ArticlePDF Available

Skin Manifestations of Inflammatory Bowel Disease

Frontiers in Physiology

February 2012
3:13

DOI:10.3389/fphys.2012.00013

Source
PubMed

License
CC BY 4.0

Authors:

Brian L Huang

University of California, Los Angeles

Inflammatory bowel disease (IBD) is a disease that affects the intestinal tract via an inflammatory process. Patients who suffer from IBD often have diseases that affect multiple other organ systems as well. These are called extraintestinal manifestations and can be just as, if not more debilitating than the intestinal inflammation itself. The skin is one of the most commonly affected organ systems in patients who suffer from IBD. The scientific literature suggests that a disturbance of the equilibrium between host defense and tolerance, and the subsequent over-activity of certain immune pathways are responsible for the cutaneous disorders seen so frequently in IBD patients. The purpose of this review article is to give an overview of the types of skin diseases that are typically seen with IBD and their respective pathogenesis, proposed mechanisms, and treatments. These cutaneous disorders can manifest as metastatic lesions, reactive processes to the intestinal inflammation, complications of IBD itself, or side effects from IBD treatments; these can be associated with IBD via genetic linkage, common autoimmune processes, or other mechanisms that will be discussed in this article. Ultimately, it is important for healthcare providers to understand that skin manifestations should always be checked and evaluated for in patients with IBD. Furthermore, skin disorders can predate gastrointestinal symptoms and thus may serve as important clinical indicators leading physicians to earlier diagnosis of IBD.

Perianal fissure in a patient with IBD. Note the longitudinal tear pattern in the anoderm.

…

Aphthous stomatitis of the oral mucosa. Note the erythematous ring around the yellow to gray colored ulceration in this minor aphthous stomatitis.

…

Erythema nodosum manifested as erythematous nodules of the skin. These lesions are often painful and assume a bruise-like appearance.

…

Pyoderma gangrenosum can start as small pustules that as they progress form larger and deeper ulcers. Classically, the borders of the lesions are mucopurulent and purple. Example of pyoderma gangrenosum lesion involving the leg (A) and parastoma (B).

…

Figures - available via license: Creative Commons Attribution 4.0 International

Content may be subject to copyright.

Content uploaded by Brian L Huang

Content may be subject to copyright.

Available via license: CC BY 4.0

Content may be subject to copyright.

REVIEW ARTICLE

published: 06 February 2012

doi: 10.3389/fphys.2012.00013

Skin manifestations of inﬂammatory bowel disease

Brian L. Huang1, Stephanie Chandra2and David Quan Shih2*

1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

2Cedars-Sinai Medical Center, Inﬂammatory Bowel and Immunobiology Institute, Los Angeles, CA, USA

Edited by:

Simon Beaven, University of

California Los Angeles, USA

Reviewed by:

Georg Singer, Medical University of

Graz, Austria

Yana Zavros, University of Cincinnati,

USA

*Correspondence:

David Quan Shih, Cedars-Sinai

Inﬂammatory Bowel and

Immunobiology Research Institute,

8700 Beverly Blvd., Suite 4066,

Los Angeles, CA 90048, USA.

e-mail: david.shih@csmc.edu

Inﬂammatory bowel disease (IBD) is a disease that affects the intestinal tract via an inﬂam-

matory process. Patients who suffer from IBD often have diseases that affect multiple

other organ systems as well. These are called extraintestinal manifestations and can be

just as, if not more debilitating than the intestinal inﬂammation itself. The skin is one of

the most commonly affected organ systems in patients who suffer from IBD.The scientiﬁc

literature suggests that a disturbance of the equilibrium between host defense and toler-

ance, and the subsequent over-activity of certain immune pathways are responsible for the

cutaneous disorders seen so frequently in IBD patients. The purpose of this review article

is to give an overview of the types of skin diseases that are typically seen with IBD and their

respective pathogenesis, proposed mechanisms, and treatments.These cutaneous disor-

ders can manifest as metastatic lesions, reactive processes to the intestinal inﬂammation,

complications of IBD itself, or side effects from IBD treatments; these can be associated

with IBD via genetic linkage, common autoimmune processes, or other mechanisms that

will be discussed in this article. Ultimately, it is important for healthcare providers to under-

stand that skin manifestations should always be checked and evaluated for in patients with

IBD. Furthermore, skin disorders can predate gastrointestinal symptoms and thus may

serve as important clinical indicators leading physicians to earlier diagnosis of IBD.

Keywords: inﬂammatory bowel disease, skin disorders, Crohn’s disease, ulcerative colitis

INTRODUCTION

OVERVIEW

Inﬂammatory bowel disease (IBD) is an idiopathic and inﬂamma-

tory disease of the intestinal tract. The two major types of IBD

are ulcerative colitis (UC) and Crohn’s disease (CD). As the name

implies, UC is limited to the colon and/or rectum (normally con-

tinuous lesions in the rectum and colon), and affects only the

inner lining (mucosal and submucosal layers) of the gut. In con-

trast, CD can affect any part of the gut from mouth to anus as

non-continuous or skip lesions (a majority of cases start in the

terminal ileum), and affect the whole thickness (transmural) of

the bowel wall.

Up to 40% of IBD patients may be complicated by extraintesti-

nal manifestations (EIMs) and in some large series of studies, the

prevalence of EIMs is higher in CD compared to UC (Vind et al.,

2006;Vavricka et al., 2011). 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 (Vavricka et al., 2011). Multiple organ

systems and almost every organ system may be affected in IBD,

including the musculoskeletal system, skin, eyes, hepatobiliary

system, lungs, kidneys, immunologic or hematologic system, and

cardiovascular system (Williams et al., 2008;Vavricka et al., 2011).

The most common EIMs of IBD are peripheral arthritis, aphthous

stomatitis, uveitis, and erythema nodosum (EN; Vavricka et al.,

2011). Among the organ systems involved, the skin is one of the

most commonly affected organ systems. The most common skin

or mucocutaneous lesions associated with IBD are EN, pyoderma

gangrenosum (PG), and aphthous stomatitis (oral ulceration;

Rothfuss et al., 2006;Larsen et al., 2010). Aphthous stomatitis or

aphthae are the most common complication of the oral mucosa,

while ﬁssure and ﬁstulae are most common complication of the

perianal mucosa. EN and PG are immunoreactive in nature as a

result of the underlying IBD disease. In addition, skin lesions in

IBD patients can also be caused by nutritional deﬁciencies, such as

pellagra and cheilitis. Medication side effects, such as cushingoid

features from steroid usage or drug eruptions from immunosup-

pressant medications have also been noted. Other skin disorders

such psoriasis and vitiligo have also been associated with IBD

(Timani and Mutasim, 2008).

MECHANISMS BETWEEN IBD AND SKIN DISORDERS

Mucosal T-cells are important in maintaining intestinal home-

ostasis, deﬁned as the balance between the mucosal epithelium,

intestinal microbes, and host immune response (van Wijk and

Cheroutre, 2010). Abnormal T-cell response to these microbial

antigens can disrupt this equilibrium and is believed to be the

mechanism that triggers the chronic inﬂammation and exces-

sive secretion of cytokines that lead to the development of IBD

(Izcue et al., 2009;van Wijk and Cheroutre, 2010;Monteleone

et al., 2011). It has been proposed that some EIM’s seen with

IBD manifest also as a result of immune dysregulation result-

ing in a lymphocyte mediated destructive process. Adams and

Eksteen (2006) proposed IBD patients with hepatic EIMs could be

explained by mucosal T-cells in the gut aberrantly traveling to the

liver, becoming exposed to hepatic antigens, and ultimately caus-

ing liver damage. This article suggested that a similar mechanism

could possibly explain the pathogenesis of other EIM’s (including

the skin) in patients with IBD (Adams and Eksteen, 2006).

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 1

Huang et al. IBD skin manifestations

Studies have implicated several immune pathways in cutaneous

disorders of IBD. In addition to the two established effector CD4

T-cells, the Th1 (cell-mediated) and Th2 (humoral), a third novel

T-helper cell has been described. Termed Th17 cells for its ability

to produce interleukin-17 (IL-17), these cells have been described

in various systemic, inﬂammatory, and autoimmune skin disor-

ders including psoriasis, contact or atopic dermatitis, scleroderma,

systemic lupus erythematosus (SLE), Bechet’s disease, and IBD

(Asarch et al., 2008). This discovery brings to light new treatment

targets for dermatologic disorders in the IBD population.

Classically, CD has been considered to be mediated by Th1

pathways with elevated levels of IFN-γand IL-12. On the other

hand, UC has been associated with Th2 mediated pathways with

elevated levels of IL-5 and IL-13 (van Wijk and Cheroutre, 2010).

However, recent evidence from mouse models challenges these

viewpoints and suggests that IL-23, induced by Th17 produced

cytokines (IL-17 and IL-22, which are present in both CD and

UC), is one of the major players in the pathogenesis of IBD (Hue

et al., 2006). This IL-23 and Th17 pathway has been proposed as a

common pathway of the development of IBD (both CD and UC)

and other autoimmune diseases as well (Ahern et al., 2008;van

Wijk and Cheroutre, 2010;Abraham and Medzhitov, 2011;Lees

et al., 2011). Most recently, high levels of expression of IL-23 was

reported in a difﬁcult to treat PG lesion. Treatment with a mon-

oclonal antibody ustekinumab for 14 weeks resulted in marked

suppression of IL-23 expression and clinical resolution of the PG

lesion (Guenova et al., 2011).

CLASSIFICATION

The cutaneous manifestations of IBD have been classiﬁed into the

following categories according to pathogenesis (Tab l e 1 ;Danese

et al., 2005;Trost and McDonnell, 2005;Passarini et al., 2007;Mnif

et al., 2010;Levine and Burakoff, 2011):

A. Speciﬁc cutaneous manifestations or granulomatous cuta-

neous lesions with the same histological features as the

underlying bowel disease.

B. Reactive cutaneous manifestation of IBD with immunologi-

cal mechanisms triggered by common antigens shared by gut

bacteria and skin.

C. Cutaneous disorders or dermatosis associated with IBD.

D. Secondary cutaneous manifestations either due to complica-

tions of IBD or adverse effects of IBD treatments.

CUTANEOUS MANIFESTATIONS WITH SAME HISTOLOGICAL

FEATURES AS THE UNDERLYING IBD

CUTANEOUS MANIFESTATIONS

Cutaneous or metastatic CD is a rare complication deﬁned as the

occurrence of speciﬁc granulomatous cutaneous lesions with the

same histopathology (non-caseating granulomas with multinucle-

ated giant cells in the dermis surrounded by lymphocytes, plasma

cells, and eosinophils) as the intestinal lesions (Georgiou et al.,

2006). It occurs more frequently in adult females with established

intestinal CD (Georgiou et al., 2006). This disorder presents com-

monly as subcutaneous nodules or non-healing ulcers in the lower

extremities with rare localization to the genital (vulvar or testic-

ular) area; pseudocondyloma mimicking genital warts can also

occur (Georgiou et al., 2006;Larsen et al., 2010). Cutaneous CD

can be divided into two clinical forms: the genital form (56%)

which occurs more in children (characterized by edema, ery-

thema, ﬁssures or ulcers of the labia, scrotum, or penis), and the

non-genital form (44%) which most commonly affects the lower

extremities (38%), abdomen and trunk (24%), upper extremi-

ties (15%), face and lips (11%), and intertriginous areas (8%;

Ploysangam et al., 1997). It seems unrelated to the activity of the

bowel disease or its response to the IBD treatment (Chalvardjian

and Nethercott, 1982;Lebwohl et al., 1984;Lestre et al., 2010).

Various treatment modalities have been tried, such as steroids

(topical, intralesional, or systemic), sulfasalazine, metronidazole,

azathioprine, methotrexate, hyperbaric oxygen, and anti-TNF-α

antibodies (Sarna et al., 2008;Lestre et al., 2010). In cases with

severe cutaneous ulcers unresponsive to medical treatment, sur-

gical resection under oral administration of zinc sulfate may be

indicated (Georgiou et al., 2006).

PERIANAL MANIFESTATIONS

Perianal CD including er ythema, abscesses, ulcers, ﬁssures,and ﬁs-

tulas, occur in about 50% of CD patients at some point during their

clinical course (Danese et al., 2005). Perianal ﬁssures and ﬁstulas,

usually one of the most common skin lesions of IBD, occur mainly

in CD (20–60%) and rarely in UC (Roberts and Bunker, 1993;Leb-

wohl and Lebwohl, 1998). Perianal ﬁssures and ﬁstula are due to

direct involvement of skin and mucosa via a similar mechanism

as the bowel disease and may antedate the signs and symptoms of

bowel disease by several years (Figure 1;Ploysangam et al., 1997;

Lebwohl and Lebwohl, 1998). Fissures are usually painless and

located posteriorly, whereas ﬁstulas manifest either as a cryptog-

landular infection or as a secondary complication of anal ﬁssures.

Fistulas can be internal or entero-cutaneous and can undermine

ulcers and destroy the anal sphincter (Danese et al., 2005).

