Inflammatory Bowel Diseases:
Clinical Review Articles
Cutaneous Manifestations in Patients With Inflammatory Bowel Diseases: Pathophysiology, Clinical Features, and Therapy
Marzano, Angelo V. MD*; Borghi, Alessandro MD†; Stadnicki, Antoni MD‡,§; Crosti, Carlo MD*; Cugno, Massimo MD‖
*Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Unità Operativa di Dermatologia, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy;
†Department of Medical Sciences, Section of Dermatology, University of Ferrara, Ferrara, Italy;
‡Department of Basic Biomedical Sciences, Medical University of Silesia, Katowice, Poland;
§Section of Gastroenterology, Multidisciplinary Hospital, Jaworzno, Poland; and
‖Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Unità Operativa di Medicina Interna, IRCCS Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
Reprints: Massimo Cugno, MD, Internal Medicine, University of Milan, Via Pace 9, Milano 20122, Italy (e-mail: email@example.com).
The authors have no conflicts of interest to disclose.
Received July 29, 2013
Accepted August 26, 2013
Abstract: The skin is one of the most common extraintestinal organ system affected in patients with inflammatory bowel disease (IBD), including both Crohn's disease and ulcerative colitis. The skin manifestations associated with IBD are polymorphic and can be classified into 4 categories according to their pathophysiology: (1) specific, (2) reactive, (3) associated, and (4) induced by IBD treatment. Cutaneous manifestations are regarded as specific if they share with IBD the same granulomatous histopathological pattern: perianal or metastatic Crohn's disease (commonly presenting with abscesses, fistulas or hidradenitis suppurativa-like features) is the prototype of this setting. Reactive cutaneous manifestations are different from IBD in the histopathology but have close physiopathological links: pyoderma gangrenosum, a neutrophil-mediated autoinflammatory skin disease typically manifesting as painful ulcers, is the paradigm of this group. Among the cutaneous diseases associated with IBD, the most commonly seen are erythema nodosum, a form of panniculitis most commonly involving bilateral pretibial areas, and psoriasis, a T helper 1/T helper 17–mediated erythematous squamous inflammatory disease. Finally, the number of cutaneous adverse reactions because of IBD therapies is progressively increasing. The most frequent drug-induced cutaneous manifestations are psoriasis-like, eczema-like, and lichenoid eruptions, as well as cutaneous lupus erythematosus for biologics, and nonmelanoma skin cancer, mainly basal cell and squamous cell carcinomas for thiopurines.
Up to 40% of patients with inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), may be complicated by extraintestinal manifestations (EIMs).1 The clinical spectrum of the EIMs varies from mild transitory to very severe manifestations, sometimes more debilitating than the underlying intestinal disease itself. In general, most of the EIMs are related to the activity of the bowel disease and, consequently, have been referred to as “inflammatory.” Others are associated with autoimmunity, whereas further manifestations result from nutritional or metabolic dysfunction. EIMs may be sequelae of intestinal bacterial overgrowth or iatrogenic complications of the therapy used to treat bowel inflammation. The frequency of these manifestations is reported to range from 21% to 41%, depending on the patient population and the criteria used in different studies.2,3 In some large series of studies, the prevalence of EIMs is higher in CD compared with UC.4,5 In a large cohort study of 950 patients, EIMs were identified in 43% of 580 patients with CD and 31% of 370 patients with UC.5 Moreover, the cumulative probability of developing EIMs increases with the duration of IBD.6 Almost every organ system may be affected in IBD, and multiple organs may be involved, including the musculoskeletal system, skin, eyes, liver and biliary tracts, lungs, kidneys, hematologic system, and cardiovascular system,5,7–9 suggesting that IBD may be a systemic disorder with predominantly bowel manifestations.10,11 Among the organ systems involved, the skin is one of the most commonly affected. Mucocutaneous findings are frequent and may occur in 22% to 75% of patients with CD12,13 and in 5% to 11% of patients with UC.14 The skin manifestations of IBD have been classified into 4 categories according to the pathomechanisms suggested for each of them11,15–18: (1) specific cutaneous manifestations with the same histological features as the underlying IBD; (2) reactive cutaneous manifestations that share one or more physiopathological mechanisms with IBD, albeit without the same histopathological features of the gastrointestinal lesions; (3) skin diseases that can be associated with IBD. These manifestations probably share human leukocyte antigen linkage and a chronic inflammatory state; (4) cutaneous manifestations because of adverse effects of IBD therapy.
