| Research Article |
Open Access |
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| Crohn's Disease and Mucocutaneous Conditions |
| Toshiyuki Yamamoto |
| Department of Dermatology, Fukushima Medical University, Fukushima, Japan |
| *Corresponding author: |
Dr. Toshiyuki Yamamoto|
Department of Dermatology
Fukushima Medical University, Hikarigaoka 1
Fukushima 960-1295, Japan
E-mail: toyamade@fmu.ac.jp |
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| Received July 12, 2011; Accepted October 17, 2011; Published October 20, 2011 |
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| Citation: Yamamoto T (2011) Crohn's Disease and Mucocutaneous Conditions. J
Clin Exp Dermatol Res S2:001. doi:10.4172/2155-9554.S2-001 |
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| Copyright: © 2011 Yamamoto T. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Abstract |
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| Crohn’s disease is an immune-mediated disorder. Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)
produced by Th1 lymphocytes have traditionally been shown to be important in the pathogenesis of Crohn’s disease.
In addition, recent studies demonstrate more complex cytokine networks, in which Th17 cells play a central role. The
expansion and maintenance of Th17 cell responses require the activity of interleukin-23 (IL-23), and thus IL-23/IL-17
axis has been suggested to play a major role in the pathogenesis of Crohn’s disease. Crohn’s disease presents with
various mucocutaneous signs, some of which show similar histological features of non-caseating granulomas with
multinucleated histiocytes. Specific mucocutaneous manifestations include metastatic (cutaneous) Crohn’s disease,
perianal fistula, and oral Crohn’s disease. Although not specific, other various manifestations which histologically show
granulomatous conditions are sometimes associated with Crohn’s disease. Also, Crohn’s disease exhibits other organ
manifestations such as joints, eyes, kidneys, liver and biliary tracts, and vasculature. Those disorders may share
pathognomonic significance attributed to common or similar mechanisms. The efficacy of TNF-targeting therapies
strongly suggests the pivotal role of TNF-α in Crohn’s disease. Anti-TNF therapies bring beneficial effects for not only
intestinal, but also mucocutaneous, joint, and ocular involvements. In this review, recent insights of the pathogenesis
of Crohn’s disease, as well as mucocutaneous manifestations associated with Crohn’s disease, are introduced. |
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| Keywords |
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| Crohn’s disease; Skin; Th17; IL-23; Metastatic Crohn |
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| Introduction |
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| Crohn’s disease (CD) is a chronic, granulomatous, inflammatory
bowel disease (IBD), and various extra-intestinal manifestations are
seen, such as skin, eyes, joints, kidneys, liver and biliary tracts, and
vascular systems. Although the etiology of CD is still not fully elucidated
as yet, a number of studies, both human as well as animal models,
indicate that environmental, genetic and immunological factors
induce chronic gut inflammation. Mucocutaneous manifestations are
frequently seen in CD, which include specific features, characteristic
granulomatous or neutrophilic disorders, and non-specific secondary
lesions due to nutritional deficiency. Some of them histologically share
similar granulomatous features. |
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| Immunological Basis of Crohn’s Disease |
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| T-cells in CD |
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| CD has been considered to be a chronic relapsing T-cell mediated
disease. Activated T-cells diffusely infiltrate into the intestinal mucosa,
submucosa, and lamina propria of patients with CD. Those T-cells are
resistant to apoptotic stimuli, and cause persistent inflammation by
secreting a number of cytokines and mediators. In particular, tumor
necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) produced by
Th1 lymphocytes are important in CD, which may play a role in the
destruction of the intestinal epithelial barrier [1]. Additionally, genetic
backgrounds, bacterial superantigens, and innate immunity mediated
by toll-like receptors (TLRs) may also be involved. Interleukin-12 (IL-
12) is produced in response to bacteria, and also important for Th 1
differentiation. IL-12 and IFN-γ mutually upregulate their production.
Expression of IFN-γ and IL-12 are enhanced in CD [2]. For T-cells
to gain access to gut, interactions of integrins, i.e. α4β7 and α4β1, and
chemokine receptors are required [3]. |
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| Th1/Th17 cytokines |
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| Recent studies demonstrate more complex cytokine networks, in
which Th17 cells play a central role, in chronic intestinal inflammation.