The recommended treatment of perianal ﬁssures is topical

application of glyceryl trinitrate (nitroglycerine) ointment and in

some cases this is followed by Botox injections into the affected

anal sphincter area (Jonas and Scholeﬁeld,2001). In cases with only

limited response to these compounds,calcium channel antagonists

(diltiazem) or lateral internal sphincterotomy may be indicated

(Fleshner et al., 1995;Singh et al., 2009). For perianal ﬁstulas,

combined medical and surgical therapies offer the best chance

for success (Lewis and Maron, 2010). Medical treatments include

antibiotics (metronidazole, ciproﬂoxacin), immunosuppressants

(azathioprine, 6-MP, cyclosporine, and tacrolimus), and inﬂix-

imab (Safar and Sands, 2007;Lewis and Maron, 2010). Surgery

include ﬁstulotomy for low ﬁstulae (below the dentate line),

advance ﬂap or ﬁstula plug for high ﬁstulae (above dentate line),

proctectomy with colostomy for severe perianal disease with rectal

involvement (Georgiou et al., 2006;Safar and Sands, 2007;Lewis

and Maron, 2010).

OROFACIAL MANIFESTATIONS

Orofacial CD may antedate the typical bowel symptoms by sev-

eral months to years. Its presentation and severity do not always

correlate with the activity of the underlying bowel disease. Orofa-

cial involvement occurs in 5–20% of CD patients and can present

as: aphthous stomatitis, pyostomatitis vegetans, angular cheilitis

Frontiers in Physiology | Gastrointestinal Sciences February 2012 | Volume 3 | Article 13 | 2

Huang et al. IBD skin manifestations

Table 1 | Summary table of cutaneous manifestations of IBD.

Cutaneous

manifestation

Presentation Incidence Pathogenesis or proposed mechanism

CD UC

SPECIFIC CUTANEOUS MANIFESTATIONSWITH THE SAME HISTOLOGICAL FEATURES AS THE UNDERLYING IBD

Orofacial:

aphthous

stomatitis, ulcers

Symptoms: round to oval shaped, can take

2–4 weeks to heal and may frequently scar

depending on size

10% 4% CD: non-caseating granuloma with similar mecha-

nism to underlying bowel pathology

Location: buccal mucosa and lips. UC: unclear

Perianal: ﬁssures,

ﬁstulas

Fissures: painless, located posteriorly 50% (≥1

episode)

Rare Direct local involvement of skin and mucosa by

underlying bowel disease

Fistulas: internal or entero-cutaneous, can

destroy the anal sphincter

Metastatic Symptoms: subcutaneous nodules or

non-healing ulcers

Rare Very rare Speciﬁc granulomatous cutaneous lesions with the

same histopathology (non-caseating granulomas

with multinucleated giant cells in the dermis) as the

intestinal lesions

Location: genital (more common in children) vs.

non-genital (more commonly affects lower

extremities, abdomen, and trunk)

Affects: adult/female predilection

REACTIVE CUTANEOUS MANIFESTATIONSWITH IMMUNOLOGICAL MECHANISMS RELATEDTO THE UNDERLYING IBD

Erythema

nodosum

Symptoms: painful, tender, warm nodules with

a bruise-like appearance

4–15% 3–10% Panniculitis, perivascular deposits of immunoglob-

ulins, and complement suggesting mechanism

related to abnormal immunological response of

common antigens between bowel bacteria and skin

Location: typically lower extremities

Affects: female predilection

Pyoderma

gangrenosum

Symptoms: non-infectious nodules that develop

into deep and painful ulcers. Often debilitating

1–2% 5–12% A type of neutrophilic dermatosis

Location: lower extremities, peristomal lesions Altered immune response (cross-reacting autoanti-

bodies to common antigens in the gut and skin),

over-expression of pro-inﬂammatory cytokines (IL-8,

IL-16, TNF-α), and neutrophil chemotaxis

Affects: female predilection Pathergy: exaggerated response of skin to local

trauma

Sweet’s

syndrome (SS)

Symptoms: fever, peripheral neutrophilia, tender

nodules/papules

Rare UC >CD A type of neutrophilic dermatosis

Location: upper limbs, face, neck. Can be

difﬁcult to distinguish from EN if affecting lower

extremities

Altered immune response (cross-reacting autoanti-

bodies)

Affects: adult/female predilection ANCA, G-CSF, or other cytokines in activation, mat-

uration, and chemotaxis of neutrophils

Bowel-associated

dermatosis–

arthritis

syndrome

(BADAS)

Symptoms: erythematous macules developing

into painful papules and pustules over 1–2 days.

Usually resolve in 1–2weeks, but can recur

every 1–6weeks. Temporally dependent on IBD

activity. Associated with fever, malaise,

abdominal pain, arthralgias

Rare UC >CD A type of neutrophilic dermatosis

Location: upper chest, arms, legs Overgrowth of gut bacteria resulting in production

of antibodies to gut bacteria antigen (peptidoglycan)

which cross-reacts with skin and joints

PDV, PSV, PPV PDV: pustules in skin folds (axillary, inguinal

regions)

Rare UC >CD Unclear, but possible related to cross-reacting anti-

gens between the bowel and skin

PSV: hyperplastic folds of buccal and labial

mucosa that progress to shallow ulcers

PPV: variants of PDV and PSV. speciﬁc marker of

IBD

Affects: adult/Caucasian/male predilection

(Continued)

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 3

Huang et al. IBD skin manifestations

Table 1 | Continued

Cutaneous

manifestation

Presentation Incidence Pathogenesis or proposed mechanism

CD UC

Leukocytoclastic

vasculitis

Symptoms: ranges from palpable purpura to

necrotic ulcers. In CD, can occur during

remission or exacerbation. In UC, precedes

onset of bowel disease.

Rare UC >CD Hypersensitivity vasculitis of small vessels due to

deposition of immune complexes

CUTANEOUS DISORDERS OR DERMATOSIS ASSOCIATEDWITH IBD

Psoriasis Symptoms: pruritic and irritated scaly patches.

Can be associated with nail changes, arthritis

11.2% 5.7% Genetic (HLA linkage) or Immunologic related mech-

anisms

Location: elbows, knees, trunk, but can occur

anywhere

Secondary

amyloidosis

Symptoms: pruritic rash due to deposits of

amyloid in the skin

0.9% 0.07% Type AA Amyloidosis, reactive systemic amyloidosis

associated with chronic inﬂammation

Vitiligo Symptoms: irregular white patches of skin Rare UC >CD Related to autoimmune or HLA linkage mechanisms

Location: face, elbows, knees, hands, feet,

genitals

Acquired

epidermolysis

bullosa

Symptoms: sub-epidermal blisters of the skin

and mucous membranes

Rare UC >CD Unclear, but related to autoantibodies to type VII

collagen in the skin and gut

SECONDARY CUTANEOUS MANIFESTATIONS EITHER DUETO COMPLICATIONS OF IBD OR ADVERSE EFFECTS OF IBDTREATMENTS

Zinc deﬁciency

(acrodermatitis

enteropathica)

Symptoms: erythematous patches and plaques

that progress to crusted vesicles, bullae, or

pustules

40% No

difference

compared

to control

Reduced mucosa availability for absorption and

chronic diarrhea

Location: mouth, anus, limbs, ﬁngers, scalp

Iron deﬁciency

anemia

Symptoms: koilonychias, angular cheilitis, pale

skin

39% 81% Malabsorption of iron and chronic intestinal bleeding

Essential fatty

acid deﬁciency

Symptoms: Xeroderma, dry skin, unspeciﬁc

eczema

CD >UC UC <CD Malabsorption

Corticosteroid

usage

Symptoms: corticosteroid induced acne Common Common Increased sebaceous gland activity

Affects: younger patients

Anti-TNF-αagents Symptoms: anti-TNF αagent induced psoriasis Total of 15

cases

described

To t al o f

three cases

described

Over-expression of IFN-αcausing predisposition to

psoriasis

and ulceration, mucosal nodularity (cobblestoning of the buccal

mucosa), nodules of gingival and alveolar mucosa, and indurated

ﬁssuring of lower lips (Trost and McDonnell, 2005;Georgiou et

al., 2006). Biopsy of the lesions in CD patients, although rarely

required, can reveal non-caseating granulomas similar to bowel

lesions.

Aphthous stomatitis or ulcers, typically seen in the buccal

mucosa and lips, consist of oral ulcers and are more commonin CD

(10%) than UC (4%; Vavricka et al., 2011). Minor aphthous ulcers

are small, shallow, round to oval shaped, have a grayish base, and

can be painful, but heal within 2 weeks without scarring (Figure 2).

On the other hand, major recurrent ulcers are larger, can last for

6 weeks, and frequently scar (Ship, 1996;Timani and Mutasim,

2008). A study showed that a majority of patients with multi-

ple aphthous ulcers had underlying IBD (Letsinger et al., 2005).

The pathogenesis of aphthous stomatitis and UC is still unclear.

Studies have not been successful in proving that these ulcers are

secondary to vitamin deﬁciencies as the lesions do not typically

improve with vitamin therapy (Basu and Asquith, 1980). Apht-

hous stomatitis occurs more often in active as opposed to inactive

IBD disease: 17.1 vs. 8.6% in CD, 4.1 vs. 3% in UC, but the latter

did not reach clinical signiﬁcance (Vavricka et al., 2011). Other

studies suggest that recurrent aphthous stomatitis and symptom

onset often parallel UC disease activity (Timani and Mutasim,

2008). Treatment of aphthous stomatitis is symptomatic and con-

sists of topical anesthetics such as viscous xylocaine, steroid elixirs,

or topical steroids. Systemic steroids are used for severe or refrac-

tory cases (Basu and Asquith, 1980;Trost and McDonnell, 2005;

Timani and Mutasim, 2008;Levine and Burakoff, 2011). For sec-

ondary bacterial superinfections, topical antibiotics can be used

although they are rarely required (Levine and Burakoff, 2011).

For orofacial CD, the treatment should be directed at the local

lesion and underlying systemic disease. For more severe or refrac-

tory orofacial CD, treatment should include systemic steroids,

immunomodulators, and anti-TNF-αtherapy (Quezada et al.,

2009).

Frontiers in Physiology | Gastrointestinal Sciences February 2012 | Volume 3 | Article 13 | 4

Huang et al. IBD skin manifestations

REACTIVE CUTANEOUS MANIFESTATIONS OF IBD

ERYTHEMA NODOSUM

Erythema nodosum, the most common cutaneous manifestation

of IBD, affects about 3–10% of UC and 4–15% of CD patients

(Lebwohl and Lebwohl, 1998;Georgiou et al., 2006;Timani and

Mutasim, 2008;Vavricka et al., 2011). Among patients with IBD,

EN has been found to affect 1.9% of females compared to 0.7% of

males (Turkcapar et al., 2006). A prospective study of 50 patients

FIGURE1|Perianal ﬁssure in a patient with IBD. Note the longitudinal

tear pattern in the anoderm.

with EN found that only 4% were eventually diagnosed with IBD

showing that EN rarely precedes the initial diagnosis of IBD (Mert

et al., 2004;Trost and McDonnell, 2005;Weinstein et al., 2005).

EN is often associated with systemic symptoms of fevers, chills,

arthralgias, or arthritis. Arthralgias and arthritis are rare in chil-

dren, but in adults they can antedate the occurrence of EN lesions

by weeks to months (Lebwohl and Lebwohl, 1998;Berkowitz and

Lebwohl, 2000). Typical EN lesions present as painful, tender,

warm nodules (1–5 cm in diameter), and raised bluish-red sub-

cutaneous lesions or plaques located on the extensor surfaces of

extremities, predominantly on the anterior surface of the lower

extremities (Figure 3;Mir-Madjlessi et al., 1985;Evans and Pardi,

2007;Timani and Mutasim,2008;Vavricka et al., 2011). These skin

nodules are non-ulcerating, palpable, and can resemble a bruise

on the skin, but are not always easily visible (Timani and Mutasim,

2008;Levine and Burakoff, 2011). EN can occur in multiple loca-

tions simultaneously and recurrence rate is approximately 20%

(Freeman, 2005).

Biopsy is generally not necessary as the diagnosis of EN may

be conﬁrmed based on the clinical presentation (Agrawal et al.,

2007). The histology of EN shows lympho-histocytic inﬁltrate of

lower dermis and focal panniculitis (Danese et al., 2005;Larsen

et al., 2010). Panniculitis is inﬂammation of the subcutaneous fat

and thus EN can occur wherever subcutaneous fat is present. The

most common site is the pretibial or shin area, but the knees,

ankles, arms, or trunk can also be affected (Levine and Burakoff,

2011). Direct immunoﬂuorescence of EN lesions reveal perivas-

cular deposits of immunoglobulins and complement, suggesting

that the pathogenesis of reactive cutaneous manifestation of IBD is

due to the abnormal immunological response of common antigens

between bowel bacteria and skin (Veloso, 1990;Fava and Danese,

FIGURE 2 | Aphthous stomatitis of the oral mucosa. Note the erythematous ring around the yellow to gray colored ulceration in this minor aphthous

stomatitis.

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 5

Huang et al. IBD skin manifestations

FIGURE 3 | Erythema nodosum manifested as erythematous nodules

of the skin. These lesions are often painful and assume a bruise-like

appearance.

2011;Khor et al., 2011). EN lesions have been noted to be corre-

lated with the underlying disease activity and worsened with colitis

ﬂares (Timani and Mutasim,2008). Typically, the time between UC

diagnosis and appearance of EN is about 5 years (Mir-Madjlessi

et al., 1985). EN in CD patients is mostly associated with colonic

involvement (Georgiou et al., 2006).

Since EN lesions mirror bowel disease activity and ﬂare up,

treatments targeting underlying IBD disease and ﬂare up always

leads to the remission of the cutaneous lesion (Orchard, 2003).