In this review, we focus on the main cutaneous manifestations associated with IBD. We also provide diagnostic and pathologic pictures of the skin lesions and therapeutic recommendations (Table 1). Concerning the cutaneous side effects of drugs used for the management of IBD, they mainly include psoriasis-like, eczema-like, and lichenoid eruptions, as well as cutaneous lupus erythematosus for biologics, and nonmelanoma skin cancer, notably basal cell and squamous cell carcinomas for thiopurines. These last aspects are not discussed here because they have been the matter of a review recently published in “Inflammatory Bowel Diseases.”19
TABLE 1-a Cutaneous ...Image Tools
Specific Cutaneous Manifestations With the Same Histological Features as the Underlying IBD
TABLE 1-b Cutaneous ...Image Tools
Specific cutaneous lesions are defined by the presence of the same histopathological features of the bowel disease, such as noncaseating granulomas with multinucleated giant cells in the dermis surrounded by lymphocytes, plasma cells, and eosinophils.20 These lesions are seen only in CD, because UC does not typically extend to external mucosal membranes.21 Specific cutaneous lesions are in turn subdivided according to the localization into continuous/contiguous and metastatic lesions. Continuous/contiguous manifestations include lesions that are in continuity with the bowel and include perianal, peristomal, and orofacial lesions. However, metastatic lesions are defined as the occurrence of specific granulomatous skin lesions remote from the intestinal disease.
Continuous/Contiguous Mucocutaneous Manifestations
Perianal inflammation is a disabling manifestation of CD involving the perineal area and occurs in 25% to 80% of patients.22–24 This wide variation is likely related to different defining criteria. Perianal disease usually occurs concurrently or after the diagnosis of the intestinal disease,25,26 but it may also precede the development of IBD.22,25 Approximately 5% of patients may predominantly suffer from anal symptoms with quiescent abdominal disease.27 Perianal CD most commonly presents as perineal abscesses and fistulas, which are frequently multiple, complex, and recurrent (Fig. 1). Other clinical features include fissures, anal ulcers, edematous skin tags, fecal incontinence, and anal stenosis; rarely, it may also be associated with cancer.28–30
Fissures constitute 20% to 35% of perianal lesions22,31 and are of bluish appearance, broad-based, with undermining edges, and painless; they may lead to abscess or fistula formation as penetrating CD according to the Montreal revision of the Vienna CD classification.32
Fistulas arise in 6% to 34% of patients with CD33,34 and are thought to occur either as a consequence of the penetration of a deep rectal cavitating ulcer or originate from cryptitis spreading into the intersphincteric space. Histologically, there is significant resemblance to the bowel lesions of CD, with transmural inflammation often granulomatous in nature. Fistulas can be internal or enterocutaneous, and they can undermine ulcers and destroy the anal sphincter. Medical treatments of perianal fistulas include antibiotics, immunosuppressants (azathioprine, 6-mercaptopurine, cyclosporine, and tacrolimus), and infliximab. Surgical treatment is frequently required.
Cavitating ulcers occur in the anus and rectum of CD patients with an incidence of 2% to 5%34,35 and seem to predict future intestinal disease.36 They are described as having a “craggy” appearance, with edematous, irregular, undermined, and detached edges,37 and they may be extremely painful.38 Other possible symptoms are discharge, pruritus, and bleeding.
Skin tags may arise from lymphoedema secondary to lymphatic obstruction. They are usually asymptomatic but may cause problems when they become enlarged and edematous. Two types of skin tags are described. The first type includes large, edematous, hard, and cyanotic skin tags, typically arising from a healed anal fissure or ulcer. This type of skin tags tends to persist. The second one, also called “elephant ear” tags, corresponds to flat and broad or narrow, soft painless skin tags,30 which resolves in about 40% of cases. The presence of skin tags is suspect of underlying CD. However, in 170 consecutive patients with IBD reviewed in a referral center, 24.6% of typical CD skin tags were also reported in UC.39 In contrast, hemorrhoids occur very infrequently in CD. In patients with CD, haemorrhoids should be treated conservatively, as the risk of complications, such as anal stenosis and nonhealing, is high.27
Oral CD occurs in 8% to 9% of the patients with CD40,41 and is considered as an orofacial extension of the granulomatous bowel disease. Oral CD can present as angular cheilitis and ulceration, mucosal nodularity (cobblestoning of the buccal mucosa), nodules of gingival and alveolar mucosa, and indurated fissuring of lower lips.15,20 Oral manifestations are frequently painful and disruptive to eating. Orofacial CD may antedate the typical bowel symptoms by several months to years. Its presentation and severity do not always correlate with the activity of the underlying bowel disease. For orofacial CD, the treatment should be directed at the local lesion and underlying systemic disease. For more severe or refractory orofacial CD, treatment should include systemic steroids, immunomodulators, and anti-TNF-α therapy.42,43
In patients with colostomies or ileostomies, complications include irritant or allergic contact dermatitis and peristomal ulcers.44 The latter condition can be caused by pressure from a poorly fitting device, fistulae to the anterior abdominal wall, peristomal pyoderma gangrenosum (PG), or infected hematomas. Irritating adhesives and solvents used to remove them, combined with occlusion by the ostomy device, may lead to irritation and maceration. Leakage of intestinal contents can lead to irritation and infection.