The expansion and maintenance of Th17 cell responses require the
activity of IL-23, and thus IL-23/IL-17 axis has been suggested to play a major role in the pathogenesis of CD. CD is associated with Th1 and
Th17 cytokine profiles. Th17 type T-cell lineage is driven from naïve
CD4 T-cell precursors by transforming growth factor-β (TGF-β) and
IL-6, whereas IL-23 expands and maintains Th-17 populations. Th17
cells include IL-17, IL-21, IL-22, TNF-α, and IL-6. IL-17A expression
and IL-17F mRNA levels are increased in the mucosa in patients with
CD [4,5]. Major sources of IL-17 were CD3+ T-cells and CD68+
macrophages. The number of IL-17 producing T-cells is higher in CD
than those in normal gut mucosa [4]. IL-23 is a heterodimeric cytokine
composed of a p40 subunit, which is shared with IL-12, and a specific
p19 subunit. The synthesis of the p40 subunit and the functional IL-
23 is enhanced in the gut of CD patients [6]. It is shown that IL-23 is
mainly secreted from activated dendritic cells in the mucosa. IL-23 is
suggested to promote inflammation directly by inducing IL-17, and also
indirectly by inhibiting regulatory T-cells (Tregs) via suppression of
fork-head box p3 (Foxp3) [7]. Additionally, mucosal cytokine network
involves various cytokines such as IL-21, IL-22, and IL-32 [8,9]. IL-
21 and IL-22 upregulate matrix metalloproteinase (MMP) production
[10], which may contribute to the matrix degradation in the intestine of
CD. Also, IL-22 enhances expression of TNF-α, and IL-8 [11], which
may induce neutrophil accumulation in the intestine of CD. |
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| Macrophages in CD |
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| Macrophages produce a number of cytokines, and play a crucial
role in tissue homeostasis, immunity, inflammation and repair
process. Macrophages are one of the major sources of TNF-α, along
with epithelial cells and mast cells [12]. TNF-α plays a crucial role in CD, and increased levels of TNF-α mRNA and protein have been
shown in intestinal tissues of CD [13]. Also, mice overexpressing
TNF-α develop CD-like bowel diseases [14]. TNF-α induces a strong
activation of NF-kB in the cross-talk with IFN-γ. NF-kB leads to the
secretion of proinflammatory cytokines and MMPs [15]. Further, NFkB
is required for the increased permeability of intestinal epithelial
tight junction [16], which may induce a defect in the intestinal barrier.
Expression of TNF is increased in the intestinal mucosa in CD [17],
especially in patients with active CD [18]. TNF- exerts its biological
effects through two TNF-α receptors; TNF-R1 (55 kD) and TNF-R2
(75 kD). Soluble levels of TNF-R1 and R2 are elevated in the colon
tissues of active CD, suggesting a dysregulated production of soluble
cytokine receptors [19]. The serologic levels of TNF-α [18], as well as
TNF-Rs [20], are also enhanced in patients with CD with the clinical
disease activity. Further, beneficial clinical efficacy of targeting TNF-α
indicates the crucial role of TNF-α in CD. |
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| The innate immune system is the first line of defense against
pathogens. Intestinal mucosa is exposed to fecal bacteria, which is
recognized through TLRs expressed on intestinal epithelial cells.
TLRs can be activated by exogenous stimuli such as bacteria or
viruses, and also by endogenous ligands. Along with the recognition
of microbial components, TLR signaling also plays an important
role in the activation of the adaptive immune system by inducing
proinflammatory cytokines and upregulating costimulatory molecules
of antigen presenting cells. A recent report shows that unique CD14+
macrophages are significantly increased in number in intestine of
patients with CD, which are functionally active and produce abundant
levels of IL-23 and TNF-α [21]. Those macrophages predominantly
produce IFN-γ, but not IL-17, which may further proceed on IL-23
production [21]. |
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| Mucocutaneous lesions of CD |
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| Mucocutaneous manifestations of CD are relatively common,
with the incidence of 10-40% [22,23]. Those are generally classified
into three subtypes; specific lesions with non-caseating granulomatous
changes, reactive lesions which are occasionally seen, and non-specific
secondary lesions due to nutritional deficiency. Granulomatous
inflammation is induced by the dysfunction of cellular inflammatory
response to remove foreign materials. Those processes may involve
several cytokines such as TNF-α and IL-1, defective neutrophil
function, and so on. |
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| Metastatic CD |
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| Metastatic CD, or cutaneous CD, is seen on the sites discontinuous
from the gastrointestinal tracts, such as the lower extremities,
intertriginous and flexural areas, trunk, and rarely genital (penis
and vulvar) regions [24]. Clinically, metastatic CD assumes papules,
subcutaneous nodules, infiltrative erythema, ulcerative or non-ulcerative
plaques, edema, lichenoid lesions, and so on. Some cases present with
only prominent swelling on the genitalia (Figure 1) [25]. Rare forms
of metastatic CD assume pyoderma gangrenosum-like, erysipelas-like,
necrobiosis, and cobblestone-like appearances [26-29]. As a rare variant,
metastatic CD is seen on the face [30]. The umbilicus is connected to
the bowel, and also involved [31]. Histology shows characteristic noncaseating
granulomatous infiltration in the dermis (Figure 2), which is
strongly immunoreactive for TNF-α (Figure 3). Otherwise, histological
features such as necrobiosis, vasculitis, and panniculitis are also
seen [32,33]. Differentiation from sarcoidosis is sometimes difficult.