However, in situations where lesions occur during the quies-

cent phase, low doses of oral steroids can lead to rapid remis-

sion of the cutaneous lesions in most cases (Georgiou et al.,

2006). Other effective alternatives include NSAIDs, potassium

iodide, colchicine, dapsone, and immunosuppressants, such as

cyclosporine, thalidomide, etc. In recalcitrant cases, inﬂiximab has

been used with successful results (Kaufman et al., 2005). In gen-

eral, EN patients have a shorter time to remission (approximately

5 weeks) than do PG patients (Tromm et al., 2001;Timani and

Mutasim, 2008).

PYODERMA GANGRENOSUM

After EN (3–8%), PG represents the second most common cuta-

neous manifestation of IBD (1–3%), but PG is also the most severe

and debilitating (Danese et al., 2005;Georgiou et al., 2006). PG is

more common in UC (5–12%) than CD (1–2%) and like EN, some

studies have shown a female predilection (Bernstein et al., 2001;

Trost and McDonnell, 2005). PG was ﬁrst described in 1930 by

Brunsting as necrotic ulcers containing purulent material (usually

sterile on culture) with expanding borders of erythema (Newell

and Malkinson, 1982). The non-infectious pustules and nodules

eventually expand outward and develop into painful deep ulcers

with undermined wound edges (Callen, 1998;Farhi and Wallach,

2008). The ulcer has sharply circumscribed and demarcated bor-

ders with a necrotic yellowish base. The ulcers can be single or

multiple, unilateral or bilateral, and can range in size from sev-

eral centimeters to the surface of an entire limb. Other than

the classical ulcerative form, PG may also occur in three other

forms: the pustular form (multiple painful pustules with halo),

bullous form (bullae which rapidly transform into painful ero-

sions and necrotic ulcers), and vegetans form (well-demarcated

shallow ulcer, which then gradually transform into an exophytic

lesion; Georgiou et al., 2006). PG usually occurs on the extensor

surface of the legs, but can appear anywhere on the skin, most

noticeably on the abdominal wall adjacent to a postsurgical stoma

(Lebwohl and Lebwohl, 1998). Peristomal PG lesions occur from

2 weeks to 3 years after ostomy creation and they typically rapidly

evolve from small, erythematous pustules to deep ulcers within

hours to days (Cairns et al., 1994). Pathergy, the proposed mech-

anism behind this occurrence, is characterized by an exaggerated

physiological response of skin lesions that develops secondary to

local trauma and has been reported in approximately 30% of cases

of PG (Callen, 1998;Blitz and Rudikoff, 2001;Ardizzone et al.,

2008). The type of trauma can range from postsurgical wounds to

minor injuries as non-traumatic as needle sticks from venipunc-

ture (Levine and Burakoff, 2011). This is the reason that PG is

worsened with debridement and occurs more often on the leg,

around stomas, or around skin biopsy sites (Figure 4). In CD

patients, PG is often associated with colonic involvement and is

usually diagnosed approximately 10 years after the initial diag-

nosis of UC (Mir-Madjlessi et al., 1985). Compared to EN, PG

often takes a more prolonged course and approximately 35% of

patients will experience relapse of PG (Rothfuss et al., 2006). Diag-

nosis of PG is usually clinical, but skin biopsy may be necessary

for conﬁrmation. PG is classiﬁed as a type of neutrophilic der-

matosis in which the inﬂammatory inﬁltrate seen on microscopic

examination shows dense dermal neutrophilic inﬁltrates without

any evidence of infection, which was described by some as sterile

abscesses (Nischal and Khopkar, 2007;Timani and Mutasim, 2008;

Cohen, 2009;Larsen et al., 2010).

The pathogenesis of PG in IBD is proposed to be an abnormal

immune response with cross-reacting autoantibodies directed at

common antigens in the bowel and skin (Crowson et al., 2003;

Feliciani et al., 2009). It is classiﬁed as one of the neutrophilic

dermatosis. Other factors such as neutrophil dysfunction, abnor-

mal T-cell response, and over-expression of pro-inﬂammatory

cytokines such as IL-8, IL-16, IL-17, and TNF-αhave also been

proposed as mechanisms in the pathogenesis of PG (Feliciani et al.,

2009;Marzano et al., 2010). A case report has implicated the IL-23

and TH17 axis as being responsible for a PG lesion that subse-

quently resolved with a monoclonal antibody targeted at inhibiting

IL-23 expression (Guenova et al., 2011).

While EN usually correlates with IBD activity, PG correlation

with IBD activity is controversial as there are much fewer PG

cases. In a study of 14 patients with UC, there was no temporal

Frontiers in Physiology | Gastrointestinal Sciences February 2012 | Volume 3 | Article 13 | 6

Huang et al. IBD skin manifestations

FIGURE4|Pyoderma gangrenosum can start as small pustules that as they progress form larger and deeper ulcers. Classically, the borders of the

lesions are mucopurulent and purple. Example of pyoderma gangrenosum lesion involving the leg (A) and parastoma (B).

relationship between the onset of bowel ﬂares and the course of

PG lesions (Thornton et al., 1980). In a study of 34 IBD patients,

PG was diagnosed in 50% of UC and 75% of CD when underlying

bowel disease was active (Levitt et al., 1991). In a study of 986

patients hospitalized for IBD, six patients (0.6%) had PG (Men-

achem and Gotsman, 2004). Of these six patients, PG appeared

6.5 years on average after the diagnosis of IBD. The majority of

patients had active colitis at the onset of PG and half of these

patients experienced other associated EIMs, including sacroili-

itis, peripheral arthritis, and EN. However, PG does not always

respond to treatment of underlying bowel disease and response

to bowel resection is unpredictable (Levitt et al., 1991;Menachem

and Gotsman, 2004). Further studies need to be done to investi-

gate the relationship between the onset of PG and the underlying

IBD activity.

When compared to EN, PG lesions tend to be more severe

and resistant to therapy thus necessitating more aggressive ther-

apy. Furthermore, PG patients appear to beneﬁt less than EN

patients from colectomy (Goudet et al., 2001). In fact, about 30%

of patients with PG do not experience improvement of their lesions

with treatment of the underlying IBD (Mir-Madjlessi et al., 1985).

In general, treatment of PG includes a combination of wound

care, topical medications,antibiotics for secondary infections, and

treatment targeted at the underlying colitis (Danese et al., 2005).

Although no individual therapy is universally effective, treatment

of PG usually involves a regimen of systemic, cutaneous, and/or

intralesional medications (Timani and Mutasim, 2008;Cohen,

2009).

Local wound care includes sterile saline lavages, topical antibac-

terial creams, and hydrocolloid dressings. Topical treatments,

such as highly potent steroids with occlusive dressings, nicotine,

benzoyl peroxide, sodium cromoglycate, hydrogen peroxide, 5-

aminosalicylic acid, and tacrolimus have shown varying success

rates (Trost and McDonnell, 2005;Georgiou et al., 2006;Callen

and Jackson, 2007). Although intralesional steroid injections can

be effective in small or localized disease, the mainstay of treatment

remains systemic steroids especially for multiple lesions or gener-

alized form of PG (Georgiou et al., 2006;Timani and Mutasim,

2008). Systemic steroid therapy typically compromises of high

dose of oral prednisone around 40–120 mg/day for the average

adult initially until lesional clearance, followed by a low mainte-

nance dose that is used to maintain remission (Crowson et al.,

2003). However, many alternatives exist. Assuming no concurrent

infection, mainstay therapy includes systemic corticosteroids at

dosages from 0.5 to 2 mg/kg/day and cyclosporine at initial dosages

of 2–5 mg/kg/day (Wollina, 2002;Timani and Mutasim, 2008).

Keeping the goal trough serum levels of cyclosporine between

150 and 350 ng/ml has been shown to have good outcomes on

PG healing (Curley et al., 1985;Matis et al., 1992;Cohen, 2009;

Turner et al., 2010). Other agents including minocycline, sul-

fasalazine, azathioprine, dapsone, potassium iodide, intravenous

immunoglobulin, intravenous steroids, mycophenolate mofetil,

cyclophosphamide, methotrexate, plasmapheresis, and hyperbaric

oxygen treatment have been employed with various success rates

(Wasserteil et al., 1992;Georgiou et al., 2006;Tutrone et al., 2007;

Timani and Mutasim, 2008;Cohen, 2009). Anti-TNF-αagents

including etanercept, inﬂiximab, and adalimumab have also been

reported to treat PG lesions effectively and are used in refractory

cases of PG (McGowan et al., 2004;Brooklyn et al.,2006;Alkhouri

et al., 2009).

When treating peristomal PG lesions, about two-thirds (12/17)

of patients respond to systemic high dose steroids and local wound

care, while the rest require additional therapy or long-term med-

ical management. A study showed that no patients were success-

fully treated with stomal revision (Cairns et al., 1994). To avoid

pathergy, unnecessary surgical interventions should be avoided.

However, surgery can be considered if medical therapies are not

successful. Proper timing of the surgery to avoid active phase of

the disease and appropriate administration of immunosuppres-

sants are essential for optimal long-term wound stabilization or

remission (Wollina, 2002;Trost and McDonnell,2005;Wittekindt

et al., 2007). For patients with extensive colitis and severe refrac-

tory PG lesions unresponsive to medical therapy, proctocolectomy

may be considered, but PG has been reported to relapse years after

proctocolectomy (Read, 1985;Levitt et al., 1991).

PYODERMATITIS VEGETANS, PYOSTOMATITIS VEGETANS,

PYODERMATITIS–PYOSTOMATITIS VEGETANS

Pyodermatitis vegetans (PDV), a rare skin manifestation of IBD

and often regarded as one of clinical forms of PG, has histopathol-

ogy similar to pyostomatitis vegetans (discussed below) but with

treatment similar to PG (Georgiou et al., 2006). PDV occurs

mainly in skin folds such as axillary or inguinal area, but can

also be present on the trunk or extremities. These lesions are

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 7

Huang et al. IBD skin manifestations

characterized by pustules that quickly rupture, forming erosions

with hemorrhagic ground, developing large raised (vegetating)

well-demarcated plaques with surrounding pustules (Georgiou et

al., 2006;Canpolat et al., 2011).

Pyostomatitis vegetans (PSV), a rare disorder of the oral

mucosa that is considered as the oral equivalent of PDV on cutis,

is relatively speciﬁc for IBD, particularly UC (Storwick et al., 1994;

Timani and Mutasim, 2008;Femiano et al., 2009). In contrast to

EN and PG which have been shown to have a female predilection,

there is a male predominance in PSV with a ratio ranging from

2:1 to 3:1 and the majority of cases occur in Caucasians (Femiano

et al., 2009;Ficarra et al., 2010). The pathogenesis of PSV is not

known yet, although abnormal immunological responses and/or

microbial factors are suggested (Kethu, 2006;Femiano et al., 2009;

Ficarra et al., 2010). Lesions are erythematous, thickened, and

hyperplastic folds of the buccal and labial mucosa with multi-

ple gray to yellow pustules, which progress to erosions forming

shallow, folded, and ﬁssured “snail tract” ulcers, due to degenera-

tion, ulceration, and suppuration of vegetating pustules (Femiano

et al., 2009). They often manifest before the diagnosis of IBD

(Hansen et al., 1983;Femiano et al., 2009). Lesions also occur

at labial attached gingiva, soft and hard palate, oral vestibule, and

tonsillar regions. They usually spare the tongue and ﬂoor of the

mouth (Femiano et al., 2009). Symptoms of burning and pain may

be present (Ficarra et al., 2010). Other than oral cavity, mucosal

membranes at the vaginal, nasal, and rarely periocular areas can

also be affected (Femiano et al., 2009). Peripheral eosinophilia has

been found in most cases reported and maybe a valuable aid for

the diagnosis of PV (Femiano et al., 2009). Histopathologically,

PSV is characterized by epithelial acanthosis and superﬁcial ulcer-

ation with intraepithelial and/or subepithelial micro abscesses

containing numerous eosinophils and neutrophils with underly-

ing connective tissues containing dense lymphocytic and plasma

cell inﬁltrate (Femiano et al., 2009;Ficarra et al., 2010).

Pyodermatitis vegetans was ﬁrst reported by Hallopeau (1898)

when he described two patients with unusual pustular dermatosis

and oral lesions for which he named pyodermite vegetans (Hallo-

peau, 1898). McCarthy (1949) proposed the term “pyostomatitis

vegetans” after he observed similar lesions isolated in the oral cav-

ity (McCarthy, 1949; Femiano et al., 2009). Recently these two

entities are considered to be variants of the same disease termed

pyodermatitis–pyostomatitis vegetans (PPV; Ficarra et al., 2010).

PDV and PSV (or together as a group PPV) are rare cutaneous

manifestation of IBD (Storwick et al., 1994;Femiano et al., 2009).

In general, bowel disease antedate oral involvement by several years

(Leibovitch et al., 2005). The rash of PPV has been reported to cor-

relate with underlying bowel disease activity (Ayangco et al., 2002;

Kitayama et al., 2010). The pathogenesis of PSV, PDV, or PPV is

not clear,but has been hypothesized to be due to aberrant immune

responses in IBD to cross-reacting antigens in the skin and bowel

resulting in mucocutaneous manifestations (Femiano et al.,2009).