When histological findings similar to those of the underlying CD develop at sites separated from the gastrointestinal tract by normal tissue, the term metastatic CD (MCD) has been applied. However, the term metastatic may be considered improper as the cutaneous lesions are not because of spread from the bowel and “noncontiguous cutaneous CD” may be a preferable definition. MCD are rare complications that may appear in a variety of regions but are found mainly in the lower extremities and intertriginous areas. Facial and genital lesions have been rarely reported.45,46 This disorder is seen most commonly in patients with colonic involvement and is generally unrelated to the bowel activity.47 MCD in adults usually appears long after the initial diagnosis of CD, and it has rarely been reported as the initial symptom. In children, MCD appears at the same time as intestinal involvement in almost half of the cases.47 Clinically, the lesions may manifest as subcutaneous nodules or erythematous plaques (Fig. 2) and secondary ulcers. Since MCD may exhibit polymorphic clinical features that resemble many other dermatoses, like cellulitis, erysipelas, hidradenitis suppurativa, or various sexually transmitted diseases, histological confirmation is mandatory. Some of these lesions may respond to treatment with topical and systemic corticosteroids.48,49 Antibiotics, azathioprine, methotrexate,47 and infliximab50,51 have been used successfully.
Reactive Skin Manifestations of IBD
Reactive skin manifestations are seen in both CD and UC. The skin lesions of these entities do not exhibit the pathologic features of the IBD lesions, but they share close physiopathological links related to the involvement of the innate immunity. These forms encompass the group of the so-called neutrophilic dermatoses, including PG, pyostomatitis vegetans (PSV), Sweet's syndrome (SS), bowel-associated dermatosis–arthritis syndrome (BADAS), oral aphthous ulcers, and aseptic abscess syndrome.
The neutrophilic dermatoses have been recently included in the group of autoinflammatory diseases,52,53 which are clinically characterized by recurrent episodes of sterile inflammation in the affected organs, in absence of high titers of circulating autoantibodies, and autoreactive T cells.53–56 These conditions are associated with a number of genetically determined alterations of the innate immune response inducing an overproduction of active IL-1β possibly leading, through the release of several proinflammatory cytokines and chemokines, to a neutrophil-mediated inflammation. Distinct neutrophilic dermatoses share similar clinical appearances and associated conditions including IBD, connective tissue diseases, myeloproliferative disorders, and medications.
PG is a rare neutrophilic dermatosis characterized by a wide variety in its clinical presentation and outcome. PG represents the second most common cutaneous manifestation of IBD and the most severe and debilitating, sometimes more incapacitating than the bowel disease itself.11,20 PG is reported to be more common in UC (5 up to 20%) than CD (1%–2%) with a slight female predilection.3,15 The peak of incidence occurs between the ages of 20 to 50 years. Cases in infants and adolescents account for only 4% of PG.57 Temporally, the correlation of PG with IBD activity is still controversial. PG tends to appear after the onset of the UC, and it usually manifests around the time of exacerbation of the underlying bowel disease.58 In only few cases, PG precedes the onset of the UC or affects patients with quiescent bowel disease.58,59
Clinically, in its classical presentation, PG begins with a sterile pustule or erythematous papule or nodule that rapidly breaks down to form a burrowing, painful ulcer with characteristic erythematous to violaceous, sharply defined, undermined borders, and a necrotic base (Fig. 3). The ulcers may enlarge or spontaneously heal, with characteristic atrophic cribriform pigmented scars.60,61 The ulcers can be single or multiple, unilateral or bilateral, and can range in size from several centimeters to the surface of an entire limb. Associated symptoms may include fever, malaise, myalgias, and arthralgias.62 PG usually develops on the extensor surface of the legs, but can appear anywhere on the skin,63 including the abdominal wall adjacent to a postsurgical stoma (Fig. 4). The mechanism behind the peristomal PG may be caused by pathergy, related to irritation caused by leakage of feces, or by the adhesive of the stomal appliance.64 It may rarely presents with a widespread clinical picture.65 Other than the classical ulcerative form, PG may also occur in other clinical subtypes. The pustular variant is characterized by multiple painful pustules with inflammatory halo, fever, and arthralgias. In the bullous form, bullae with perilesional erythema rapidly transform into painful, shallow erosions, and necrotic ulcers.66 Vegetans subtype presents with more superficial ulceration, without purulent base, undermined borders or surrounding erythema, which gradually transform into an exophytic lesion.20,65 PG may rarely affect mucous membranes, particularly genitalia and oral mucosa67; when oral involvement occurs, differential diagnosis with PSV (see Pyostomatitis Vegetans section) should be considered. Extracutaneous involvement can also rarely occur, with almost any organ system being potentially affected in a context defined as neutrophilic disease.67,68 In a percentage of patients ranging from 33% to 50%, PG is associated with various systemic diseases in addition to IBD, notably rheumatologic and hematological disorders, sarcoidosis, or malignancy. In IBD, classic and pustular PGs are the subtypes most frequent; whereas in myeloproliferative diseases, bullous PG is the most common variant.69,70 Vegetans PG is usually not associated with any systemic diseases. PG can arise as a consequence of drug therapies. Drug-induced PG can be triggered by agents, such as granulocyte–macrophage colony-stimulating factor, interferon, propylthiouracil,71 pegfilgrastim (a granulocyte-stimulating factor),72 gefitinib (an inhibitor of epidermal growth factor receptor),73 and recently tumor necrosis factor alpha (TNF-α) antagonists.
