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Surgical Wound Closure and Healing
DOI: http://dx.doi.org/10.5772/105978
as well. For example, while it is accepted that slowly absorbing sutures decrease the
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risk of incisional hernia after midline closure relative to faster absorbing sutures
[23], a fast-absorbing antibacterial suture did not increase the incisional hernia rate
compared to non-antibacterial slowly absorbing suture in a 3-year follow-up study of
over one thousand patients [42]. Understanding the features and clinical benefits of
different wound closure choices can be an important contribution to optimal surgical
wound healing.
Acknowledgements
Ethicon, Inc. has provided publication support.
Wound Healing - Recent Advances and Future Opportunities
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[20]
Chintamani. Editorial. Ten
commandments of safe and optimum
[25] Sheik-Ali S, Guets W. Absorbable
vs non absorbable sutures for
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wndm.2018.09.004
[26] Xu B, Xu B, Wang L, Chen C,
Yilmaz TU, Zheng W, etal. Absorbable
versus nonabsorbable sutures for
skin closure: A meta-analysis of
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Chapter 4
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Skin Blister Formation and
Subepidermal Bullous Disorders
Gamze TaşAygar and MüzeyyenGönül
Abstract
B
listering diseases comprise a large group of clinically polymorphic and sometimes
devastating diseases. Blistering diseases are evaluated according to the level of the
blister, the mechanism of blister formation and the type of inflammation. There are
many connections in the normal structure of the skin that hold the cells together.
These connections both hold the cells in the epidermis together and ensure that these
cells attach to the basement membrane. As a result of damage to these connections by
genetic, immune, infectious or physical reasons, intercellular connections are broken
and blistering developments due to the accumulation of extracellular fluid in the intercellular spaces. Autoimmune bullous diseases are classified according to the decomposition site of the epidermis. While the pemphigus group is used to classify diseases
with intraepidermal separation, the pemphigoid group diseases are used to classify
diseases with subepidermal separation. In this section, pemphigoid group diseases,
such as bullous pemphigoid, mucous membrane pemphigoid, acquired epidermolysis
bullosa, linear IgA bullous dermatosis, and anti-p200 pemphigoid, will be explained
with a brief introduction to blistering diseases of the skin.
Keywords: blistering diseases, subepidermal bullous disorders, pemphigoid,
linear IgA bullous dermatosis, mucous membrane pemphigoid,
anti-p200 pemphigoid
. Introduction
Skin blistering diseases are clinically polymorphic large-group disorders and they
sometimes may be devastating. These disorders may be classified according to [1]
the level of the blister: subcorneal, mid epidermis, suprabasal, subepidermal; [2] the
mechanism of blister formation (spongiosis, acantholysis, blistering degeneration,
or epidermolysis); and [3] the type of inflammation (neutrophilic, lymphocytic,
eosinophilic, mixed) [1]. In this section, pemphigoid group diseases such as bullous
pemphigoid, mucous membrane pemphigoid, acquired epidermolysis bullosa, linear
IgA bullous dermatosis, and anti p-200 pemphigoid will be explained with a brief
introduction to blistering diseases of the skin. The features of subepidermal bullous
disorders were summarized in Table .
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Tense blisters with
urticarial papules and
plaque
Acral and cephalic
distribution and mucosal
involvement
subepidermal separation
and a moderate to dense
inflammatory infiltrate
in the upper dermis,
with a predominance of
neutrophils
DIF: Linear deposits of
immunoglobulin IgG
and C3 along the BMZ
Bullous pemphigoid
Mucous membrane
pemphigoid
Acquired epidermolysis
Vesicles and tense bullae are
located on erythematous or
normal ground in the trunk,
extensor surfaces, buttocks, and
face.
Annular erythematous lesions
with a ring of vesicles
skin lesions heal without scarring,
mucosal lesions may result in
significant scarring.
The mucosal involvement is more
often in children than in adults
Subepidermal blisters are
associated with a dermal infiltrate
of neutrophils, eosinophils, and
mononuclear cells. Neutrophil
microabscesses at the tip of the
dermal papillae
DIF: The linear accumulation of
bullosa
Linear IgA bullous
dermatosis
Responds well to bullous
pemphigoid treatment
IgA along the BMZ. IgG, IgM, and
C3 accumulation may be seen
Bullous pemphigoid,
Mucous membrane pemphigoid
epidermolysis bullosa acquisita,
anti-p200 pemphigoid, toxic
epidermal necrolysis
Dapsone
sulfonamides
oral corticosteroids,
tetracycline and nicotinamide
colchicine
trimethoprim-sulfamethoxazole
Acquired epidermolysis bullosa Linear IgA bullous dermatosis Anti-p pemphigoid
Skin fragility, tense bullae, erosions,
milium, and scar formation in
trauma areas, especially the extensor
surfaces of the acral regions
In inflammatory type, the lesions
can be seen on all skin and mucous
membranes
Subepidermal blister with
eosinophilic-rich infiltrate,
DIF: linear deposition of C3 and IgG
along the BMZ
Bullous pemphigoid
Mucous membrane pemphigoid
Linear IgA bullous dermatosis
Anti-p200 pemphigoid
Protecting from local traumas and
infections.
