) [2]. Greenstein et aL, in an Cutaneous polyarteritis nodosa older study of 498 patients with CD, noted that cutaneous manifestations are more common when Miscellaneous associations the large intestine is involved [3]. Epidermolysis bullosa acquisita Mucocutaneous manifestations of IBD may be Clubbing Vitiligo classified as specific lesions, reactive lesions, and Acne fulminans miscellaneous associations (Table 1). For complete Psoriasis ness, cutaneous manifestations secondary to malab Vasculitis sorption [4, 5] or treatment may also be considered, Secondary amyloidosis but will not be treated in this text. Specific lesions refer to those lesions that are due to direct involve ment of the skin by the same disease process that aff'ects the gastrointestinal tract. This includes 8] for explication of the most current treatments of fissures, fistulas, and metastatic CD [2]. In contrast, the entities discussed herein. reactive lesions do not show the same pathologic features as are found in the gastrointestinal tract, but instead represent a reaction to the underlying IBD. The pathogenesis of reactive lesions remains Specific cutaneous iesions of speculative; most are probably immunologically uicerative coiitis and Croiin's mediated, some because of cross-antigenicity between the skin and the gut mucosa [6]. disease In this review only the more common and Fissures and fistulas are the most common clinically significant specific and reactive cutaneous cutaneous manifestations of IBD, and may even be manifestations of IBD will be discussed. An attempt the presenting complaint in CD. In contrast, they will be made to compare and contrast the various occur infrequently in UC. The most commonly entities with regard to their prevalence in either CD affected site is the perineum, especially the perianal or UC; treatment issues will not be considered in this area, although peristomal skin and the abdominal chapter. The reader is referred to various sources [7, wall may also be affected. In a study of 569 patients
Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.J, Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 757-762. © 2003 Kluwer Academic Publishers. Printed in Great Britain 758 Cutaneous manifestations of inflammatory bowel disease
the intervening mucosa is edematous, a 'cobblestone' appearance develops [10]. The oral manifestations of CD tend to vary by location within the mouth. The buccal mucosa appears to be the most common site of cobble- stoning, while the gingival and alveolar mucosae often exhibit tiny nodular growths [12]. Linear ulcers are more common in sulci [12]; the lips may become swollen, hardened, or ulcerated, especially at the angles of the mouth [13]. Because of the granulo matous histology the lip changes have been called cheilitis glandularis [14]. It is unclear from previous studies how often granulomatous inflammation of Figure 1. Predominantly septal panniculitis with secondary the lip is associated with CD as compared to being involvement ot surrounding fat lobules, typical of erythema associated with Melkerson-Rosenthal syndrome or nodosum. being idiopathic. Finally, there may even be inflam mation and ulceration of the epiglottis and larynx [10]. with CD, perianal fissures and fistulas were found in While nodules or ulcers with granulomatous 36% of patients [9]. Only 25% of those patients with histology strongly implicate CD, the role of aphthous small bowel disease alone had perianal involvement, ulcers is less clear. Some studies [12] have suggested whereas more than 40% of patients with colonic that they are a non-specific finding, while others [10] disease exhibited perianal disease [9]. The perianal suggest that they may be the most frequent oral fissures and fistulas of 1BD are typically multiple and lesions seen in CD. Aphthae, oral lesions, and oral involve the anus circumferentially. Abscesses, under ulcerations have been estimated to occur in between mined ulcers, and skin tags or 'pseudo' skin tags 4% and 20% of CD patients [15, 16]. In the UCEDS formed by edematous skin are often noted on the study only five of 569 patients {\%) had aphthae at perineum. The edema can be so severe as to produce the beginning of the study, but another 23 (4%) lymphedema [10]. Histologic examination of the developed them during the study even on systemic perianal inflammatory lesions characteristically therapy [17]. These figures are not incompatible with shows transmural inflammation with lymphoid the presence of aphthae in the general population. aggregates and non-caseating sarcoidal-type Although aphthae in CD have not been studied in granulomas typical of CD. In one series of 29 depth histologically, they do not appear to be biopsies, granulomas were identified in 25 [11]. The granulomatous. clinical and histologic findings may help distinguish Despite these caveats the presence of apthhae can CD from UC, as perianal disease is rare in UC. suggest the diagnosis of CD [16]. If a