Awareness of the extraintestinal manifestations of Crohn disease is increasing in dermatology and gastroenterology, with enhanced identification of entities that range from granulomatous diseases recapitulating the underlying inflammatory bowel disease to reactive conditions and associated dermatoses. In this review, the underlying etiopathology of Crohn disease is discussed, and how this mirrors certain skin manifestations that present in a subset of patients is explored. The array of extraintestinal manifestations that do not share a similar pathology, but which are often seen in association with inflammatory bowel disease, is also discussed. Treatment and pathogenetic mechanisms, where available, are discussed.
Key points
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Cutaneous manifestations of inflammatory bowel disease (IBD) can often be the presenting sign of underlying gastrointestinal disease, and clinicians should have a low threshold to initiate evaluation for underlying gastrointestinal (GI) disease when patients present with representative skin lesions.
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In patients with known IBD, dermatologic manifestations are common, occurring in up to one-third of patients.
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Cutaneous extraintestinal manifestations are traditionally divided into 3 categories: (1) disease-specific lesions that show the same histopathologic findings as the underlying GI disease, (2) reactive lesions that are inflammatory lesions that do not share the GI pathology, and (3) associated conditions believed caused by HLA linkage phenomenon.
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For many extraintestinal manifestations, the cutaneous disease course does not always mirror the GI disease course, presenting a therapeutic challenge.
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Consultation and coordination of care with gastroenterology are essential for optimal patient benefit.
Crohn disease
Introduction
Crohn disease (CD) is an inflammatory condition of the gastrointestinal (GI) tract, characterized by unpredictable periods of symptomatic relapses and remissions. The incidence of CD in the United States is approximately 3.1 to 14.6 per 100,000 person-years. CD can affect any location in the GI tract, from the mouth to the anus, but most commonly presents in the terminal ileum (30%), colon (20%), or small bowel and colon (45%). In addition, CD can affect other organs, including the eyes, skin, and liver, and joints, which are termed extraintestinal manifestations (EIMs).
Etiopathogenesis
The underlying cause of CD is not known, although several factors have been identified that contribute to disease onset. These factors include genetic, microbial, environmental (smoking), immunologic, vascular, and psychosocial factors. Medications such as nonsteroidal antiinflammatory drugs (NSAIDs) and oral contraceptives have also been implicated in the onset and worsening of CD, although this remains controversial. The chronic inflammation in CD is driven by a dysregulated immune system and is dependent on both the Th-1 and Th-17 pathways. Although there is a component of genetic susceptibility in the cause of CD, it does not follow a Mendelian inheritance pattern, and disease onset is likely triggered by exposure to 1 or more triggers in a genetically susceptible individual. Most of the CD-related genes that have been found help to regulate the interaction of gut microbiota and the mucosal immune system.
Clinical Presentations
The clinical presentation of CD can be variable, although most patients present with abdominal pain, diarrhea, rectal bleeding, weight loss, fatigue, fevers, and malnutrition. CD can present at any age, from pediatrics to patients in the sixth or seventh decades of life, but most commonly presents in early adulthood. Complications of CD are also common, because of the transmural inflammation associated with the disease, and patients may present with symptoms caused by these complications. The fibrostenotic phenotype of CD leads to the development of small bowel or colonic strictures, and patients often present with bowel obstructions. In addition, fistulae may form between the GI tract and other organs, including the bladder, skin, vagina, or other locations in the bowel. A subset of patients with CD present with perianal manifestations of the disease, including perianal fistulae and abscesses.
Diagnosis and treatment
The diagnosis of CD is made by a combination of laboratory studies, radiographic imaging, and ileocolonoscopy with biopsy. Several different classes of medications are used to treat both the inflammation and symptoms associated with CD, including mesalamine products, short-term corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), biological therapies (infliximab, adalimumab, certolizumab pegol, natalizumab, vedolizumab), antibiotics, antidiarrheals, and bile-acid sequestrants. The goals of treatment are to achieve mucosal healing, avoid the development of complications and surgery, and to optimize quality of life. Approximately 70% of patients with CD require surgery during their lifetime, and many have postoperative recurrence and require additional surgical interventions.