Employing immunosuppressants and systemic steroids to treat

PSV has variable efﬁcacy for treating symptoms and maintaining

remission (Timani and Mutasim, 2008). Local therapies includ-

ing hydrogen peroxide, topical steroids, and antibacterial mouth-

washes are usually not effective in controlling disease activity. A

case report demonstrated successful PSV remission with topical

ﬂuocinonide gel, but the patient relapsed and ultimately required

total colectomy to achieve and maintain remission (Calobrisi et al.,

1995;Femiano et al., 2009). In fact, subtotal colectomy in a patient

with UC resulted in the development of PPV and relapse of bowel

disease 5 years after surgery (Kitayama et al., 2010).

NEUTROPHILIC DERMATOSES

Neutrophilic dermatoses include Sweet’s syndrome (SS) and

bowel-associated dermatosis–arthritis syndrome (BADAS). SS,

ﬁrst described by R. D. Sweet and named after him, is character-

ized by the abrupt onset of tender and red to purple inﬂammatory

nodules or papules that coalesce to form plaques, affecting the

upper limbs, face, or neck. In addition to painful and edema-

tous nodules and plaques, vesicles, bullae, or pustules may also

be present (Georgiou et al., 2006;Nischal and Khopkar, 2007).

Patients with colonic disease and females between the ages of 30

and 50 have increased risk for developing SS (Ardizzone et al.,

2008;Timani and Mutasim, 2008). SS is also known as acute neu-

trophilic dermatosis as it is typically accompanied by fever and

peripheral neutrophilia with >70% neutrophils while cutaneous

lesions usually show dense aseptic neutrophilic inﬁltration (Geor-

giou et al., 2006). These lesions are tender and non-pruritic in

nature, but can be difﬁcult to distinguish from EN when they affect

the lower extremities (Guhl and Garcia-Diez, 2008). Skin biopsy,

which shows neutrophilic inﬁltrates in the reticular dermis, can be

helpful in reaching a diagnosis when there is doubt (Kemmett and

Hunter, 1990;Georgiou et al., 2006;Timani and Mutasim, 2008;

Cohen, 2009). Patients may also experience fatigue,headache, and

other non-speciﬁc constitutional symptoms. SS can affect extra-

cutaneous organ systems including, but are not limited to the

musculoskeletal, ocular, hepatic, pulmonary, and renal systems

(Cohen et al., 1988).

Although the pathogenesis is unclear, SS usually develops as a

reactive response to some type of underlying systemic disease, such

as infection, malignancy, medications, or IBD (Vij et al., 2010). In

fact, studies have shown that patients with SS have some type of

underlying systemic disease in 50% of cases and an underlying

malignancy in 20% of cases (Kemmett and Hunter, 1990;Souissi

et al., 2007). UC and CD are the most common systemic diseases

associated with SS (Timani and Mutasim, 2008). SS is associated

with active bowel disease (67–80%; Georgiou et al., 2006;Ardiz-

zone et al., 2008). The onset of symptoms from SS usually occur

after the initial diagnosis of IBD, but may antedate the onset of

IBD (21%) and has also been reported to occur 3 months after

proctocolectomy in patients with UC (Darvay, 1996;Ardizzone

et al., 2008). Similar to other reactive manifestations of IBD, the

pathogenesis of SS has been hypothesized to be related to an altered

immune response to common antigens in the skin and gut bac-

teria (Ali and Duerksen, 2008). Furthermore, ANCA and G-CSF

or other cytokines have been proposed to play a pathogenetic role

in activation, maturation, and chemotaxis of neutrophils in SS

(Diaz-Peromingo et al., 2001;Cohen and Kurzrock, 2003).

First line treatment of SS involves systemic steroids and studies

have shown marked symptom improvement with a 6week steroid

course (Cohen et al., 1988;Souissi et al., 2007).When dealing with

localized disease, topical, or intralesional steroids are sometimes

used with good effects (Timani and Mutasim, 2008). However,

Frontiers in Physiology | Gastrointestinal Sciences February 2012 | Volume 3 | Article 13 | 8

Huang et al. IBD skin manifestations

recurrence of SS is relatively common with as many as 1/3 of

patients re-experiencing symptoms despite treatment (Kemmett

and Hunter, 1990). Skin lesions that have not been treated have

been documented to heal on their own, but can leave behind

scars (Kemmett and Hunter, 1990;Timani and Mutasim, 2008).

Other ﬁrst line options for treatment include colchicine and potas-

sium iodide. Other agents such as indomethacin and clofazimine

can be used if ﬁrst line agents are ineffective or cannot be toler-

ated. (Cohen and Kurzrock, 2002;Cohen, 2009). Treatments with

immunosuppressants and anti-TNF-αhave been reported to be

successful in SS (Ali and Duerksen, 2008;Cohen, 2009;Larsen

et al., 2010).

The BADAS, previously named as bowel bypass syndrome as

it was originally reported to occur in up to 20% of patients after

laparoscopic jejuno-ileal bypass surgery for obesity, can occur as a

complication after various intestinal surgeries, in patients with

diverticulitis or appendicitis, and in patients with IBD (Geor-

giou et al., 2006;Ashok and Kiely, 2007;Patton et al., 2009;Tu

et al., 2011). The clinical characteristics of BADAS syndrome are

recurrent episodes of fever, malaise, abdominal pain, arthritis,

and polyarthralgias of the upper extremities involving the asym-

metric large joints and interphalangeal joints of the ﬁngers with

accompanying tenosynovitis, and by the appearance of character-

istic cutaneous lesions (Ashok and Kiely, 2007). These cutaneous

lesions consist of erythematous macules (3–10 mm in diameter),

developing into edematous and painful papules with central asep-

tic vesicles or pustules (2–4 mm in diameter) over the subsequent

1–2 days, which are located on the upper chest and arms (usually

on the deltoid muscle region) and EN-like lesions in the legs. These

maculopapular rashes occur in crops, resolve within 1–2 weeks

without leaving scars and can recur every 1–6 weeks. These cuta-

neous lesions are temporally dependent on IBD activity (Ashok

and Kiely, 2007;Patton et al., 2009).

The histology of BADAS is characterized by perivascular neu-

trophilic, mononuclear, and eosinophilic (depending on the stage

of the lesions) inﬁltrate with dermal edema, intraepidermal pus-

tules, minimal alterations of the walls of capillaries and venules

without the features of leukocytoclastic vasculitis or ﬁbrinoid

necrosis (Georgiou et al., 2006;Nischal and Khopkar, 2007). Sim-

ilar to PG and SS, BADAS has been classiﬁed in the spectrum

of aseptic neutrophilic dermatoses with histopathology showing

dense neutrophil inﬁltration and no destruction of vessel walls

(Nischal and Khopkar, 2007;Patton et al., 2009). By immuno-

ﬂuorescence staining, the deposition of immunoglobulins and

complement has frequently been observed at the dermo-epidermal

junction. The pathogenesis of BADAS is hypothesized to be due to

immune complex-mediated vessel damage, followed by increased

migration and accumulation of neutrophils in the perivascular

area (Jorizzo et al., 1984). The circulating immune complexes

are believed to form due to an immunological response against

antigenic bacterial peptidoglycans in the gut, with subsequent

deposition in the skin and joints (Jorizzo et al., 1984;Nischal and

Khopkar, 2007;Patton et al., 2009). It is theorized that overgrowth

of bacteria, such as seen in active IBD, diverticulitis, appendici-

tis, blind loop after bypass surgery, or in the inﬂamed bowel

segment after surgery, result in inﬂammation, and the forma-

tion of abnormal immunological responses to bacterial antigens

especially peptidoglycans (Georgiou et al., 2006;Patton et al.,

2009). Similar pathophysiology is also thought to involve the cuta-

neous manifestations of EN, PG, and SS (Georgiou et al., 2006;

Nischal and Khopkar, 2007).

The management of the BADAS includes the treatment of

the underlying bowel disorder and the administration of sys-

temic steroids and antibiotics for inhibition of bacterial over-

growth (tetracycline, metronidazole, ciproﬂoxacin), although the

response to these antibiotics are inconsistent (Georgiou et al.,2006;

Patton et al., 2009). NSAIDs may be used to alleviate arthralgias or

arthritis, but the potential toxicity of NSAIDs on IBD should make

the decision to use NSAIDs based on weighing the risk-beneﬁt

ratio for each individual patient (Singh et al., 2009). Other drugs

such as colchicine, dapsone,and sulfasalazine have been tried with

variable successful rates (Georgiou et al., 2006).

LEUKOCYTOCLASTIC VASCULITIS

Leukocytoclastic vasculitis, one of the rare cutaneous manifes-

tation of IBD, is characterized histopathologically by neutrophil

inﬁltration and nuclear debris of inﬂamed postcapillary venules

with endothelial enlargement and ﬁbrinoid necrosis (Akbulut

et al., 2008). The skin presentation ranges from palpable purpura

(mediated by deposition of immune complexes in postcapillary

venules) on the lower extremities and ankles to necrotic ulcers

(Tsiamoulos et al., 2008). Similar to other reactive cutaneous man-

ifestations of IBD, the pathogenesis of leukocytoclastic vasculitis

with histology showing hypersensitivity vasculitis of small vessels

is proposed to be circulating immune complexes (Mackel and Jor-

don, 1982;Iannone et al., 2003;Akbulut et al., 2008;Tsiamoulos

et al., 2008). In CD, leukocytoclastic vasculitis occurs not only

during the onset of bowel disease, but also during periods of exac-

erbation. On the other hand, in UC, leukocytoclastic vasculitis

most commonly precede the onset of bowel disease with a lag-

ging period ranging from 1 month to 2 years (Iannone et al., 2003;

Akbulut et al., 2008;Tsiamoulos et al., 2008). In most cases of

leukocytoclastic vasculitis, treating the underlying IBD results in

resolution of the lesions (Akbulut et al., 2008;Tsiamoulos et al.,

2008).

CUTANEOUS DISORDERS OR DERMATOSIS ASSOCIATED

WITH IBD

These disorders include hidradenitis suppurativa, phlebitis, ery-

thema multiforme, urticaria, lichen planus, secondary amyloido-

sis, and various autoimmune skin disorders, such as acquired

epidermolysis bullosa (blistering lesions of the knees, elbows,

hands, and feet), bullous pemphigoid, linear IgA bullous der-

matosis, vitiligo, and psoriasis (Georgiou et al., 2006;Levine and

Burakoff, 2011). Rarely has IBD been reported to be associated

with skin neoplasm such as Bowen’s disease and squamous cell

carcinoma, which require surgical excision (Georgiou et al., 2006).

Acquired epidermolysis bullosa or epidermolysis bullosa

acquisita (EBA) is characterized by autoantibodies to type VII

collagen (detected in both the skin and colon of normal individ-

uals), which was also detected in 13/19 CD and 4/31 UC patients

(Chen et al., 2002;Hoffmann and Kruis, 2004). In fact, EBA has

been reported to be most frequently (25%) associated with CD

(Hoffmann and Kruis, 2004). This ﬁnding suggests that chronic

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 9

Huang et al. IBD skin manifestations

inﬂammation in the intestine predisposed IBD patients to develop

autoantibodies against type VII collagen in the gut, which in turn

attacks the skin at the dermal–epidermal junction resulting in

the blistering skin lesions seen in EBA (Hundorfean et al., 2010).

Future research is needed to provide more insight in this hypoth-

esis. Compared to an incidence of 0.3% of vitiligo in the normal

population, the incidence of vitiligo is higher in CD (0.5%) and

UC (1.1%; Pashankar et al., 1999). The pathogenesis of vitiligo in

IBD has been proposed to be autoimmune or genetic HLA linkage

in nature (Pashankar et al., 1999;Quan et al., 2010). Secondary

amyloidosis is rare in IBD and occurs as a systemic response to

chronic inﬂammation. The systemic amyloidosis in IBD is type

AA amyloidosis and is more common in CD (0.9%) than UC

(0.07%) most likely as a result of a higher degree of inﬂammation

in CD (Sattianayagam et al., 2009).

The most frequently associated cutaneous disease is psoriasis

which occurs in 7–11% of the IBD population compared to 1–2%

of general population (Danese et al., 2005). In one study,psoriasis

was found to be more prevalent in CD (11.2%) than UC (5.7%;

Yates et al., 1982;Vavricka et al., 2011). The association of IBD with

psoriasis is believed to be both genetically and immunologically

related (Georgiou et al., 2006). In a recent study of 146 patients

with both IBD and psoriasis compared to a control of 146 patients

with only psoriasis, it was found that patients with both IBD and

psoriasis had signiﬁcantly higher rates of autoimmune thyroidi-

tis (6.8 vs.2.1%), hepatitis (6.2 vs. 0.7%), and diabetes (26.7 vs.

11.0%; Binus et al., 2011). Individuals with both IBD and psoriasis

also had signiﬁcantly higher CRPs, ESRs, and sero-negative arthri-

tis (41.1%) compared to individuals with only psoriasis. Certain

gene loci on chromosomes 3, 4, 6, and 16 are associated with both

CD and psoriasis (Georgiou et al., 2006). A recent study showed

that a striking overlap of loci between diseases of CD, UC, pso-

riasis, ankylosing spondylitis, and primary sclerosing cholangitis

(Cho and Brant, 2011). These studies suggest that genetic predis-

positions or HLA linkages for certain speciﬁc immune response

patterns and common inﬂammatory pathways may play an impor-

tant role in the association of these diseases (Georgiou et al., 2006;

Binus et al., 2011).