biopsy shows a Perifistular and peristomal disease is less helpful granulomatous histology, CD should be the major diagnostically; since once a colostomy has been consideration in the microscopic differential diag performed or cutaneous fistulas have developed, the nosis. Recurrent aphthae may be the first manifesta diagnosis of CD is secured. tion of CD; thus a history of their presence may prove useful in the work-up of patients with chronic diarrhea and/or abdominal pain. Oral Crohn's disease Examination of the oral cavity allows clinicians to readily observe two of the classic morphologic Metastatic Crohn's disease features of CD: ulceration and cobblestoning. The ulcers are often tiny, herpetiform, occasionally Metastatic CD refers to nodules, plaques, or ulcer linear, and may resemble ordinary aphthae. They ated lesions that demonstrate a granulomatous his can, of course, become large, undermining and tology identical to that of the IBD, and that are indolent. When linear ulcers or tissues connect and located in the skin and subcutaneous tissue at sites distant from the gastrointestinal lesions of CD. Metastatic cutaneous CD is rare; studies [18] have Scott W. Binder 759 emphasized a flexural distribution, and have shown that metastatic CD may be non-ulcerative and may even mimic erythema nodosum [19, 20]. Metastatic CD can be viewed as still another 'great imitator' both clinically and histologically. Cases have been initially diagnosed as factitial dermatitis, intertrigo, severe acne, hidradenitis suppurativa, chronic cellulitis, or erythema nodosum among many other entities [10]. Metastatic CD does not seem to appear in the absence of gastrointestinal CD. Histologically, most patients present with typical sarcoidal granulomas, raising the micro scopic differential diagnosis of infection, sarcoid, and a foreign-body reaction. Rarely, cases of meta Figure 3. Focal ulceration of the epidermis with underlying static CD may differ histologically. Two patients with predominantly neutrophilic infiltrate, characteristic of erythema nodosum-like lesions showed granulo pyoderma gangrenosum and other neutrophilic dermatoses. matous perivasculitis [10].
EN does not appear to be a good marker for CD. In large series of patients with EN, very few have CD [2]. Furthermore, all nodose lesions on the extremi ties of CD patients are not erythema nodosum. Histologically, in addition to the septal panniculitis of EN, one may see polyarteritis or granulomatous inflammation. Thus, in a CD patient with EN-like lesions clinically, a biopsy of sufficient depth and size to evaluate the subcutaneous fat as well as the dermis is a necessity. EN is believed to represent the expression of a hyperimmune response and may be seen in associa tion with various disease entities and as a reaction to Figure 2. Close-up view of the septal inflammatory process various drugs (Figs 1 and 2). The possibility of a drug includes characteristic multinucleated giant cells and small non-caseating granulomata. reaction should be considered in all patients with EN, especially those being treated with sulfa derivatives. It is interesting to note that studies have suggested that EN may be the most common extra- colonic manifestation of UC in children [1] and that Reactive cutaneous lesions of IBD usually the lesions heal without scarring. Erythema nodosum (EN) typically presents as tender red nodules on the anterior aspect of the lower legs that gradually resolve in several weeks. EN has been reported in 1-10% of patients with UC, how Pyoderma gangrenosum ever, a more reasonable figure is around 4% [21], and Pyoderma gangrenosum (PG) usually begins with it appears to be more common in female patients. It small papules, plaques, or hemorrhagic blisters that may occur before the diagnosis of IBD or in conjunc rapidly enlarge and ulcerate with violaceous under tion with a clinical flare-up of the disease, and it may mined edges. The lesions may occur anywhere on the occur in unusual locations and in chronic forms [2]. skin, but most frequently are located on the lower Ulceration is common and concomitant arthropathy extremities. Patients may give a history of preceding is often noted. Significant skin involvement may be trauma to the area. Lesions are sterile and are accompanied by fever and malaise [21]. characterized by a dense dermal infiltrate of neutro phils (Figs 3 and 4). PG has been noted in approxi- 760 Cutaneous manifestations of inflammatory bowel disease
UC [27]. The lesions consist of grouped erythema tous vesiculopustules (3-5 mm in size) that sequen tially crust and heal, resulting in postinflammatory hyperpigmentation. Some authors consider this entity to be a forme fruste of PG; cases have been reported in which most lesions of a vesiculopustular eruption have resolved while a few lesions developed into typical PG [28, 29]. Histologic examination reveals intraepidermal neutrophilic abscesses with mixed inflammatory dermal infiltrates [27].