Systemic/Extraintestinal Associations
As mentioned earlier, multiple EIMs of CD have been described ( Table 1 ). Arthritis and arthralgias are most common, occurring in up to 50% of patients in some studies. Ophthalmologic manifestations are rarely seen (<5% of cases), including episcleritis and anterior uveitis, and tend to occur when the GI disease is active. Hepatobiliary abnormalities may be related either to CD itself or, often, to the medications used to treat it. Common hepatobiliary manifestations of CD include granulomatous hepatitis, amyloidosis, fatty liver, pericholangitis, cholelithiasis, primary sclerosing cholangitis (PSC), portal vein thrombosis, and cholangiocarcinoma. Patients with CD are also at an increased risk of developing venous thromboembolic disease, with a 3-fold higher risk than control patients.
| Skin Finding | Therapy | Highest Level of Evidence Cited |
|---|---|---|
| Vulvoperineal CD | Metronidazole | D |
| Azathioprine with topical steroid | D | |
| Infliximab | D | |
| Infliximab with hyperbaric O 2 | E | |
| Intralesional steroids | E | |
| Genital lymphedema | Metronidazole | D |
| Topical steroid with support | D | |
| Surgery | D | |
| Lymphangioma circumscripta | Surgery/laser | D |
| Orofacial granulomatosis | Mesalamine/prednisolone | D |
| Diet modification | B | |
| Steroid mouthwash/gels | E | |
| Infliximab | B | |
| Adalimumab | B | |
| Erythema nodosum | Prednisone | D |
| TNF inhibitors | D | |
| Colchicine | D | |
| Hydroxychloroquine | D | |
| Dapsone | D | |
| Pyoderma gangrenosum | Intralesional steroids | E |
| Topical potent corticosteroids | E | |
| Topical calcineurin inhibitors | D | |
| Topical dapsone | D | |
| Cromolyn sodium | D | |
| Topical 5-aminosalicylic acid | D | |
| Prednisone | C | |
| Azathioprine | D | |
| 6-mercaptopurine | D | |
| Cyclosporine | D | |
| Methotrexate | D | |
| Mycophenolate mofetil | D | |
| Infliximab | C | |
| Adalimumab | C | |
| Peristomal pyoderma gangrenosum | Topical potent corticosteroids | D |
| Intralesional steroids | D | |
| Crushed dapsone | D | |
| Dapsone gel | E | |
| Corticosteroid inhalers | D | |
| TNF inhibitors | D | |
| Ustekinumab | D | |
| Stoma closure | D | |
| Pyostomatitis vegetans | Topical steroids | D |
| Antiseptic mouthwashes | D | |
| Azathioprine | D | |
| Dapsone | D | |
| Prednisolone | D | |
| Infliximab | D | |
| Oral aphthous ulcers | Viscous lidocaine | NA |
| Topical steroids | NA | |
| Sweet syndrome | Prednisone | D |
| Colchicine | D | |
| Dapsone | D | |
| Cyclosporine | D | |
| Cyclophosphamide | D | |
| Indomethacin | D | |
| Clofazimine | D | |
| Leukocytoclastic vasculitis | Prednisone | D |
| Epidermolysis bullosa acquisita | Dapsone | D |
| Sulfapyridine | D | |
| Colchicine | D | |
| Cyclosporine | D | |
| Mycophenolate mofetil | D | |
| Rituximab | D | |
| Intravenous immunoglobulin | D | |
| Extracorporeal phototherapy | D |
In addition to these EIMs, dermatologic manifestations of CD are common, occurring in up to one-third of patients; the remainder of this article is devoted to these cutaneous manifestations of CD.
Crohn disease
Introduction
Crohn disease (CD) is an inflammatory condition of the gastrointestinal (GI) tract, characterized by unpredictable periods of symptomatic relapses and remissions. The incidence of CD in the United States is approximately 3.1 to 14.6 per 100,000 person-years. CD can affect any location in the GI tract, from the mouth to the anus, but most commonly presents in the terminal ileum (30%), colon (20%), or small bowel and colon (45%). In addition, CD can affect other organs, including the eyes, skin, and liver, and joints, which are termed extraintestinal manifestations (EIMs).
Etiopathogenesis
The underlying cause of CD is not known, although several factors have been identified that contribute to disease onset. These factors include genetic, microbial, environmental (smoking), immunologic, vascular, and psychosocial factors. Medications such as nonsteroidal antiinflammatory drugs (NSAIDs) and oral contraceptives have also been implicated in the onset and worsening of CD, although this remains controversial. The chronic inflammation in CD is driven by a dysregulated immune system and is dependent on both the Th-1 and Th-17 pathways. Although there is a component of genetic susceptibility in the cause of CD, it does not follow a Mendelian inheritance pattern, and disease onset is likely triggered by exposure to 1 or more triggers in a genetically susceptible individual. Most of the CD-related genes that have been found help to regulate the interaction of gut microbiota and the mucosal immune system.