The histopathological features of PG, albeit nonspecific, are helpful in ruling out other causes of ulceration. Microscopy demonstrates a dense dermal and hypodermal infiltrate, mainly composed of neutrophils, and necrosis of the epidermis; a variable number of lymphocytes, macrophages, and sometimes plasma cells are also present. Laboratory tests are performed to evaluate for associated disorders rather than to establish a diagnosis of PG. From a pathogenetic point of view, PG is regarded as a prototype of cutaneous autoinflammatory disease,56 whose physiopathological model has been discussed above for the neutrophilic disorders in general. Immunohistochemical studies have recently contributed to clarify some pathomechanisms of the PG ulcer formation; the latter have shown that the wound bed is the site of neutrophil recruitment; whereas in the wound edge, activated T lymphocytes and macrophages pave the way to ulcer formation.74 Moreover, the chemokine IL-8 is immunohistochemically overexpressed in the wound bed of PG, where there is the predominant neutrophil recruitment and consequent tissue damage, also supported by the intense expression of metalloproteinase (MMP)-9. Finally, the increased expression of IL-17, a proinflammatory cytokine produced primarily by a T helper cell subset termed Th17, suggests its potential role in the PG pathophysiology.74 PG is associated with high morbidity and sometimes mortality because of sepsis or other serious infections.66 Relapses are common and their frequency has been reported in up to 70% of cases.75 Moreover, scarring and disfigurement must be considered. Hallmarks of therapy for PG are the complete suppression of inflammatory disease activity, promotion of wound healing, treatment of secondary infections, treatment of underlying associated diseases, and control of pain.60 In mild cases, dressing changes, prevention of trauma, and supportive care may be sufficient for re-epithelialization to occur. In case of a more widespread disease or rapidly progressive course, systemic treatment is mandatory. Corticosteroids, like prednisolone, 1 to 2 mg per kg per day, are widely used for initial therapy. Cyclosporine A, at a daily dosage of 2 to 5 mg/kg administered intravenously, is an accepted treatment for widespread PG after initial steroids or in combination with steroids.76 Case reports have documented the utility of colchicine, clofazimine, thalidomide, mycophenolate, and immunomodulators such as pimecrolimus and tacrolimus.77 In addition, intravenous immunoglobulins have been shown to be effective.78 In steroid-refractory PG, especially when associated with IBD (particularly CD), TNF-α inhibitors, particularly infliximab, may also have a role as a steroid-sparing agent. PG can respond to the basic treatment of IBD, but its relationship with disease activity is less obvious than in other mucocutaneous EIMs, such as erythema nodosum (EN)79; indeed, about 30% of patients with PG do not experience improvement of their lesions with treatment of the underlying IBD.80
PSV is an uncommon disease of the oral mucosa whose concurrence with IBD has been reported in approximately 70% of cases. Although this entity has been classified among the specific skin lesions of IBD, we suggest that it may simply represent the rare occurrence of oral involvement in patients with PG. PSV is characterized by edematous mucosa covered by numerous friable gray-to-yellow pustules, some being considered true abscesses, producing hemorrhagic ulcerations with vegetating features of the bed (Fig. 5). Any part of the oral cavity may be involved,81,82 but the tongue and floor of the mouth are usually spared.83 Long-standing disease leads to fissuring with a “snail track appearance,” in addition to cobblestoning. Symptoms of burning and pain may be present.84 Other than oral cavity, mucosal membranes at the vaginal, nasal, and rarely periocular areas can also be involved.85 Histopathologically, PSV is characterized by epithelial acanthosis and superficial ulceration with intraepithelial and/or subepithelial microabscesses.83,84 PSV usually parallels the activity of the underlying bowel disease,84 and there are reports of mucosal lesions after regression of IBD flare or after surgical treatment of IBD.