SECONDARY CUTANEOUS MANIFESTATIONS DUE TO

COMPLICATIONS OF IBD OR ITS TREATMENTS

MANIFESTATIONS SECONDARY TO MALNUTRITION AND

MALABSORPTION

Skin manifestations of IBD secondary to malnutrition and/or mal-

absorption include the acquired form of acrodermatitis entero-

pathica (zinc deﬁciency), pellagra (niacin deﬁciency), scurvy (vit-

amin C deﬁciency), purpura (vitamin C and K deﬁciency), stom-

atitis/glossitis/angular cheilitis (vitamin B deﬁciency), xeroderma,

or dry skin and unspeciﬁed eczema (essential fatty acid deﬁ-

ciency), hair and nail abnormalities (malabsorption of amino acid

and protein; Trost and McDonnell, 2005;Georgiou et al., 2006;

O’Sullivan and O’Morain, 2006). The acquired form of acroder-

matitis enteropathica, due to zinc deﬁciency, is the most common

nutritional-deﬁcient cutaneous manifestation of IBD and more

common in CD than UC (Dronﬁeld et al., 1977;McClain et al.,

1980;Danese et al., 2005). The skin lesions present as psoriasis

involving an erythematous patch and plaque, which may evolve

into crusted vesicles, bullae, or pustules. The lesions occur fre-

quently around the mouth, anus,limbs, ﬁngers, and scalp (Danese

et al., 2005;von Felbert and Hunziker, 2010). Adequate supple-

mentation of the deﬁcient nutrients or vitamins is the treatment

of choice. For example, acrodermatitis enteropathica is treated

with zinc sulfate 220 mg/day (Danese et al., 2005;Georgiou et al.,

2006).

SECONDARY CUTANEOUS MANIFESTATIONS DUE TO ADVERSE

EFFECTS OF IBD TREATMENT

Skin manifestations from adverse effects can result in a broad range

of secondary cutaneous manifestations, such as drug eruptions,

urticaria, angioedema, hair loss, lichen planus, erythema multi-

forme, bullous dermatosis/reaction, Stevens–Johnson syndrome,

acne, psoriasis and so on (Georgiou et al., 2006;Fiorino et al.,

2009). The following are examples of drugs used in IBD treat-

ments that can cause secondary cutaneous complications: 5-ASA,

metronidazole, ciproﬂoxacin, azathioprine, 6-MP, methotrexate,

cyclosporine, steroids, anti-TNF-αagents, etc. (Georgiou et al.,

2006;Passarini et al., 2007).

Anti-TNF-αagents have been used successfully in the treatment

of IBD and psoriasis, but when treating IBD, anti-TNF-αagents

such as inﬂiximab and adalimumab can paradoxically induce pso-

riasis lesions after the third or fourth infusion (Passarini et al.,

2007;Fiorino et al., 2009). The psoriasis lesions regressed after

withdrawing the anti-TNF-αagents in 16 out of 17 patients (Fior-

ino et al., 2009). Although there have only been 18 reported cases

of anti-TNF αinduced psoriasis in the IBD population, but clin-

icians should still be aware of this potential side effect (Fiorino

et al., 2009). It has been suggested that inhibition of TNF-αinduces

over-expression of cutaneous IFN-αwhich then causes predispo-

sition to psoriasis (Iborra et al., 2011). The treatment of psoriasis

induced by anti-TNF-αagents is cessation of the offending agents

and topical steroid therapy (Iborra et al., 2011).

CONCLUSION

The most common cutaneous manifestations of IBD are EN and

PG (Levine and Burakoff, 2011). All IBD patients should be closely

examined for skin manifestations as some skin lesions may be

related to IBD activity. Manifestation of one EIM increases the

risk of developing additional EIMs, and all EIMs affect both mor-

bidity and mortality in IBD (Monsen et al., 1990;Das, 1999;

Vavricka et al., 2011). Similar to other EIMs of IBD, skin lesions

may postdate, occur with, or antedate the onset of the underlying

disease process (Apgar, 1991). Since dermatological manifesta-

tions can precede bowel disease or bowel exacerbation, idiopathic

skin lesions such as EN, PG, recurrent multiple aphthous stom-

atitis, or PPV should alert clinicians to evaluate the possibility

of underlying IBD so that early diagnosis and intervention with

the appropriate therapy can be initiated (Levine and Burakoff,

2011).

ACKNOWLEDGMENTS

We thank the Cedars-Sinai IBD Center for helpful discussions. We

thank Cindy Ting for critical reading of the manuscript.

Frontiers in Physiology | Gastrointestinal Sciences February 2012 | Volume 3 | Article 13 | 10

Huang et al. IBD skin manifestations

REFERENCES

Abraham, C., and Medzhitov,R. (2011).

Interactions between the host innate

immune system and microbes in

inﬂammatory bowel disease. Gas-

troenterology 140, 1729–1737.

Adams, D. H., and Eksteen, B. (2006).

Aberrant homing of mucosal T cells

and extra-intestinal manifestations

of inﬂammatory bowel disease. Nat.

Rev. Immunol. 6, 244–251.

Agrawal, D., Rukkannagari, S., and

Kethu, S. (2007). Pathogenesis and

clinical approach to extraintesti-

nal manifestations of inﬂammatory

bowel disease. Minerva Gastroen-

terol. Dietol. 53,233–248.

Ahern, P. P., Izcue, A., Maloy, K. J., and

Powrie, F. (2008). The interleukin-

23 axis in intestinal inﬂammation.

Immunol. Rev. 226, 147–159.

Akbulut, S., Ozaslan, E., Topal, F.,

Albayrak, L., Kayhan, B., and Efe,

C. (2008). Ulcerative colitis pre-

senting as leukocytoclastic vasculitis

of skin. World J. Gastroenterol. 14,

2448–2450.

Ali, M., and Duerksen, D. R. (2008).

Ulcerative colitis and Sweet’s syn-

drome: a case report and review of

the literature. Can. J. Gastroenterol.

22, 296–298.

Alkhouri, N., Hupertz, V., and Mahajan,

L. (2009). Adalimumab treatment

for peristomal pyoderma gangreno-

sum associated with Crohn’s disease.

Inﬂamm. Bowel Dis. 15, 803–806.

Apgar, J. T. (1991). Newer aspects of

inﬂammatory bowel disease and its

cutaneous manifestations: a selec-

tive review. Semin. Dermatol. 10,

138–147.

Ardizzone, S., Puttini, P. S., Cassinotti,

A., and Porro, G. B. (2008). Extrain-

testinal manifestations of inﬂamma-

tory bowel disease. Dig. Liver Dis.

40(Suppl. 2), S253–S259.

Asarch, A., Barak, O., Loo, D. S., and

Gottlieb, A. B. (2008). Th17 cells:

a new therapeutic target in inﬂam-

matory dermatoses. J. Dermatolog.

Treat. 19, 318–326.

Ashok, D., and Kiely, P. (2007). Bowel

associated dermatosis – arthritis

syndrome: a case report. J. Med. Case

Reports 1, 81.

Ayangco,L., Rogers, R. S. III., and Sheri-

dan, P. J. (2002). Pyostomatitis veg-

etans as an early sign of reactivation

of Crohn’s disease: a case report. J.

Periodontol. 73, 1512–1516.

Basu, M. K., and Asquith, P. (1980).

Oral manifestations of inﬂamma-

tory bowel disease. Clin. Gastroen-

terol. 9, 307–321.

Berkowitz, E. Z., and Lebwohl, M.

(2000). Cutaneous manifestations

of inﬂammatory bowel disease. J.

Eur. Acad. Dermatol. Venereol. 14,

349–350.

Bernstein, C. N., Blanchard, J. F., Raw-

sthorne, P., and Yu, N. (2001). The

prevalence of extraintestinal diseases

in inﬂammatory bowel disease: a

population-based study. Am.J.Gas-

troenterol. 96, 1116–1122.

Binus, A. M., Han, J., Qamar, A. A.,

Mody,E. A., Holt,E. W., and Qureshi,

A. A. (2011). Associated comorbidi-

ties in psoriasis and inﬂammatory

bowel disease. J. Eur. Acad. Der-

matol. Venereol. doi: 10.1111/j.1468-

3083.2011.04153.x

Blitz, N. M., and Rudikoff, D. (2001).

Pyoderma gangrenosum. Mt. Sinai

J. Med. 68, 287–297.

Brooklyn, T. N., Dunnill, M. G., Shetty,

A., Bowden, J. J.,Williams, J. D., Grif-

ﬁths, C. E., Forbes, A., Greenwood,

R., and Probert, C. S. (2006). Inﬂix-

imab for the treatment of pyoderma

gangrenosum: a randomised, double

blind, placebo controlled trial. Gut

55, 505–509.

Cairns, B. A., Herbst, C. A., Sartor, B.

R., Briggaman, R. A., and Koruda,

M. J. (1994). Peristomal pyo-

derma gangrenosum and inﬂamma-

tory bowel disease. Arch. Surg. 129,

769–772.

Callen, J. P. (1998). Pyoderma gan-

grenosum. Lancet 351, 581–585.

Callen, J. P., and Jackson, J. M. (2007).

Pyoderma gangrenosum: an update.

Rheum. Dis. Clin. North Am. 33,

787–802, vi.

Calobrisi, S. D., Mutasim, D. F.,

and Mcdonald, J. S. (1995). Pyos-

tomatitis vegetans associated with

ulcerative colitis. Temporary clear-

ance with ﬂuocinonide gel and

complete remission after colec-

tomy. OralSurg.OralMed.Oral

Pathol. Oral Radiol. Endod. 79,

452–454.

Canpolat, F., Cemil, B. C., Yilmazer, D.,

Yesilli, O., and Eskioglu, F. (2011).

Pyoderma vegetans associated with

ulcerative colitis: a case with good

response to steroids. CaseRep.Der-

matol. 3, 80–84.

Chalvardjian, A., and Nethercott, J. R.

(1982). Cutaneous granulomatous

vasculitis associated with Crohn’s

disease. Cutis 30, 645–655.

Chen, M., O’toole, E. A., Sanghavi, J.,

Mahmud, N., Kelleher, D., Weir, D.,

Fairley, J. A., and Woodley, D. T.

(2002). The epidermolysis bullosa

acquisita antigen (type VII colla-

gen) is present in human colon and

patients with Crohn’s disease have

autoantibodies to type VII collagen.

J. Invest. Dermatol. 118, 1059–1064.

Cho, J. H., and Brant, S. R. (2011).

Recent insights into the genetics of

inﬂammatory bowel disease. Gas-

troenterology 140, 1704–1712.

Cohen, P. R. (2009). Neutrophilic der-

matoses: a review of current treat-

ment options. Am. J. Clin. Dermatol.

10, 301–312.

Cohen, P. R., and Kurzrock, R. (2002).

Sweet’s syndrome: a review of cur-

rent treatment options. Am. J. Clin.

Dermatol. 3, 117–131.

Cohen, P. R., and Kurzrock, R. (2003).

Sweet’s syndrome revisited: a review

of disease concepts. Int. J. Dermatol.

42, 761–778.

Cohen, P. R., Talpaz, M., and Kurzrock,

R. (1988). Malignancy-associated

Sweet’s syndrome: review of the

world literature. J. Clin. Oncol. 6,

1887–1897.

Crowson, A. N., Mihm, M. C. Jr., and

Magro, C. (2003). Pyoderma gan-

grenosum: a review. J. Cutan. Pathol.

30, 97–107.

Curley, R. K., Macfarlane, A. W.,

and Vickers, C. F. (1985). Pyo-

derma gangrenosum treated with

Cyclosporine A. Br. J. Dermatol. 113,

601–604.

Danese, S., Semeraro, S., Papa, A.,

Roberto, I., Scaldaferri, F., Fedeli,

G., Gasbarrini, G., and Gasbar-

rini, A. (2005). Extraintestinal man-

ifestations in inﬂammatory bowel

disease. World J. Gastroenterol. 11,

7227–7236.

Darvay, A. (1996). Sweet’s syndrome

preceding inﬂammatory bowel dis-

ease. Clin. Exp. Dermatol. 21, 175.

Das, K. M. (1999). Relationship

of extraintestinal involvements in

inﬂammatory bowel disease: new

insights into autoimmune patho-

genesis. Dig. Dis. Sci. 44, 1–13.

Diaz-Peromingo, J. A., Garcia-Suarez,

F., Sanchez-Leira, J., and Saborido-

Frojan, J. (2001). Sweet’s syndrome

in a patient with acute ulcerative col-

itis: presentation of a case and review

of the literature. Yale J. Biol. Med. 74,

165–168.

Dronﬁeld, M. W., Malone, J. D., and

Langman, M. J.(1977). Zinc in ulcer-

ative colitis: a therapeutic trial and

report on plasma levels. Gut 18,

33–36.

Evans, P. E., and Pardi, D. S. (2007).

Extraintestinal manifestations of

inﬂammatory bowel disease: focus

on the musculoskeletal, dermato-

logic, and ocular manifestations.

MedGenMed 9, 55.

Farhi, D., and Wallach, D. (2008). The

neutrophilic dermatoses. Dermatol.

Nurs. 20, 274–282.

Fava, F., and Danese, S. (2011). Intesti-

nal microbiota in inﬂammatory

bowel disease: friend of foe? Wor ld

J. Gastroenterol. 17, 557–566.

Feliciani, C., De Simone, C., and Ame-

rio, P. (2009). Dermatological signs

during inﬂammatory bowel dis-

eases. Eur. Rev. Med. Pharmacol. Sci.