Figure 4. Close-up reveals a predominantly neutrophilic Pyoderma vegetans dermatosis surrounding reactive blood vessels without Pyoderma vegetans has been described in several evidence of vasculitis. These histologic findings are typical of patients with UC [21, 30]. It initially appears mainly any of the various neutrophilic dermatoses, including pyoderma gangrenosum. in intertriginous areas with vegetating plaques and vesiculopustules that resolve with postinflammatory hyperpigmentation. Mucosal involvement may also occur (pyostomatitis vegetans). Histologically, the malely 5% of patients with UC and is roughly three principal features include pseudoepitheliomatous times more common in UC than in CD [22]. How hyperplasia and intraepidermal abscesses that ever, one series found a higher incidence of PG in CD contain neutrophils and eosinophils. Pyoderma it occurred in 8% of these patients [23]. Approxi vegetans may also represent a forme fruste of PG mately 50% of patients with PG have underlying UC (Fig. 3) [21]. [23, 24]. This makes UC by far the most common identifiable underlying cause. The course of IBD- associated PG tends to parallel that of the underlying Cutaneous vasculitis and gastrointestinal disease [6, 25] and may even begin years before the onset of bowel symptoms [26]. polyarteritis nodosa The pathogenesis of PG, as well as the basis of its Cutaneous vasculitis is a rare cutaneous manifesta standing association with UC, remain obscure. tion of IBD [31]. Both leukocytoclastic vasculitis and Evidence favors an altered immune response and cutaneous polyarteritis nodosa have been reported. most investigators believe that the pathogenesis of Vasculitis is more commonly associated with UC the skin disorder and its association with UC are whereas polyarteritis nodosa has been documented both based on immunologic mechanisms. Confusion only in association with CD [2]. persists in the fact that the immune defects reported Necrotizing (leukocytoclastic) vasculitis generally vary greatly from patient to patient, and no one presents as palpable purpura, ulcerations, and, common defect has as yet become apparent. No rarely, gangrene [2]. The usual sites of involvement consistent genetic markers have been identified in are the legs and anal areas. Mixed cryoglobulinemia various groups of patients studied [21]. may sometimes be demonstrated in these patients. The treatment of PG, as with EN, is first directed Histologic examination reveals fibrin thrombi and/ at the underlying disease but, in contrast to the latter, or fibrinoid necrosis of blood vessel walls with PG may not respond nearly as rapidly during remis associated leukocytoclasia and extravasated erythro sions of UC. In fact, PG has been reported occurring cytes. years after apparent cure of UC [21]. Cutaneous polyarteritis nodosa is characterized by tender or painful erythematous nodules which often ulcerate. They are commonly located on the legs but may affect other areas of the body. The Vesiculopustular eruption lesions can be clinically mistaken for EN, metastatic A vesiculopustular eruption that can be localized or CD or PG. The biopsy specimen exhibits a necrotiz generalized has been described in some patients with ing leukocytoclastic panarteritis that may show Scott W. Binder 761 granulomatous features and often a variable Table 2. Skin conditions more common in Crohn's disease than infiltrate of eosinophils. Associated features of cuta ulcerative colitis neous polyarteritis nodosa include livedo reticularis, Fissures and fistulas peripheral neuropathy, arthralgias, and myalgias; Oral Crohn's disease severe systemic involvement does not occur. Cuta Metastatic Crohn's disease neous polyarteritis nodosa usually runs a benign but Cutaneous polyarteritis nodosa Epidermolysis bullosa acquisita chronic course that is usually unrelated to the activity Vitiligo of the bowel disease [31, 32]. Cutaneous polyarteritis Acne fulminans nodosa usually presents after the diagnosis of CD Palmar erythema has been established, but may occur before the diagnosis of IBD [31-34]. Circulating immune com plexes have been demonstrated and may contribute to the pathogenesis [33, 34]. Table 3. Sl