topical corticosteroids
colchicine
dapsone
oral prednisone
IVIG
Pulse steroidsmycophenolate mofetil
cyclosporine
azathioprine
rituximab
Methotrexate
cyclophosphamide
plasma exchange
pemphigoid
Mucosal blistering, ulceration,
and subsequent scarring in
the mucous membranes( oral
mucosa, ocular conjunctiva,
nasopharynx, larynx, anogenital
region, and esophagus)
and vesiculobullous lesions,
ulceration, erosions, and scars in
the head and the upper body.
Subepithelial blisters with
or without significant mixed
inflammatory infiltrates and
lamellar fibrosis in the upper
dermis.
DIF: The linear deposition of
IgG, IgA, or C3 along the BMZ
Bullous pemphigoid,
epidermolysis bullosa acquisita,
anti-p200 pemphigoid,
pemphigus vulgaris
Low-risk patients: Topical or
intralesional corticosteroids,
topical tacrolimus
High-risk patients: Dapsone
and/or prednisone, tetracycline,
doxycycline
pulsed steroid therapy,
cyclophosphamide, IVIG,
rituximab,
azathioprine, mycophenolate
mofetil, methotrexate,
cyclophosphamide
Bullous pemphigoid Mucous membrane
Tight bullae located on
erythematous or normal
ground in the lower
abdomen, flexor surfaces
of the limbs, groin, and
axilla.
It may also present with
only pruritus or urticarial
plaques.
Subepidermal blisters
with moderate to dense
inflammatory infiltrate,
especially eosinophils.
DIF: The linear IgG and/
or C3 deposition along the
BMZ
epidermolysis bullosa
acquisita, mucous
membrane pemphigoid,
anti-p200 pemphigoid,
pemphigus vulgaris,
Oral/topical corticosteroids
Azathioprine
Mycophenolate mofetil
Oxytetracycline/doxycyclin
Methotrexate
Dapsone
Chlorambucil
Cyclophosphamide
Omalizumab
Intravenous
immunoglobulin(IVIG),
Plasmaphereses
Clinical
symptoms
Pathology
Differential
diagnosis
Treatments
DIF: direct immunofluorescence microscopy, Ig: Immunoglobulin, C3: complement 3, BMZ: basement membrane zone.
Table 1.
Features of subepidermal bullous disorders.
Skin Blister Formation and Subepidermal Bullous Disorders DOI:http://dx.doi.org/10.5772/110472
. Blistering formation mechanisms
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There are different mechanisms underlying vesicle and bulla formations, these are
spongiosis, achantholysis, ballooning degeneration, and cytolysis (epidermolysis) [1, 2].
. Loss of intercellular cohesion
Acantholysis
be many causes of primary acantholysis, the most known being pemphigus group
diseases caused by autoantibodies against desmosome proteins. This condition can be
caused by bacterial toxins, as in staphylococcal scalded skin syndrome, or by a genetic
defect in the kertinocyte cell membrane, as in Hailey–Hailey disease [3–5].
Spongiosis
lular cohesion although the intercellular connections are structurally normal. Loss
of cohesion appears as small cavities in the epidermis in histopathology. It is called
spongiosis because of its sponge-like appearance. As the severity of inflammation
increases, the small spaces formed coalesce to form vesicle-bulla formation. The best
example of this situation is allergic contact dermatitis [6].
Ballooning degeneration
plasm swollen due to intracellular edema. Necrosis of these cells and loss of attachment to neighboring cells is the cause of secondary acantholysis. It is characteristically
seen in infections caused by some viruses, such as herpes, smallpox, and Coxsakie [7].
Cytolysis
In the epidermolytic form epidermolysis bullosa, bullae form due to post-traumatic
damage to genetically defective basal layer cells [8].
2.1.1 Desmosomes, hemidesmosomes, and basal membrane
is the loss of intercellular cohesion for various reasons. There may
, which describes intercellular edema causes secondary loss of intercel-
is the appearance of affected spinous cells with pale cyto-
of basal layer cells of the epidermis causes loss of epidermal cohesion.