13(Suppl. 1), 15–21.

Femiano, F., Lanza, A., Buonaiuto, C.,

Perillo, L., Dell’ermo, A., and Cir-

illo, N. (2009). Pyostomatitis veg-

etans: a review of the literature.

Med. Oral. Patol. Oral.Cir. Bucal. 14,

E114–E117.

Ficarra, G., Baroni, G., and Massi, D.

(2010). Pyostomatitis vegetans: cel-

lular immune proﬁle and expression

of IL-6, IL-8 and TNF-alpha. Head

Neck Pathol. 4, 1–9.

Fiorino, G., Allez, M., Malesci, A., and

Danese, S. (2009). Review article:

anti TNF-alpha induced psoriasis in

patients with inﬂammatory bowel

disease. Aliment. Pharmacol. Ther.

29, 921–927.

Fleshner, P. R., Michelassi, F., Rubin,

M., Hanauer, S. B., Plevy, S. E., and

Targan, S. R. (1995). Morbidity of

subtotal colectomy in patients with

severe ulcerative colitisunresponsive

to cyclosporin. Dis. Colon Rectum 38,

1241–1245.

Freeman, H. J. (2005). Erythema

nodosum and pyoderma gangreno-

sum in 50 patients with Crohn’s

disease. Can. J. Gastroenterol. 19,

603–606.

Georgiou, G., Pasmatzi, E., Monastirli,

A., and Tsambaos, D. (2006). Cuta-

neous manifestations of inﬂamma-

tory bowel disease. Hosp. Chron. 1,

158–168.

Goudet, P., Dozois, R. R., Kelly, K.

A., Ilstrup, D. M., and Phillips, S.

F. (2001). Characteristics and evo-

lution of extraintestinal manifesta-

tions associated with ulcerative coli-

tis after proctocolectomy. Dig. Surg.

18, 51–55.

Guenova, E., Teske,A., Fehrenbacher, B.,

Hoerber, S., Adamczyk, A., Schaller,

M., Hoetzenecker, W., and Bieder-

mann, T. (2011). Interleukin 23

expression in pyoderma gangreno-

sum and targeted therapy with

ustekinumab. Arch. Dermatol. 147,

1203–1205.

Guhl, G., and Garcia-Diez, A. (2008).

Subcutaneous sweet syndrome. Der-

matol. Clin. 26, 541–551, viii–ix.

Hallopeau, H. (1898). “Pyodermiteveg-

etante” ihre Beziehungen zur der-

matitis herpetiformis und dem pem-

phigus vegetans. Arch. Dermatol.

Syphilol. 43, 289–306.

Hansen, L. S., Silverman, S. Jr., and

Daniels, T. E. (1983). The differen-

tial diagnosis of pyostomatitis vege-

tans and its relation to bowel disease.

Oral Surg. Oral Med. Oral Pathol. 55,

363–373.

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 11

Huang et al. IBD skin manifestations

Hoffmann, R. M., and Kruis, W.

(2004). Rare extraintestinal man-

ifestations of inﬂammatory bowel

disease. Inﬂamm. Bowel Dis. 10,

140–147.

Hue, S., Ahern, P., Buonocore, S., Kull-

berg, M. C., Cua, D. J., Mcken-

zie, B. S., Powrie, F., and Maloy,

K. J. (2006). Interleukin-23 drives

innate and T cell-mediated intesti-

nal inﬂammation. J. Exp. Med. 203,

2473–2483.

Hundorfean, G., Neurath, M. F., and

Sitaru, C. (2010). Autoimmunity

against type VII collagen in inﬂam-

matory bowel disease. J. Cell. Mol.

Med. 14, 2393–2403.

Iannone, F., Scioscia, C., Musio, A.,

Piscitelli, D., and Lapadula, G.

(2003). Leukocytoclastic vasculitis as

onset symptom of ulcerative colitis.

Ann. Rheum. Dis. 62, 785–786.

Iborra, M., Beltran, B., Bastida, G.,

Aguas, M., and Nos, P. (2011). Inﬂix-

imab and adalimumab-induced pso-

riasis in Crohn’s disease: a paradox-

ical side effect. J. Crohns Colitis 5,

157–161.

Izcue, A., Coombes, J. L., and Powrie, F.

(2009). Regulatory lymphocytes and

intestinal inﬂammation. Annu. Rev.

Immunol. 27, 313–338.

Jonas, M., and Scholeﬁeld, J. H. (2001).

Anal ﬁssure. Gastroenterol. Clin.

North Am. 30, 167–181.

Jorizzo, J. L., Schmalstieg, F. C.,

Dinehart, S. M., Daniels, J. C.,

Cavallo, T., Apisarnthanarax, P.,

Rudloff, H. B., and Gonzalez,

E. B. (1984). Bowel-associated

dermatosis-arthritis syndrome.

Immune complex-mediated vessel

damage and increased neutrophil

migration. Arch. Intern. Med. 144,

738–740.

Kaufman, I., Caspi, D., Yeshurun, D.,

Dotan, I., Yaron, M., and Elkayam,

O. (2005). The effect of inﬂiximab

on extraintestinal manifestations of

Crohn’s disease. Rheumatol. Int. 25,

406–410.

Kemmett, D., and Hunter, J. A.

(1990). Sweet’s syndrome: a clini-

copathologic review of twenty-nine

cases. J. Am. Acad. Dermatol. 23,

503–507.

Kethu, S. R. (2006). Extraintesti-

nal manifestations of inﬂammatory

bowel diseases. J. Clin. Gastroenterol.

40, 467–475.

Khor, B., Gardet, A., and Xavier, R. J.

(2011). Genetics and pathogenesis of

inﬂammatory bowel disease. Nature

474, 307–317.

Kitayama, A., Misago, N., Okawa, T.,

Iwakiri, R., and Narisawa, Y. (2010).

Pyodermatitis-pyostomatitis vege-

tans after subtotal colectomy for

ulcerative colitis. J. Dermatol. 37,

714–717.

Larsen, S., Bendtzen, K., and Nielsen, O.

H. (2010). Extraintestinal manifes-

tations of inﬂammatory bowel dis-

ease: epidemiology, diagnosis, and

management. Ann. Med. 42, 97–114.

Lebwohl, M., Fleischmajer,R., Janowitz,

H., Present, D., and Prioleau, P. G.

(1984). Metastatic Crohn’s disease. J.

Am. Acad. Dermatol. 10, 33–38.

Lebwohl, M., and Lebwohl, O. (1998).

Cutaneous manifestations of

inﬂammatory bowel disease.

Inﬂamm. Bowel Dis. 4, 142–148.

Lees, C. W.,Barrett, J. C., Parkes, M., and

Satsangi, J. (2011). New IBD genet-

ics: common pathways with other

diseases. Gut 60, 1739–1753.

Leibovitch, I., Ooi, C., Huilgol, S.

C., Reid, C., James, C. L., and

Selva, D. (2005). Pyodermatitis-

pyostomatitis vegetans of the eye-

lids case report and review of

the literature. Ophthalmology 112,

1809–1813.

Lestre, S., Ramos, J.,Joao, A., and Serrao,

V. (2010). Cutaneous Crohn’s disease

presenting as genital warts: success-

ful treatment with adalimumab. Eur.

J. Dermatol. 20, 504–505.

Letsinger, J. A., Mccarty, M. A., and

Jorizzo, J. L. (2005). Complex aph-

thosis: a large case series with eval-

uation algorithm and therapeutic

ladder from topicals to thalido-

mide. J. Am. Acad. Dermatol. 52,

500–508.

Levine, J. S., and Burakoff, R. (2011).

Extraintestinal manifestations of

inﬂammatory bowel disease. Gas-

troenterol. Hepatol. (N Y) 7, 235–241.

Levitt, M. D., Ritchie, J. K., Lennard-

Jones, J.E., and Phillips, R. K. (1991).

Pyoderma gangrenosum in inﬂam-

matory bowel disease. Br. J. Surg. 78,

676–678.

Lewis, R. T., and Maron, D. J.

(2010). Efﬁcacy and complications

of surgery for Crohn’s disease. Gas-

troenterol. Hepatol. (N Y) 6, 587–596.

Mackel, S. E., and Jordon, R. E. (1982).

Leukocytoclastic vasculitis. A cuta-

neous expression of immune com-

plex disease. Arch. Dermatol. 118,

296–301.

Marzano, A. V., Cugno, M., Trevisan,

V., Fanoni, D., Venegoni, L., Berti,

E., and Crosti, C. (2010). Role

of inﬂammatory cells, cytokines

and matrix metalloproteinases in

neutrophil-mediated skin diseases.

Clin. Exp. Immunol. 162, 100–107.

Matis, W. L., Ellis, C. N., Grifﬁths, C.

E., and Lazarus, G. S. (1992). Treat-

ment of pyoderma gangrenosum

with cyclosporine. Arch. Dermatol.

128, 1060–1064.

McCarthy, F. P. (1949). Pyostomatitis

vegetans; Report of three cases. Arch.

Derm. Syphilol. 60, 750–764.

McClain, C., Soutor, C., and Zieve, L.

(1980). Zinc deﬁciency: a compli-

cation of Crohn’s disease. Gastroen-

terology 78, 272–279.

McGowan, J. W. T., Johnson, C. A., and

Lynn, A. (2004). Treatment of pyo-

derma gangrenosum with etaner-

cept. J. Drugs Dermatol. 3, 441–444.

Menachem, Y., and Gotsman, I. (2004).

Clinical manifestations of pyo-

derma gangrenosum associated with

inﬂammatory bowel disease. Isr.

Med. Assoc. J. 6, 88–90.

Mert, A., Ozaras, R., Tabak, F.,Pekmezci,

S., Demirkesen, C., and Ozturk,

R. (2004). Erythema nodosum: an

experience of 10 years. Scand. J.

Infect. Dis. 36, 424–427.

Mir-Madjlessi, S. H., Taylor, J. S.,

and Farmer, R. G. (1985). Clinical

course and evolution of erythema

nodosum and pyoderma gangreno-

sum in chronic ulcerative colitis: a

study of 42 patients. Am.J.Gastroen-

terol. 80, 615–620.

Mnif, L., Amouri, A., and Tahri, N.

(2010). Cutaneous manifestations of

inﬂammatory bowel disease. Tunis.

Med. 88, 420–423.

Monsen, U., Sorstad, J., Hellers, G.,

and Johansson, C. (1990). Extra-

colonic diagnoses in ulcerative col-

itis: an epidemiological study. Am. J.

Gastroenterol. 85, 711–716.

Monteleone, G., Pallone, F., and Mac-

donald, T. T. (2011). Emerging

immunological targets in inﬂam-

matory bowel disease. Curr. Opin.

Pharmacol. 11, 640–645.

Newell, L. M., and Malkinson, F. D.

(1982). “Pyoderma (ecthyma) gan-

grenosum” by Brunsting, Goecker-

man, and O’Leary, October 1930.

Commentary: pyoderma gangreno-

sum. Arch. Dermatol. 118, 743–773.

Nischal, K. C., and Khopkar, U. (2007).

An approach to the diagnosis of neu-

trophilic dermatoses: a histopatho-

logical perspective. Indian J. Derma-

tol. Venereol. Leprol. 73, 222–230.

Orchard, T. (2003). Extraintestinal

complications of inﬂammatory

bowel disease. Curr. Gastroenterol.

Rep. 5, 512–517.

O’Sullivan, M., and O’Morain, C.

(2006). Nutrition in inﬂammatory

bowel disease. Best Pract. Res. Clin.

Gastroenterol. 20, 561–573.

Pashankar, D., Prendiville, J., and Israel,

D. M. (1999). Vitiligo and Crohn’s

disease in children. J. Pediatr. Gas-

troenterol. Nutr. 28, 227–229.

Passarini, B., Infusino, S. D., Barbi-

eri, E., Varotti, E., Gionchetti, P.,

Rizzello, F., Morselli, C., Tambasco,

R., and Campieri, M. (2007). Cuta-

neous manifestations in inﬂamma-

tory bowel diseases: eight cases of

psoriasis induced by anti-tumor-

necrosis-factor antibody therapy.

Dermatology (Basel) 215, 295–300.

Patton,T.,Jukic, D.,and Juhas, E. (2009).

Atypical histopathology in bowel-

associated dermatosis-arthritis syn-

drome: a case report. Dermatol.

Online J. 15, 3.

Ploysangam, T., Heubi, J. E., Eisen, D.,

Balistreri, W. F., and Lucky, A. W.

(1997). Cutaneous Crohn’s disease

in children. J. Am. Acad. Dermatol.

36, 697–704.

Quan, C., Ren, Y. Q., Xiang, L. H., Sun,

L. D., Xu, A. E., Gao, X. H., Chen,

H. D., Pu, X. M., Wu, R. N., Liang,

C. Z., Li, J. B., Gao, T. W., Zhang, J.

Z., Wang, X. L., Wang, J.,Yang, R. Y.,

Liang, L., Yu, J. B., Zuo, X. B., Zhang,

S. Q., Zhang, S. M., Chen, G., Zheng,

X. D., Li, P., Zhu, J., Li, Y. W., Wei,

X. D., Hong, W. S., Ye, Y., Zhang, Y.,

Wu, W. S., Cheng, H., Dong, P. L.,

Hu, D. Y., Li, Y., Li, M., Zhang, X.,

Tang, H. Y., Tang, X. F., Xu, S. X., He,

S. M., Lv, Y. M., Shen, M., Jiang, H.

Q., Wang, Y., Li, K., Kang, X. J., Liu, Y.