A variety of treatments has been reported. The disease is known to be resistant to local treatment with topical steroids and antibiotic mouthwashes. High-dose systemic steroids may be effective,81 even if recurrence is common after withdrawal of the steroid. Sulfasalazine, dapsone, azathioprine, cyclosporine, and topical tacrolimus represent alternative treatments.86–89 Few cases of PSV have been reported to resolve after complete colectomy.90
In 1964, Sweet91 described an acute febrile neutrophilic dermatosis that is nowadays known as SS, and it is characterized by abrupt onset of fever, peripheral neutrophilia, tender erythematous skin lesions, and a diffuse neutrophilic dermal infiltrate.92–94 SS presents most frequently between 30 and 50 years of age, with a predilection for women (women:men, 3:1).95 Clinically, skin lesions are tender, red or reddish purple papules or nodules. The individual lesions may coalesce and form irregular, sharply bordered plaques, often displaying characteristic pseudovesiculations (Fig. 6), or more rarely pustules on the surface.93,95 With time, the lesions develop central clearing, giving annular or arcuate patterns, and in approximately 20% of patients may show target-like features resembling erythema multiforme. All lesions of classical SS will remain for weeks to months before resolving spontaneously,93 without scarring. Lesions may recur in one-third to two-thirds of patients.96 The face, neck, upper chest, and back and extremities, notably the back of the hands, are frequently involved.95 The lesions may also appear on sites of biopsy or other traumas.93 Oral, genital, and ocular manifestations have been reported.85,95 In addition to fever (reported in 48% to 83% of patients), arthralgia, general malaise, headache, and myalgia may accompany cutaneous manifestations.95,97 Extracutaneous SS can rarely occur in bones, central nervous system, kidneys, intestines, liver, heart, bronchi and lungs, muscles, and spleen.93 An elevated erythrocyte sedimentation rate and peripheral leukocytosis with neutrophilia are the most consistent laboratory findings in SS; however, they are not always present.93,95
Histologically, the most typical features of SS are represented by edema of the dermal papillae and by a dense infiltrate in the dermis, predominantly composed of neutrophils85,93,97 (Fig. 6); also, lymphocytes or histiocytes may be present in the inflammatory infiltrate.93,98 Jordaan,99 in 1989, recognized 3 stages of the SS dermal infiltrate (lymphocytic, neutrophilic, and histiocytic). Moreover, Requena et al100 described a variant of SS, that they named histiocytoid SS. Even though the histopathological diagnostic criteria of SS consistently include the lack of vasculitis, vasculitis changes may be occasionally observed.101 SS, PG, and other neutrophilic dermatosis may occur in the same patient.95
SS can be idiopathic, parainflammatory, paraneoplastic, associated with pregnancy,95 and drug induced.102 The incidence of SS in IBD is much rarer than that of PG; to date, about 40 cases of SS have been reported in association with IBD. SS seems to be predominant in patients with CD rather than in those with UC, the rate of association being about 70% and 30%, respectively.103–106 Patients with colonic disease and women aged between 30 and 50 years have increased risk for developing SS.10,14 Although the syndrome has been described also in some patients with quiescent IBD, the occurrence of the disorder has mainly been reported during relapse of disease. Based on reported data, 28% of the cases will present at the time of diagnosis of IBD, 52% after the diagnosis, and only 20% before the diagnosis.107 IBD and SS are likely to share pathogenetic mechanisms related to the autoinflammation.56 Patients with IBD, particularly UC, may develop a pustular variant of SS, characterized by pustules overlying erythematous papules or red-based pustules.108,109 In patients with IBD-associated SS, arthritis and arthralgias are often seen.107
First-line treatment of SS involves systemic steroids such as prednisone at a starting dose of 0.5 to 1.0 mg/kg and then at tapering doses. Marked symptom improvement may be achieved after a 6-week course of steroids.110 High-potency topical steroids or intralesional glucocorticoids may be used for localized disease. Other first-line options for treatment include colchicine and potassium iodide. Treatments with immunosuppressants like cyclosporine (initial doses of 2–5 mg/kg daily), in monotherapy or in combination with steroids, dapsone (1.5–2 mg/kg daily), azathioprine (1.5–2 mg/kg daily), and cyclophosphamide (1–1.5 mg/kg daily), and TNF-α blockers have been reported to be successful in refractory SS cases.111–113
Bowel-associated Dermatosis–arthritis Syndrome
BADAS is a rare neutrophilic dermatosis characterized by fever and/or flu-like symptoms followed by myalgias, arthralgias, or nondeforming arthritis affecting mainly the small peripheral joints and polymorphic cutaneous manifestations. The disease occurs most commonly from days to years after bowel bypass surgery, but possible associations with IBD have been reported.114,115 BADAS usually follows a chronic relapsing course, albeit self-healing cases have been reported.114 The cutaneous manifestations are usually described as PG-like, but features mimicking those of several other ND, notably SS, hidradenitis suppurativa, and neutrophilic panniculitis, have been described. Although BADAS has been suggested to result from the deposition of circulating immune complexes containing bacterial antigens related to the bacterial overgrowth in the bowel, its actual etiology remains unknown. However, the substantial clinical overlap with the spectrum of ND strongly suggests a pathophysiology related to neutrophil-mediated inflammation.116 Our recent report of a patient with a cutaneous picture consisting with PASH syndrome following bowel bypass surgery supports this hypothesis.117
Steroids represent the mainstay of treatment. In refractory cases, other immunosuppressive agents, such as azathioprine, cyclosporine, or TNF-α antagonists may be effective in controlling both skin and intestinal symptoms. Systemic and topical antibiotics are ineffective but may be useful for treating superinfection of opened skin lesions.118,119
Oral Aphthous Ulcers