Clinical Presentations
The clinical presentation of CD can be variable, although most patients present with abdominal pain, diarrhea, rectal bleeding, weight loss, fatigue, fevers, and malnutrition. CD can present at any age, from pediatrics to patients in the sixth or seventh decades of life, but most commonly presents in early adulthood. Complications of CD are also common, because of the transmural inflammation associated with the disease, and patients may present with symptoms caused by these complications. The fibrostenotic phenotype of CD leads to the development of small bowel or colonic strictures, and patients often present with bowel obstructions. In addition, fistulae may form between the GI tract and other organs, including the bladder, skin, vagina, or other locations in the bowel. A subset of patients with CD present with perianal manifestations of the disease, including perianal fistulae and abscesses.
Diagnosis and treatment
The diagnosis of CD is made by a combination of laboratory studies, radiographic imaging, and ileocolonoscopy with biopsy. Several different classes of medications are used to treat both the inflammation and symptoms associated with CD, including mesalamine products, short-term corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), biological therapies (infliximab, adalimumab, certolizumab pegol, natalizumab, vedolizumab), antibiotics, antidiarrheals, and bile-acid sequestrants. The goals of treatment are to achieve mucosal healing, avoid the development of complications and surgery, and to optimize quality of life. Approximately 70% of patients with CD require surgery during their lifetime, and many have postoperative recurrence and require additional surgical interventions.
Systemic/Extraintestinal Associations
As mentioned earlier, multiple EIMs of CD have been described ( Table 1 ). Arthritis and arthralgias are most common, occurring in up to 50% of patients in some studies. Ophthalmologic manifestations are rarely seen (<5% of cases), including episcleritis and anterior uveitis, and tend to occur when the GI disease is active. Hepatobiliary abnormalities may be related either to CD itself or, often, to the medications used to treat it. Common hepatobiliary manifestations of CD include granulomatous hepatitis, amyloidosis, fatty liver, pericholangitis, cholelithiasis, primary sclerosing cholangitis (PSC), portal vein thrombosis, and cholangiocarcinoma. Patients with CD are also at an increased risk of developing venous thromboembolic disease, with a 3-fold higher risk than control patients.
| Skin Finding | Therapy | Highest Level of Evidence Cited |
|---|---|---|
| Vulvoperineal CD | Metronidazole | D |
| Azathioprine with topical steroid | D | |
| Infliximab | D | |
| Infliximab with hyperbaric O 2 | E | |
| Intralesional steroids | E | |
| Genital lymphedema | Metronidazole | D |
| Topical steroid with support | D | |
| Surgery | D | |
| Lymphangioma circumscripta | Surgery/laser | D |
| Orofacial granulomatosis | Mesalamine/prednisolone | D |
| Diet modification | B | |
| Steroid mouthwash/gels | E | |
| Infliximab | B | |
| Adalimumab | B | |
| Erythema nodosum | Prednisone | D |
| TNF inhibitors | D | |
| Colchicine | D | |
| Hydroxychloroquine | D | |
| Dapsone | D | |
| Pyoderma gangrenosum | Intralesional steroids | E |
| Topical potent corticosteroids | E | |
| Topical calcineurin inhibitors | D | |
| Topical dapsone | D | |
| Cromolyn sodium | D | |
| Topical 5-aminosalicylic acid | D | |
| Prednisone | C | |
| Azathioprine | D | |
| 6-mercaptopurine | D | |
| Cyclosporine | D | |
| Methotrexate | D | |
| Mycophenolate mofetil | D | |
| Infliximab | C | |
| Adalimumab | C | |
| Peristomal pyoderma gangrenosum | Topical potent corticosteroids | D |
| Intralesional steroids | D | |
| Crushed dapsone | D | |
| Dapsone gel | E | |
| Corticosteroid inhalers | D | |
| TNF inhibitors | D | |
| Ustekinumab | D | |
| Stoma closure | D | |
| Pyostomatitis vegetans | Topical steroids | D |
| Antiseptic mouthwashes | D | |
| Azathioprine | D | |
| Dapsone | D | |
| Prednisolone | D | |
| Infliximab | D | |
| Oral aphthous ulcers | Viscous lidocaine | NA |
| Topical steroids | NA | |
| Sweet syndrome | Prednisone | D |
| Colchicine | D | |
| Dapsone | D | |
| Cyclosporine | D | |
| Cyclophosphamide | D | |
| Indomethacin | D | |
| Clofazimine | D | |
| Leukocytoclastic vasculitis | Prednisone | D |
| Epidermolysis bullosa acquisita | Dapsone | D |
| Sulfapyridine | D | |
| Colchicine | D | |
| Cyclosporine | D | |
| Mycophenolate mofetil | D | |
| Rituximab | D | |
| Intravenous immunoglobulin | D | |
| Extracorporeal phototherapy | D |
In addition to these EIMs, dermatologic manifestations of CD are common, occurring in up to one-third of patients; the remainder of this article is devoted to these cutaneous manifestations of CD.