Q., Sun, L., Liu, Z. F.,Xie, S. Q., Zhu,

C. Y., Xu, Q., Gao, J. P., Hu,W. L., Ni,

C., Pan, T. M., Yao, S., He, C. F., Liu,

Y. S., Yu, Z. Y., Yin, X. Y., Zhang, F.

Y., Yang, S., Zhou, Y., and Zhang, X.

J. (2010). Genome-wide association

study for vitiligo identiﬁes suscepti-

bility loci at 6q27 and the MHC. Nat.

Genet. 42, 614–618.

Quezada, S., Turner, P. L., Alexiev, B.,

Daly,B., and Cross, R. (2009). Severe

refractory orofacial Crohn’s disease:

report of a case. Dig. Dis. Sci. 54,

2290–2295.

Read,A. E. (1985). Pyoderma gangreno-

sum. Q. J. Med. 55, 99–101.

Roberts, N., and Bunker, C. (1993). The

gut and the skin. Br.J.Hosp.Med.50,

31–39.

Rothfuss, K. S., Stange, E. F., and Her-

rlinger, K. R. (2006). Extraintesti-

nal manifestations and complica-

tions in inﬂammatory bowel dis-

eases. World J. Gastroenterol. 12,

4819–4831.

Safar, B., and Sands, D. (2007). Perianal

Crohn’s disease. Clin. Colon Rectal

Surg. 20, 282–293.

Sarna, J., Sharma, A., and Marfatia,

Y. S. (2008). Bilateral nonhealing

ulcers in groin: an interesting case of

Metastatic Crohn’s disease. Indian J.

Sex Transm. Dis. 29, 98–100.

Sattianayagam, P. T., Hawkins, P. N.,

and Gillmore, J. D. (2009). Systemic

amyloidosis and the gastrointesti-

nal tract. Nat. Rev. Gastroenterol.

Hepatol. 6, 608–617.

Frontiers in Physiology | Gastrointestinal Sciences February 2012 | Volume 3 | Article 13 | 12

Huang et al. IBD skin manifestations

Ship, J. A. (1996). Recurrent aphthous

stomatitis. An update. Oral Surg.

Oral Med. Oral Pathol. Oral Radiol.

Endod. 81, 141–147.

Singh, S., Graff, L. A., and Bernstein, C.

N. (2009). Do NSAIDs, antibiotics,

infections, or stress trigger ﬂares

in IBD? Am. J. Gastroenterol. 104,

1298–1313; quiz 1314.

Souissi, A., Benmously, R., Fenniche,

S., Zarrouk, M., Marrek, H., Deb-

biche, A., Ayed, M. B., and Mokhtar,

I. (2007). Sweet’s syndrome: a pro-

pos of 8 cases. Tunis. Med. 85,

49–53.

Storwick, G. S., Prihoda, M. B., Ful-

ton, R. J., and Wood, W. S. (1994).

Pyodermatitis-pyostomatitis vege-

tans: a speciﬁc marker for inﬂam-

matory bowel disease. J. Am. Acad.

Dermatol. 31, 336–341.

Thornton, J. R., Teague, R. H., Low-Beer,

T. S., and Read, A. E. (1980). Pyo-

derma gangrenosum and ulcerative

colitis. Gut 21, 247–248.

Timani, S., and Mutasim, D. F. (2008).

Skin manifestations of inﬂamma-

tory bowel disease. Clin. Dermatol.

26, 265–273.

Tromm, A., May, D., Almus, E.,Voigt, E.,

Greving, I., Schwegler,U., and Griga,

T.(2001). Cutaneous manifestations

in inﬂammatory bowel disease. Z.

Gastroenterol. 39, 137–144.

Trost, L. B.,and McDonnell, J. K. (2005).

Important cutaneous manifesta-

tions of inﬂammatory bowel disease.

Postgrad. Med. J. 81, 580–585.

Tsiamoulos, Z., Karamanolis, G.,

Polymeros, D., Triantafyllou, K.,

and Oikonomopoulos, T. (2008).

Leukocytoclastic vasculitis as an

onset symptom of Crohn’s dis-

ease. Case Rep. Gastroenterol. 2,

410–414.

Tu, J., Chan, J. J., and Yu, L. L. (2011).

Bowel bypass syndrome/bowel-

associated dermatosis arthritis

syndrome post laparoscopic gas-

tric bypass surgery. Australas. J.

Dermatol. 52, e5–e7.

Turkcapar, N., Toruner, M., Soykan,

I., Aydintug, O. T., Cetinkaya,

H., Duzgun, N., Ozden, A., and

Duman, M. (2006). The preva-

lence of extraintestinal manifes-

tations and HLA association in

patients with inﬂammatory bowel

disease. Rheumatol. Int. 26, 663–668.

Turner, R. B., Emer, J. J., Weill, M.,

Winterﬁeld, L., Friedman, S., and

Qureshi, A. A. (2010). Rapid res-

olution of pyoderma gangrenosum

after treatment with intravenous

cyclosporine. J. Am. Acad. Dermatol.

63, e72–e74.

Tutrone, W. D., Green, K., Weinberg, J.

M., Caglar, S., and Clarke, D. (2007).

Pyoderma gangrenosum: dermato-

logic application of hyperbaric oxy-

gen therapy. J. Drugs Dermatol. 6,

1214–1219.

van Wijk, F., and Cheroutre, H. (2010).

Mucosal T cells in gut homeostasis

and inﬂammation. Expert Rev. Clin.

Immunol. 6, 559–566.

Vavricka, S. R., Brun, L., Ballabeni, P.,

Pittet, V., Prinz Vavricka, B. M.,

Zeitz, J., Rogler, G., and Schoepfer,

A. M. (2011). Frequency and risk

factors for extraintestinal manifes-

tations in the Swiss inﬂammatory

bowel disease cohort. Am.J.Gas-

troenterol. 106, 110–119.

Veloso, T. (1990). Complement deposits

in inﬂammatory bowel disease. Gas-

troenterology 99, 1541–1542.

Vij, A., Modi, G. M., Suwattee, P., Cock-

erell, C. J., and Hsu, S. (2010).

Chronic, recurrent neutrophilic der-

matosis: a case report. Dermatol.

Online J. 16, 1.

Vind, I., Riis, L., Jess, T., Knud-

sen, E., Pedersen, N., Elkjaer, M.,

Bak Andersen, I., Wewer, V., Nor-

regaard, P., Moesgaard, F., Bendt-

sen, F., and Munkholm, P. (2006).

Increasing incidences of inﬂamma-

tory bowel disease and decreas-

ing surgery rates in Copenhagen

City and County, 2003-2005: a

population-based study from the

Danish Crohn’s colitis database. Am.

J. Gastroenterol. 101, 1274–1282.

von Felbert, V., and Hunziker, T. (2010).

Acrodermatitis enteropathica-like

skin lesions due to Crohn’s disease-

associated zinc deﬁciency. Hautarzt

61, 927–929.

Wasserteil, V., Bruce, S., Sessoms, S. L.,

and Guntupalli, K. K. (1992). Pyo-

derma gangrenosum treated with

hyperbaric oxygen therapy. Int. J.

Dermatol. 31, 594–596.

Weinstein, M., Turner, D., and Avitzur,

Y. (2005). Erythema nodosum as a

presentation of inﬂammatory bowel

disease. CMAJ 173, 145–146.

Williams, H., Walker, D., and Orchard,

T. R. (2008). Extraintestinal man-

ifestations of inﬂammatory bowel

disease. Curr. Gastroenterol. Rep. 10,

597–605.

Wittekindt, C., Luers, J. C., Klussmann,

J. P., and Huttenbrink, K. B. (2007).

Pyoderma gangrenosum in the head

and neck. Arch. Otolaryngol. Head

Neck Surg. 133, 83–85.

Wollina, U. (2002). Clinical manage-

ment of pyoderma gangrenosum.

Am. J. Clin. Dermatol. 3, 149–158.

Yates, V. M., Watkinson, G., and Kel-

man, A. (1982). Further evidence

for an association between psori-

asis, Crohn’s disease and ulcera-

tive colitis. Br. J. Dermatol. 106,

323–330.

Conﬂict of Interest Statement: The

authors declare that the research was

conducted in the absence of any com-

mercial or ﬁnancial relationships that

could be construed as a potential con-

ﬂict of interest.

Received: 23 October 2011; accepted: 17

January 2012; published online: 06 Feb-

ruary 2012.

Citation: Huang BL, Chandra S

and Shih DQ (2012) Skin man-

ifestations of inﬂammatory bowel

disease. Front. Physio. 3:13. doi:

10.3389/fphys.2012.00013

This article was submitted to Frontiers

in Gastrointestinal Sciences, a specialty of

Frontiers in Physiology.

Shih. This is an open-access article dis-

tributed under the terms of the Cre-

ative Commons Attribution Non Com-

mercial License, which permits non-

commercial use, distribution, and repro-

duction in other forums, provided the

original authors and source are credited.

www.frontiersin.org February 2012 | Volume 3 | Article 13 | 13

Causal relationship between inflammatory bowel disease and erythema nodosum: A two‐sample bidirectional Mendelian randomization study

Article

Full-text available

Jan 2024
SKIN RES TECHNOL

Background Previous studies have demonstrated the coexistence of erythema nodosum (EN) and inflammatory bowel disease (IBD), while the exact etiology of the co‐occurrence of the two disorders remains uncertain. Methods A bidirectional two‐sample Mendelian randomization (MR) design was employed to determine the causal link between EN and IBD. Genetic variations associated with Crohn's disease (CD) and ulcerative colitis (UC) were derived from accessible genome‐wide association studies pertaining to European ancestry. The FinnGen database was used to find the genetic variations containing EN. In the forward model, IBD was identified as the exposure, whereas in the reverse model, EN was identified as the exposure. The causal link between IBD and EN was examined using a range of different analysis techniques, the primary one being the inverse variance weighted (IVW) method, including inverse variance weighted‐fixed effects (IVW‐FE) and inverse‐variance weighted‐multiplicative random effects (IVW‐MRE). To strengthen the results, assessments of sensitivity, heterogeneity, and pleiotropy were also conducted. Results MR results showed that IBD increased the risk of EN (IVW‐MRE: OR = 1.242, 95% CI = 1.068–1.443, p = 0.005). Furthermore, there was a strong correlation found between CD and a higher risk of EN (IVW‐FE: OR = 1.250, 95% CI = 1.119–1.396, p = 8.036 × 10⁻⁵). However, UC did not appear to be linked to EN (IVW‐FE: OR = 1.104, 95% CI = 0.868–1.405, p = 0.421). The reverse MR analysis findings did not imply that EN was linked to IBD. Horizontal pleiotropy did not appear to exist, and the robustness of these findings was confirmed. Conclusion The current investigation found that in European populations, IBD and its subtype CD could raise the incidence of EN.

Role of gut-derived bacterial lipopolysaccharide and peripheral TLR4 in immobilization stress-induced itch aggravation in a mouse model of atopic dermatitis

Article

Full-text available

Mar 2024

Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)–induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.

Crohn’s Disease: Basic Characteristics of the Disease, Diagnostic Methods, the Role of Biomarkers, and Analysis of Metalloproteinases: A Review

Article

Full-text available

Oct 2023

Crohn’s disease is a chronic inflammatory bowel disease that affects the ileum and/or large intestine. At the same time, it can also affect any other part of the human body, i.e., from the mouth to the anus. In Crohn’s disease, the physiology and functioning of the epithelial barrier are inhibited due to the correlation of various factors, such as the environment, genetic susceptibility or intestinal microbiota. The symptoms are very troublesome and cause a significant reduction in quality of life, sometimes occurring with paralyzing permanent damage to the digestive tract, requiring enteral or parenteral nutrition throughout life. In order to make a proper and accurate diagnosis, an appropriately selected diagnostic path in a given clinical entity is necessary. Standard diagnostic methods are: laboratory examination, histopathological examination, endoscopic examination, X-ray, computed tomography, ultrasound examination and magnetic resonance imaging. Medical biology and the analysis of metalloproteinases have also proved helpful in diagnosing changes occurring as a result of Crohn’s disease. Here we provide a thorough review of the latest reports on Crohn’s disease and its genetic conditions, symptoms, morphology, diagnosis (including the analysis of Crohn’s disease biomarkers, i.e., metalloproteinases) and treatment.

Identifying atopic dermatitis risk loci in 1,094,060 individuals with sub analysis of disease severity and onset

Article

Apr 2024
J INVEST DERMATOL

19-Year-Old Man With Abdominal Pain, Vomiting, Bloody Diarrhea, and Rash

Article

Mar 2024
MAYO CLIN PROC

The Skin and Disorders of the Digestive System

Chapter

Mar 2024

This chapter concentrates on bowel, hepatic and pancreatic diseases in which cutaneous signs or symptoms are prominent, but also discusses situations either where the skin and the digestive system are affected by the same disease process or where a skin disease itself has an effect on the latter one. Special attention is paid to cutaneous involvement in inflammatory bowel disease and skin signs of liver disease.