Oral aphthous ulcers are reactive lesions frequently encountered in patients with IBD. Because nutritional deficiencies in iron, folic acid, and vitamin B12 secondary to active IBD predispose toward aphthous ulcer formation, oral aphthae had classically been considered as multifactorial in origin.120 However, based on their histopathological pattern consisting of a neutrophil-mediated inflammation, the aphthous ulcers associated with IBD may be regarded as a form of neutrophilic dermatosis. Aphthae appear as round or oval painful ulcers, with a yellowish or grayish pseudomembranous base and an erythematous border. They are located on the buccal and labial mucosa, lateral and ventral tongue, soft palate, and oropharynx. Minor and major aphthae can be observed. Minor aphthae are shallow, typically <10 mm in diameter, and they usually heal within 2 weeks without sequelae. Major aphthae are larger and deeper and can last for 4 to 6 weeks and heal with scarring. A less common form of recurrent aphthous stomatitis is characterized by numerous ulcers that can fuse to produce herpetiforme lesions. Aphthous stomatitis or ulcers, typically seen in the buccal mucosa and lips, are more common in CD (10% of patients) than UC.5 However, recurrent aphthous stomatitis affects approximately 4% of patients with UC. The onset is abrupt and usually coincides with recurrence or exacerbation of the underlying UC,14,121 even though other studies failed to find a significant correlation with UC activity.5 A study showed that a majority of patients with multiple aphthous ulcers had underlying IBD.122
Treatment of the IBD may result in remission of the oral aphthous stomatitis. Symptomatic relief with topical corticosteroid and topical anesthetics such as viscous xylocaine and steroid elixir may be beneficial. Systemic steroids are used for severe or refractory cases.14,15,18,123
Aseptic Abscess Syndrome
Aseptic abscess syndrome is an emerging clinicopathological entity within the spectrum of neutrophilic dermatoses, first described by André et al.124 Typical presentation includes fever, loss of weight, abdominal pain, and leukocytosis, together with aseptic lesions histologically characterized by inflammatory infiltrates mainly consisting of neutrophils. Deep abscesses are mainly located in the spleen, but almost all the organs can be affected, both intra-abdominal (lymph nodes, liver, and pancreas) and extra-abdominal (lung and brain). Sometimes, more superficial abscesses can be present (peripheral lymph nodes, muscles, pharynx, and testicles); and in 20% of the patients, skin manifestations including cutaneous abscesses (Fig. 7) and features resembling classic neutrophilic dermatoses, notably PG and SS, can be detected.125 The association with IBD is consolidated, being present in 66% of patients, and it justifies the execution of colonoscopy to rule out an underlying intestinal disorder. More rarely, the condition is associated to relapsing polychondritis, or is idiopathic. The diagnosis is based on the clinical presentation, radiological aspects, pathological and laboratory findings, and the exclusion of alternative diagnoses, especially infectious diseases. Because of its aseptic nature, the disease does not respond to antibiotics but regresses quickly when treated with systemic corticosteroids, albeit it frequently follows a relapsing course. Immunosuppressive treatment is required in almost half of the patients, and anti-TNF-α agents may be used.125 The etiology of the aseptic abscesses syndrome is still unknown, but sharing some features with disorders like IBD or ND suggests the presence of a genetic susceptibility and a close relationship with the autoinflammatory disorders. This hypothesis is supported by the finding of an increased number of CCTG microsatellite repeats in the PSTPIP1 promoter region.126
Dermatoses Associated with IBD
EN, the most common cutaneous manifestation of IBD, affects about 3% to 10% of patients with UC and 4% to 15% of patients with CD.5,14,20,127 The disease affects primarily women between the ages of 25 and 40 years.128 When EN occurs in association with UC, it is typically associated with exacerbation of the colitis even if the severity of the EN does not necessarily parallel the severity of the underlying bowel disease.80 EN rarely precedes the diagnosis of UC.129 EN in patients with CD is mostly associated with colonic involvement.20
The primary lesions are painful, deep, warm, bluish red, tender nodules, 1 to 5 cm in diameter, and distributed symmetrically over the anterior lower legs (Fig. 8). These skin nodules are palpable, do not exhibit suppuration or ulceration, and they change in color to a yellowish hue resembling a bruise on the skin. Old lesions often coexist with the appearance of new nodules, so that nodules at various stages of their evolution may be observed. The eruption may be accompanied by fever, malaise, synovitis, and arthritis. Even though pretibial surfaces are the commonest localization of EN, the knees, ankles, arms, or trunk can also be involved.18 EN heals spontaneously within 6 weeks, without atrophy or scarring, but recurrence occurs in 20% of cases. The histopathology reveals a septal panniculitis; neutrophils typically predominate in early lesions. Granulomatous features may be found in both early and late lesions; whereas, fibrotic subcutaneous septa with multinucleate giant cells are present in late lesions. However, biopsy is generally not necessary as EN may be diagnosed based on the clinical features. Routine laboratory findings include leukocytosis >10,000 per cubic millimeter, elevated erythrocyte sedimentation rate, and increased C-reactive protein levels.130
EN is believed to be a delayed hypersensitivity reaction and has been associated with a number of heterogeneous conditions other than IBD. The inciting antigen is identified in approximately 40% of cases, whereas the disease is idiopathic in most patients. Identifiable causes include bacterial infections (e.g., streptococcal infections, tuberculosis), fungal infections (e.g., histoplasmosis), drugs (e.g., oral contraceptive pills), malignancy (lymphomas), and pregnancy.131 Sarcoidosis and Behçet disease are other associated conditions. In a recent Spanish study on 106 patients with EN, sarcoidosis, accounting for 22% of cases, was the most frequent systemic disease causing EN.132 The prevalent underlying cause varies by the population and the geographic location. In children, streptococcal infections seem to be the most common cause. Given the broad variety of possible triggers for EN, a thorough history and physical examination are essential for narrowing the list of possible etiologies. A reasonable laboratory and radiologic workup might include antistreptolysin O or anti-DNase-B levels, a chest x-ray, stool cultures, a tuberculin skin test, and a urine pregnancy test.