Metastatic CD is not always in parallel with intestinal activity, and rarely
precedes the onset of bowel involvement several years [34,35]. Anti-
TNF therapy is effective for refractory metastatic CD [36]. |
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Figure 1: Metastatic CD showing extensive swelling of genitalia, which appeared
prior to the onset of CD. |
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Figure 2: Histopathology of metastatic CD showing non-caseating granuloma. |
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Figure 3: TNF-α expression. |
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| Perianal fistula |
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| Perianal abscess and fistulas are common, and sometimes appear
as the first sign of CD (Figure 4). A perianal fistula is a pathological
connection between the anorectal mucosal surface and the perianal
skin. The ratio of perianal fissures and fistulas are reported to be 36%
of patients [23]. Histological features show non-specific inflammation
with multi-nucleated giant cells (Figure 5). Recent findings suggest
failures in the tissue injury/repair process, myofibroblasts phenotypic
changes, MMP production, and epithelial-mesenchymal transition are
involved in the perianal fistula lesions [37]. |
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Figure 4: Perianal fistula. |
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Figure 5: Histopathology of perianal fistula showing infiltrates of lymphocytes,
histiocytes, and giant cells. |
|
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| Oral CD |
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| Lesions of oral CD present with cobblestone appearance of the
mucosal surfaces, lip swelling, ulcerations, and tiny nodules [38].
Additionally, various non-specific symptoms include labial, buccal
and gingival swelling, buccal abscesses, mucosal hyperplasia, fissuring,
gingivitis, candidiasis, angular fissures, perioral erythema, scaling, and
so on. Biopsy specimen from lesions of oral CD shows granulomas and
inflammatory changes characteristic of CD. |
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| Cheilitis granulomatosa (orofacial granulomatosis) |
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| Cheilitis granuloma presents with chronic or recurrent diffuse
swelling of the lips, (Figure 6). Histopathology reveals the formation
of scattered aggregates of non-caseating granulomas and epithelioid
histiocytes. Although the etiology is unknown, cheilitis granulomatosa
is important as an early or even the initial sign of CD [34]. The
association of cheilitis granulomatosa with CD is seen with a ratio of
10-48% [39,40]. |
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Figure 6: Cheilitis granuloma. |
|
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| Erythema nodosum |
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| Erythema nodosum (EN) is a panniculitis which presents with
tender, erythematous nodules mainly on the extremities, predominantly
on the lower legs. It is generally considered to be a benign and selflimiting
hypersensitivity reaction to various inciting factors. EN may
be idiopathic, following infection, drug-induced, or also in association
with other disorders including IBD. In a few series of EN objecting
a large number of cases, CD is recognized in 1-2% [23] (Figure 7).
Histologically, EN of early onset is characterized by a neutrophilic
inflammatory infiltrate in the septa of the subcutaneous tissue.
Sometimes, neutrophilic abscesses are observed in the subcutaneous
tissues. Histological features show lobular panniculitis with granuloma
formation (Figure 8). Studies of T-cell clonality of intestinal tissue of
CD have shown proliferation of T-cell subsets expressing TCRs with
Vβ11, Vβ12, Vβ13, Vβ15, and Vβ17 [41,42]. TCR Vβ in the lesional
skin of EN showed Vβ8, Vβ14, Vβ15, Vβ17, and Vβ20 [43]. It is of
note that several common TCR subunit families are detected in the
intestinal and skin lesions of CD, with some differences. |
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Figure 7: Erythema nodosum associated with CD. |
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Figure 8: Histopathology showing septal panniculitis including giant cells. |
|
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| Pyoderma gangrenosum |
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| Pyoderma gangrenosum (PG) is a disease characterized by
refractory, sterile, deep ulcers predominantly in the extremities in
women aged between 20 and 60 years (Figure 9). PG is occasionally associated with several systemic diseases such as IBD, hematologic
malignancy, Takayasu’s arteritis, neutrophilic dermatoses, and
rheumatoid arthritis (RA). Clinical classification of PG includes
ulcerative, pustular, bullous and vegetans type. Ulcerative type PG is
most common, which rapidly enlarges with central deep ulceration and
undermined borders. Bullous type PG is the most frequently seen in
association with hematologic disorders. It is well-known that minor
trauma precipitates PG, and there are several reports of PG occurring
at percutaneous surgical sites, such as breast surgery, pacemaker
implantation, splenectomy, hysterectomy, endoscopic tube insertion,
cholecystectomy, and cesarean delivery. Those phenomena mean
hyper-reactivity of the skin in response to minor trauma. |
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Figure 9: Pyoderma gangrenosum associated with CD. |
|
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| Psoriasis |
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| Psoriasis is immunologically mediated by aberrant, skin-directed
T-cells. Recent progress shows that Th1/Th17 type T-cell subsets
play a distinct role in the pathogenesis of psoriasis. IL-23 released
from dendritic cells (DC) (TNF-α and inducible nitric oxide synthase
(iNOS)-producing DC; Tip-DC) leads to activation and proliferation
of Th17 cells. The Th17 subsets release IL-17A and IL-22, which promote neutrophil and keratinocyte hyperproliferation, respectively.