Cutaneous manifestations of Crohn disease
The skin and oral mucosa represent easily accessible sites to monitor for development of EIMs of inflammatory bowel disease (IBD) and, consequently, there is a growing appreciation for the number of associated skin findings that occur. Estimates of prevalence vary widely for each EIM, but some range as high as 43% of patients, indicating that an understanding of these entities is critical to the effective care of patients with IBD in both the gastroenterology and dermatology settings. Cutaneous lesions of IBD have traditionally been divided into 3 categories reflective of their etiopathology: (1) specific lesions (those that have the same histopathologic findings as the underlying GI disease), (2) reactive lesions (those in which the inflammatory process does not share the GI pathology), and (3) associated conditions (believed to be caused by HLA linkage phenomenon and sequelae of chronic inflammation). In the current era of ever-expanding therapeutic options for IBD, some investigators have proposed a fourth category of EIMs, namely those that are therapy related. These EIMs are discussed in connection with the disease-associated conditions in light of certain skin findings that have potential overlap between these last 2 categories.
Disease-specific cutaneous manifestations
Perianal Fissures/Fistulae and Acrochordae
Perianal fissures and fistulae ( Fig. 1 ) are one of the specific lesions of CD and are a commonly encountered finding in up to one-third of patients. This finding is strongly associated with colonic involvement of CD compared with those patients with small bowel disease only. Chronic inflammation in the setting of fissures and fistulae promotes development of cutaneous abscesses and acrochordae.
Metastatic (Cutaneous) Crohn Disease
Metastatic CD refers to inflammatory lesions that extend to involve areas not typically considered as part of the spectrum of the underlying IBD. Clinically, this manifests as erythematous and violaceous plaques, nodules, and ulcerations with epithelioid granulomatous inflammation primarily localized on the extremities or intertriginous skin ( Fig. 2 ). The face and genitalia are less commonly involved. A tissue biopsy is usually necessary to establish the diagnosis, because the clinical appearance of the lesions can have overlapping features with several other disorders. As the name suggests, metastatic CD is, by definition, separated from the GI tract by normal tissue and thereby excludes classic perianal CD. According to previously published data, metastatic Crohn is one of the rarer cutaneous manifestations of CD. The timing to development of metastatic lesions varies widely but has been reported to occur after the initial diagnosis of CD in most adults and around the same time as diagnosis of CD in approximately half of childhood cases of CD. These lesions can be particularly frustrating to the clinician, because surgical correction of the affected portion of bowel does not always improve metastatic CD, highlighting the observation that skin and intestinal disease do not always mirror each other in this setting. Several specific manifestations of cutaneous CD are discussed in greater detail in the following sections.
Vulvoperineal Crohn disease
Granulomatous infiltration of the skin of the vulva and perineum in CD is a rarely reported finding that may precede the development of GI manifestations by months to years. The initial presentation may be highlighted by vulvar or perineal pain. This pain can progress to cutaneous ulcerations and fistulas in some cases ( Fig. 3 ). There have been reported cases of adolescent vulvoperineal Crohn that initially presented as lesions suspicious for sexual abuse. Involvement of the perineum is seen more frequently in women and at a younger age, with noted predominance of colonic over small bowel involvement of the GI tract. Without a history of previous GI symptoms, a skin biopsy showing epithelioid granulomas is the finding most likely to lead to a diagnosis of vulvoperineal CD. A poorer prognosis for these patients has been documented in terms of surgical healing as well as need for proctectomy. Because surgical outcomes are poor, selected cases have been successfully medically managed with a variety of approaches, including metronidazole, azathioprine plus topical steroid, and infliximab. Several investigators have recently suggested that a combination of infliximab and hyperbaric oxygen may provide synergistic benefit in managing this presentation of CD, although clinical evidence is still lacking. Anecdotally, we have noted success with serial intralesional corticosteroid injections into the vulva and perineal skin (L.M.G., personal observation).