When EN is associated with IBD, because skin lesions mirror bowel disease activity and flare up, treatments targeting underlying IBD usually lead to the remission of the cutaneous manifestations.133 Supportive therapy, including bed rest and avoidance of contact irritation of affected areas, has a relevant role. However, in situations where lesions occur during the quiescent phase, low doses of oral steroids can lead to rapid remission of the cutaneous lesions in most cases.20 Other effective alternatives include immunomodulating agents such as colchicine, dapsone, and thalidomide and immunosuppressants such as cyclosporine, azathioprine, and methotrexate. In resistant or highly relapsing cases, TNF-α antagonists have been used with successful results.134
Psoriasis is a papulosquamous skin disease (Fig. 9), which together with EN, is the most frequently associated cutaneous disease, occurring in 7% to 11% of the patients with IBD compared with 1% to 3% of general population.11 Data aggregated from 5 independent case–control studies have found the prevalence of psoriasis at 8.9% in patients with CD but only 1.4% in control patients.135 A recent retrospective study on a large population found a statistically significant association between psoriasis and IBD.136 Another study showed that 10% of patients with CD had a first-degree relative with psoriasis, whereas the prevalence was 2.9% in control patients.137 Psoriasis has been found to be more prevalent in CD (11.2%) than UC (5.7%).5,138 The association between these conditions suggests a genetic link. Indeed, genetic markers that are linked to both psoriasis and CD have been identified in specific regions on chromosomes 16, 6, 4, and 3.135 Furthermore, a striking overlap of loci between IBD and psoriasis, ankylosing spondylitis and primary sclerosing cholangitis seems plausible.139 Overall, a genetic predisposition or HLA susceptibility for certain specific immune response patterns and common inflammatory pathways may be involved in the association of IBD and psoriasis.20,140 In addition to genetic connections, IBD and psoriasis share relevant pathogenetic features, which could explain this association. Both IBD and psoriasis are chronic inflammatory diseases mediated by an aberrant activation of Th1 lymphocytes producing cytokines such as TNF-α, IFN-γ, and IL-12. The clinical relevance of these findings is highlighted by the efficacy of several drugs that target T lymphocytes and Th1 cytokines, notably anti-TNF-α agents, for both diseases. Moreover, in psoriasis and CD, an important role for Th17 cells, producing IL-17, IFN-γ, and IL-21, has also been found.141,142 Increased levels of IL-17 and IL-23 in the intestinal mucosa of patients with CD and also in the serum and in the cutaneous lesions of patients with psoriatic have been reported.143
There is no relationship between the course of psoriasis and the activity of IBD. In patients with both CD and psoriasis, the onset of psoriasis usually precedes that of CD.144,145 Topical corticosteroids, salicylic acid, and vitamin D analogs are used in mild disease. In severe cases, systemic retinoids, methotrexate, cyclosporine, and TNF-α antagonists have to be considered.
Both cutaneous small-vessel vasculitis and cutaneous polyarteritis nodosa (C-PAN) are uncommon skin manifestations of IBD. Cutaneous small-vessel vasculitis is the most common type of cutaneous vasculitis and affects mainly the skin postcapillary venules.146 The cutaneous picture is typically polymorphous147 and ranges from palpable purpura to urticarial and necrotic ulcerative lesions predominantly involving the legs (Fig. 10), whereas its extracutaneous, particularly renal, manifestations are relatively uncommon. The skin lesions of cutaneous small-vessel vasculitis arise as a simultaneous crop and usually resolve within several weeks or a few months; approximately 10% of patients follow a chronic relapsing course more than a period ranging from few to several years. The histopathological pattern is the so-called leukocytoclastic vasculitis, characterized by dermal perivascular infiltrates mainly composed of neutrophils with karyorrhexis of nuclei and fibrinoid necrosis of vessel walls148 (Fig. 10). The therapeutic approach in patients with mild disease consists of only topical corticosteroids, whereas, systemic corticosteroids, namely methylprednisolone at the initial dose of 0.8 to 1 mg/kg daily, are the first-line agents for patients with painful ulcerative necrotic skin lesions. A number of steroid-sparing immunosuppressants, notably cyclosporine (2–5 mg/kg daily), may be associated to corticosteroid in highly relapsing cases or used in monotherapy in patients in whom corticosteroids are contraindicated.146 Polyarteritis nodosa is a rare, severe necrotizing vasculitis of small- and medium-sized arteries149 affecting multiple organ systems; C-PAN is a variant of polyarteritis nodosa confined to the skin, although controversy exists on whether or not it simply represents an early or less aggressive form of polyarteritis nodosa.146,150 C-PAN presents as a single or multiple tender nodules commonly located on the distal lower extremities. Early in the course of C-PAN, lesions show the typical pattern of leukocytoclastic vasculitis, whereas later in the disease process, the infiltrate is predominantly composed of lymphocytes and histiocytes151; granulomatous features reminiscent of those of classic CD may be seen when there is coexistence with IBD.152 Up to 10% of C-PAN cases are associated with IBD.153 Treatment of C-PAN consists of systemic corticosteroids, namely methylprednisolone at the initial dose of 0.8 to 1 mg/kg daily, which usually controls the disease. Low-dose methotrexate (7.5–20 mg/wk) may be considered for cases unresponsive to corticosteroids.146