Advancements in non-invasive skin sampling: Clinical conditions characterization via the assessment of skin surface cytokine biomarkers

Article

Feb 2024
EXP DERMATOL

The skin is increasingly recognized as a biological active organ interacting with the immune system. Given that the epidermal skin layer actively releases various cytokines, non‐invasive skin sampling methods could detect these cytokines, offering insights into clinical conditions. This study aims non‐invasively measuring cytokine levels directly from the skin surface to characterize different inflammatory chronic disorders in the adult and elderly population: psoriasis, diabetes type 2, rosacea, chronic kidney disease (CKD) and aging. Cytokines IL‐1β, IL‐8 and IL‐10 were sampled from healthy subjects and patients aged 18–80 using skin surface wash technique. A well with sterile phosphate‐buffered saline solution was placed on the skin for 30 min, and the extracted solution was collected from the well for further cytokine levels analysis using ELISA assay. Results show distinct cytokine profiles in different pathological processes, healthy controls, affected and unaffected areas. Aging was associated with increased IL‐1β, IL‐8, and IL‐10 levels in skin. In diabetes, IL‐1β and IL‐8 levels were elevated in lesional areas, while IL‐10 levels were decreased in non‐lesional skin. Psoriatic lesions showed elevated levels of IL‐1β and IL‐8. Rosacea patients had lower IL‐10 levels in both lesional and non‐lesional areas. CKD patients exhibited significantly lower IL‐10 levels compared to healthy individuals. In conclusion, skin surface wash‐derived cytokine profiles could serve as “alert biomarkers” for disease prediction, enabling early detection. Additionally, this method's cost‐effectiveness allows pre‐screening of molecules in clinical studies and holds potential as a tool for biomarkers and omics analysis, enhancing disorder characterization and disease management.

The Mind–Skin Connection: A Narrative Review Exploring the Link Between Inflammatory Skin Diseases and Psychological Stress

Article

Feb 2024
J EUR ACAD DERMATOL

Inflammatory skin diseases are known to negatively impact patient psychology, with individuals experiencing higher rates of stress and subsequent diminished quality of life, as well as mental health issues including anxiety and depression. Moreover, increased psychological stress has been found to exacerbate existing inflammatory skin diseases. The association between inflammatory skin diseases and psychological stress is a timely topic, and a framework to better understand the relationship between the two that integrates available literature is needed. In this narrative review article, we discuss potential neurobiological mechanisms behind psychological stress due to inflammatory skin diseases, focusing mainly on proinflammatory cytokines in the circulating system (the brain-gut-skin communications) and the default mode network in the brain. We also discuss potential descending pathways from the brain that lead to aggravation of inflammatory skin diseases due to psychological stress, including the central and peripheral hypothalamic-pituitary-adrenal axes, peripheral nerves and the skin barrier function.

A Catastrophic Biodiversity Loss in the Environment Is Being Replicated on the Skin Microbiome: Is This a Major Contributor to the Chronic Disease Epidemic?

Article

Full-text available

Nov 2023

There has been a catastrophic loss of biodiversity in ecosystems across the world. A similar crisis has been observed in the human gut microbiome, which has been linked to “all human diseases affecting westernized countries”. This is of great importance because chronic diseases are the leading cause of death worldwide and make up 90% of America’s healthcare costs. Disease development is complex and multifactorial, but there is one part of the body’s interlinked ecosystem that is often overlooked in discussions about whole-body health, and that is the skin microbiome. This is despite it being a crucial part of the immune, endocrine, and nervous systems and being continuously exposed to environmental stressors. Here we show that a parallel biodiversity loss of 30–84% has occurred on the skin of people in the developed world compared to our ancestors. Research has shown that dysbiosis of the skin microbiome has been linked to many common skin diseases and, more recently, that it could even play an active role in the development of a growing number of whole-body health problems, such as food allergies, asthma, cardiovascular diseases, and Parkinson’s, traditionally thought unrelated to the skin. Damaged skin is now known to induce systemic inflammation, which is involved in many chronic diseases. We highlight that biodiversity loss is not only a common finding in dysbiotic ecosystems but also a type of dysbiosis. As a result, we make the case that biodiversity loss in the skin microbiome is a major contributor to the chronic disease epidemic. The link between biodiversity loss and dysbiosis forms the basis of this paper’s focus on the subject. The key to understanding why biodiversity loss creates an unhealthy system could be highlighted by complex physics. We introduce entropy to help understand why biodiversity has been linked with ecosystem health and stability. Meanwhile, we also introduce ecosystems as being governed by “non-linear physics” principles—including chaos theory—which suggests that every individual part of any system is intrinsically linked and implies any disruption to a small part of the system (skin) could have a significant and unknown effect on overall system health (whole-body health). Recognizing the link between ecosystem health and human health allows us to understand how crucial it could be to maintain biodiversity across systems everywhere, from the macro-environment we inhabit right down to our body’s microbiome. Further, in-depth research is needed so we can aid in the treatment of chronic diseases and potentially change how we think about our health. With millions of people currently suffering, research to help mitigate the crisis is of vital importance.

MEDICAL REVIEWS Oral Considerations in Inflammatory Bowel Disease

Article

Full-text available

Oct 2023

Sajad Buch

Extra-intestinal signs of inflammatory bowel disease (IBD) can reach a site as far as oral cavity. The oral cavity manifestations of IBDs are many and more likely missed by the general practitioners and gastro- enterologists.

Extraintestinal manifestations and complications in inflammatory bowel diseases

Article

Full-text available

Aug 2006
WORLD J GASTROENTERO

Cutaneous Manifestations οf Inflammatory Bowel Disease

Article

Full-text available

Nov 2005

A B S T R A C T Cutaneous lesions are among the most frequent extraintestinal manifestations of IBD. They may precede, occur with or postdate the onset of the intestinal disease and can significantly contribute to the morbidity and impairment of the overall quality of life of the affected patients. In this article, the cutaneous manifestations of IBD are re- viewed with particular emphasis on their clinicopathological and therapeutic aspects.

Erythema nodosum and pyoderma gangrenosum in 50 patients with Crohn's disease

Article

Oct 2005
CAN J GASTROENTEROL

HJ Freeman

Erythema nodosum and pyoderma gangrenosum may occur in Crohn's disease. In the present evaluation of consecutive patients with Crohn's disease spanning more than two decades, erythema nodosum was seen in 45 patients and pyoderma gangrenosum was seen in seven patients. Forty-one of 566 women (7.2%) and nine of 449 men (2.0%) were affected. Of these, 45 (4.4%) had erythema nodosum and seven (0.7%) had pyoderma gangrenosum, including two (0.2%) with both dermatological disorders at different times during their clinical courses. Recur-rent erythema nodosum was also detected in nine patients (20%) including eight women, while recurrent pyoderma gangrenosum was seen in two patients (28.6%). were was an age-dependent effect on the appearance of erythema nodosum in women, with the highest percentages seen in those younger than 20 years of age. Detection rates for erythema nodosum in women only approached the low mens' rates in Crohn's disease at older than 40 years of age. Most patients with these dermatological disorders had colonic disease with or without ileal involvement as well as complex disease, usually with penetrating complications. The present study documents a sex-based and age-dependent effect on the clinical expression of erythema nodosum in Crohn's disease. This suggests that some components of the inflammatory process in Crohn's disease may be modulated by estrogen-mediated events, particularly in adolescents and young adults.

Genetics and genetic markers in inflammatory bowel disease

Article

Jan 1998

Crohn's disease and ulcerative colitis are related, complex genetic disorders. A present hypothesis holds that several genes are associated with inflammatory bowel disease, some of which are common to both Crohn's disease and ulcerative colitis and others associated exclusively with one disease or the other. In complex genetic diseases, gene-gene and gene-environment interactions affect the final phenotypic expression. Therefore, careful refinement of phenotypic classifications through clinical examination and subclinical markers may assist in the search for genes for specific diseases. Given the association of inflammatory bowel disease with other autoimmune diseases (eg, psoriasis, ankylosing spondylitis), the possibility of common 'autoimmune genes' is discussed. Progress in candidate genes is reviewed. Genome-wide searches in families multiply affected with inflammatory bowel disease have demonstrated a confirmed linkage region for Crohn's disease on chromosome 16 and evidence for linkage on chromosome 12 in families with inflammatory bowel disease.

Treatment of Pyoderma Gangrenosum With Cyclosporine

Article

Aug 1992
ARCH DERMATOL

Wendy L. Matis

• Background and Design.— Pyoderma gangrenosum is a chronic inflammatory ulcerative skin disease of unknown origin, often associated with various diseases including inflammatory bowel disease, inflammatory arthritis, monoclonal gammopathies, hepatitis, and myeloproliferative disorders. Treatment of associated systemic disorders may improve the ulcers, but lesions may be recalcitrant and persist for months to years. Therapy for pyoderma gangrenosum includes high-dose systemic corticosteroids, sulfa drugs such as sulfasalazine, clofazimine, and immunosuppressive agents such as mercaptopurine and azathioprine; these drugs are sometimes ineffective.Results.— We present a series of 11 patients with pyoderma gangrenosum, with a wide range of underlying diseases, whose ulcers were refractory to usual therapy and who were treated with low-dose cyclosporine. Ten of the 11 patients cleared rapidly and completely with cyclosporine therapy.Conclusions.— Cyclosporine should be seriously considered as a primary form of treatment for pyoderma gangrenosum.(Arch Dermatol. 1992;128:1060-1064)

Cutaneous manifestations of inflammatory bowel disease

Article

Sep 2000

Sweet’s Syndrome

Article

Apr 2002

Sweet’s syndrome was originally described in 1964 by Dr Robert Douglas Sweet as an ‘acute febrile neutrophilic dermatosis’. The syndrome is characterized by pyrexia, elevated neutrophil count, painful red papules, nodules, plaques (which may be recurrent) and an infiltrate consisting predominantly of mature neutrophils that are diffusely distributed in the upper dermis. In addition to skin and mucosal lesions, Sweet’s syndrome can also present with extra-cutaneous manifestations. Sweet’s syndrome can be classified based upon the clinical setting in which it occurs: classical or idiopathic Sweet’s syndrome, malignancy-associated Sweet’s syndrome and drug-induced Sweet’s syndrome.

Inflammatory bowel disease

Article

Mar 1999
PRIMARY CARE

Maureen O'Reilly Brown

Although it is a relatively uncommon disorder, inflammatory bowel disease (IBD) is a significant contributor to colorectal pathology because of its chronicity, unpredictable relapsing course, high surgical morbidity, and strong association with colorectal cancer risk. This article focuses on the colorectal manifestations of IBD. Primary care providers need to be familiar with clinical presentation, approaches to diagnosis, medical and surgical management, postoperative morbidity, and long-term prognosis. The term inflammatory bowel disease encompasses two related but usually distinct entities, ulcerative colitis and Crohn's disease. Both are polygenetic disorders that appear to share some, but not all, susceptibility genes.131 Although these diseases clearly appear to be immunologically mediated, the specific immunoregulatory defects in IBD are unknown. Precipitating and perpetuating stimuli have yet to be identified. Ulcerative colitis is a mucosal disease of the colon and is characterized by diffuse, continuous inflammation from the rectum to the most proximal margin of disease. It has been recognized and reported for well over 100 years.69 Crohn's disease was first formally identified as a distinct entity in 1932. It is a transmural disease of the intestinal wall that can affect any part of the gastrointestinal tract, typically in a discontinuous distribution. Although ileocolic involvement has long been recognized, Crohn's disease limited to the colon was not described until 1959.

Pyostomatitis vegetans associated with ulcerative colitis

Article

Apr 1995
ORAL SURG ORAL MED O

Pyostomatitis vegetans is a rare condition characterized by pustules that affect the oral mucosa. It is consistently associated with inflammatory bowel disease and is usually resistant to treatment. We present the case of a 65-year-old white man with pyostomatitis vegetans that was associated with ulcerative colitis and adenocarcinoma of the colon. Fluocinonide gel resulted in a complete but temporary clearance of the lesions. Complete remission was achieved immediately after a total colectomy. (ORAL SURG ORAL MED ORAL PATHOL ORAL RADIOL ENDOD 1995;79:452-4) Pyostomatitis vegetans is a rare oral condition characterized by miliary pustules that primarily affect the labial gingiva as well as the buccal and labial mucosa. It is consistently associated with inflammatory bowel disease (IBD) and is a highly specific marker for IBD. 1 Since McCarthy's 2 original description, 33 cases have been reported in the literature including the one reported here. The response of the lesions to a wide variety of topical and systemic medications is variable and usually poor) Cutaneous conditions that are associated with IBD include pyoderma gangrenosum, necrotizing vasculitis, erythema nodosum/panniculitis, epidermolysis bullosa acquisita, aphthous stomatitis, and pyostomatitis vegetans. Of all these conditions, the last has the most unique association with IBD and is seen almost exclusively in patients with IBD. The nature of the association of pyostomatitis vegetans and the other conditions with IBD is not clear.

Bilateral nonhealing ulcers in groin: An interesting case of Metastatic Crohn′s disease

Article

Jan 2008

Metastatic Crohn's disease is a rare granulomatous extraintestinal manifestation of Crohn's disease. We are reporting a case of a 22-year-old male with knife-cut ulcers in his groin, and a biopsy suggestive of Metastatic Crohn's disease.

Skin Manifestations of Inflammatory Bowel Disease

Abstract and Figures

Recommended publications

A capture-recapture estimate of inflammatory bowel disease prevalence: The Florence population-based...

Risk Indicators for Inflammatory Bowel Disease

Severe heart disease in coeliac sprue and inflammatory Bowel disease: a common pathogenesis?

Inflammatory Bowel Disease: Psychiatric Status of Patients Before and After Disease Onset