Recent investigations suggest genetic and pathologic connections
between psoriasis and CD [44]. The prevalence of psoriasis is 9.6% in
136 patients with CD, whereas only 2.2% in controls [45]. On the other
hand, psoriatic patients, in particular those with arthritis, frequently
show microscopic inflammatory changes of colonic mucosa even in
the absence of bowel symptoms [46], which suggest that colon is also
one of the organs susceptible by psoriasis. Both psoriasis and CD is
associated with genetic susceptibility loci of IL-12B and IL-23R [47]. |
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| Sweet’s syndrome |
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| Sweet’s syndrome (SS) (acute febrile neutrophilic dermatosis) is
characterized by fever, polymorphonuclear neutrophilic leukocytosis,
and multiple, raised, painful erythematous plaques with superficial
small pustules on the face and limbs. SS can arise as an idiopathic
syndrome, in association with infection (i.e. upper respiratory tract),
paraneoplastic (i.e. especially haematological malignancy), pregnancy,
and drugs. Also, SS often occur in patients with immunologic disorders
such as RA and IBD, most of which are CD [48]. SS is suggested to be
a hypersensitivity reaction to infectious (bacterial, viral), chemical, or
even tumor-associated antigens, possibly mediated by T-cell-dependent
immune responses. The secreted cytokines such as IL-1, IL-6 and IL-8
are suggested to trigger neutrophil chemotaxis and activation. Also, IL- 17 promotes neutrophil migration [49], and thus may play a role in
the induction of SS. Neutrophils produce reactive oxygen and nitrogen
metabolites which may induce gut inflammation [50]. |
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| Miscellaneous conditions |
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| Lichen nitidus is a chronic inflammatory reaction, which clinically
presents small round papules with waxy appearance. Histologically, it
is characterized by focal cellular mononuclear cell infiltrates into the
upper dermis with multi-nucleated epithelioid histiocytes (Figure 10).
Lichen nitidus is sometimes associated with several disorders, including
CD [51]. Granulomatous vasculitis presents with tender, ulcerated
papules and nodules on the extremities, histologically characterized
by granulomatous vasculitis with intramural inflammatory cells and
fibrin deposition [52]. Other non-granulomatous miscellaneous
diseases include erythema multiforme, epidermolysis bullosa acquisita,
porokeratosis, hidradenitis suppurativa, anetoderma, polyarteritis
nodosa, and so on [53-56]. |
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|
Figure 10: Histopathology of lichen nitidus showing focal subepidermal
infiltration of lymphocytes, histiocytes, and multi-nucleated giant cells. |
|
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| Skin manifestations induced by paradoxycal effects of TNFtargeting
therapies |
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| Biologics targeting TNF-α are widely used with dramatical effects for
CD, as well as RA and psoriasis; however, psoriasis-like or palmoplantar
pustulosis-like lesions are paradoxically induced during anti-TNF-α
therapies (Figure 11) [57,58]. On the other hand, development of CD
during etanercept therapy for psoriasis has also been reported [59].
The most promising explanation for this paradoxical effect is that
TNF inhibition can interfere with the balance with IFN-α, which may
promote an autoimmune response [60]. Other possibilities include that
persistent TNF depletion results in downregulation of T-cell responses
and in turn induction of novel regulatory pathways. |
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|
Figure 11: Pustulation on the sole resembling palmoplantar pustulosis during
infliximab therapy. |
|
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| Conclusion |
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| Because CD develops numerous mucocutaneous manifestations,
which may precede the intestinal disease, dermatologists should be
aware of various symptoms. Along with the progress of pathophysiology
of CD, better understandings of immunobiology of mucocutaneous
signs are expected. |
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