Epidermolysis Bullosa Acquisita
Epidermolysis bullosa acquisita (EBA) is an autoimmune disease manifesting as subepidermal blistering and scarring, mainly localized in anatomical areas prone to trauma, such as the hands, knees (Fig. 11), and feet; mucosae may also be involved. EBA is characterized by autoantibodies of the IgG-isotype specific to type VII collagen, the main constituent of anchoring fibrils at the dermal–epidermal junction.154 Binding of autoantibodies to type VII collagen triggers an inflammatory reaction, including fixation of complement and Fc-dependent activation of leucocytes.155 Activated granulocytes release reactive oxygen intermediates and proteases leading to epithelial injury and blister formation.156,157 Clinically, EBA may manifest as tense vesicles and bullae, evolving into erosions. The blisters may be hemorrhagic and usually heal with scar and milia formation. Inflammatory features, including erythema, urticarial plaques, and pruritus may occur. EBA diagnosis needs to be confirmed by immunopathological studies including direct immunofluorescence on perilesional skin and indirect immunofluorescence on sodium split skin. Direct immunofluorescence reveals deposits of IgG (rarely IgA) and or C3 at the dermal–epidermal junction (Fig. 11C), whereas indirect immunofluorescence shows IgG (rarely IgA) and or C3 at the floor of the split skin (Fig. 11D). Recently, an immunoenzymatic method has been set up to detect circulating autoantibodies against type VII collagen.154 Systemic diseases are often associated with EBA, including CD and, less frequently, UC.158 A study found that the prevalence of IBD in patients with EBA was about 25%.159 The pathogenetic mechanism underlying the association between EBA and IBD may be related to the epitope-spreading phenomenon. In fact, type VII collagen is also expressed in the basement membrane of intestinal epithelium. It may be hypothesized that chronic inflammation in the intestine predisposes patients with IBD to develop autoantibodies against type VII collagen, which in turn attack the skin at the dermal–epidermal junction resulting in the typical blistering lesions of EBA.160 The onset of the gastrointestinal symptoms generally precedes or occurs simultaneously with the autoimmune skin disease.160,161 Less frequently, the diagnosis of IBD follows the development of the blistering disorder.160,162 The treatment of EBA is represented by immunosuppressants and anti-inflammatory agents, including systemic corticosteroids, dapsone,163 colchicine,164 cyclosporine,165 mycophenolate mofetil,166 azathioprine, and recently, the anti-CD20 mAb rituximab.167
Among the EIMs of IBD, the skin is one of the most frequently involved organ systems. In addition to mucocutaneous manifestations affecting sites that are in continuity with the bowel, namely perianal, peristomal, and orofacial regions, showing the same granulomatous histology seen in IBD, there are both skin diseases associated with IBD and reactive cutaneous manifestations. Whereas, the former, albeit linked to IBD, are distinctive entities, such as EN and psoriasis, the latter are regarded as a skin expression of IBD because of sharing physiopathological pathways. Among this setting, there are PG and SS, 2 classic neutrophilic dermatoses that have recently been classified among autoinflammatory diseases. Autoinflammatory diseases are clinically characterized by recurrent episodes of sterile inflammation in the affected organs, without high titers of circulating autoantibodies and autoreactive T cells. All the above conditions may precede, occur simultaneously, or follow the onset of the intestinal disease. The immunosuppressive treatment for the underlying IBD usually, albeit not always, achieves the control of the mucocutaneous manifestations. So, all patients with IBD should be closely examined for skin manifestations by gastroenterologists. However, it is mandatory for dermatologists to be alert in any patient presenting with any neutrophilic dermatosis for the possibility of an underlying IBD. Finally, the protean cutaneous adverse reactions caused by immunosuppressants, particularly TNF-α inhibitors, used for the management of IBD, mainly include psoriasis-like, eczema-like, and lichenoid eruptions, drug-induced cutaneous lupus erythematosus, and nonmelanoma skin cancer. Cutaneous manifestations should be promptly recognized and correctly diagnosed by gastroenterologists and dermatologists together to quickly establish an adequate treatment.
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Crohn's disease; ulcerative colitis; pyoderma gangrenosum; Sweet's syndrome; erythema nodosum; vasculitis; psoriasis; epidermolysis bullosa acquisita
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