Preservation of the integrity of the epidermis depends on secure adhesion between
adjacent keratinocytes, and between basal keratinocytes and the underlying epidermal basement membrane (BM). The major adhesion units are hemidesmosomes and
desmosomes. As a result of damage to these connections by genetic, immune, infectious, or physical reasons, intercellular connections are broken and extracellular fluid
accumulates in the intercellular spaces. This fluid accumulation appears as vesicles,
intact or opened bullae, and erosions [2].
Desmosomes are structures that connect the intracellular skeleton to the cell
membrane and other cells. Proteins, such as desmogleins, desmocollins, plakoglobins,
plakophilins, and desmoplakins form the structure of the desmosome. The genetic
absence of these proteins or the autoantibodies developed against these proteins cause
genetic and autoimmune bullous diseases [9–11].
Basal keratinocytes adhere to connective tissue via extracellular matrix proteins
that constitute BM [12]. Epidermal BM between the epidermis and dermis contains
four principal basement membrane components; laminins, type IV collagens, perlecan, and nidogens [13].
Laminin-332, the most abundant laminin, distribute both throughout the epi
dermal BM and condenses in hemidesmosomes. Laminin-511 supports keratinocyte
adhesion too and both laminins are important in maintaining the structural integrity
of the BM and interact with integrin a3b1 and a6b4. In addition to integrin receptors,
laminin-332 interacts with multiple proteins such as collagen XVII, syndecan 1 and 4,
perlecan, nidogen 1, fibulin 2, and collagen VII [13, 14].
-
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Collagen IV is the second major component of BM and is vital for maintaining
epidermal BM integrity. The laminin and collagen IV networks need to be connected
for BM stability. This task in the epidermal BM is performed by nidogens. Perlecan
is an additional possible linker. Another BM component, fibrillin 1, interacts with
perlecan and forms microfibrils participating in the anchorage of the epidermal BM
to the papillary matrix [13, 15].
Collagen VII (anchoring fibrils) expressed by both epidermal keratinocytes and
dermal fibroblasts has evolved as a specialized non-redundant component of the DEJ
ensuring the firm attachment of the epidermal BM to the papillary matrix [13, 16]. As
opposed to anchoring filaments, anchoring fibrils are much larger and have a characteristic structure anti-parallel alignment of type VII collagen molecules [16].
Epidermal BM has evolved to contain additional supportive structures that
ensure firm adhesion of the epidermis to the dermis. This zone known as the dermalepidermal junction (DEJ) is a functional unit composed of the plasma membrane of
the basal keratinocyte with its hemidesmosomes, a lamina lucida, lamina densa, and
a sublamina densa fibrous zone or reticular layer. DEJ plays a vital role in regulating
communication between the epidermis and dermis and tissue reconstruction and
repair [13–15].
Hemidesmosomes are cell-matrix junctions that connect epidermal keratinocytes
to the BM. The core of each hemidesmosome consists of 180kDa-bullous pemphigoid
antigen (BP180, type XVII collagen, BPAG2), the two subunits of the α6β4 integrin,
and a tetraspanin protein termed CD151. In BM, BP180 and α6β4 integrin interact
with laminin–332. The cytoplasmic tail of the β4 integrin subunit binds both BP180
and two members of the plakin family, the 230kDa bullous pemphigoid antigen
(BP230 or BPAG1e) and plectin [12].
Subepidermal autoimmune bullous diseases (SABDs) are diseases characterized by
subepidermal blisters that develop as a result of antibodies against DEJ components
that are important structural proteins for the maintenance of dermo-epidermal
integrity [17]. Bullous pemphigoid, mucous membrane pemphigoid, acquired epidermolysis bullosa, and linear IgA bullous dermatosis will be explained in these group
disorders in this chapter.
. Bullous phemphigoid
Bullous phemphigoid is the most common autoimmune blistering disease which
affects the elderly, particularly in patients older than 70years. The median age for
bullous pemphigoid is 80years. The incidence of the disease has increased significantly in last years due to the increased life expectancy of the aging population
[18,19]. BP has a significantly increased fatality, with 1-year mortality rates ranging
from 6 to 41% in literature [17]. Infections are most important cause of death. Risk
factors for mortality are advanced age, non-white ancestry, low health insurance
accessibility, and the presence of neurological comorbidity and functional impairment at presentation [17, 20].
In the previous decades, neurological conditions including Parkinson’s disease,
dementia, stroke, epilepsy, and multiple sclerosis have been identified to be highly
associated with BP patients. This association may be explained by the cross-reactivity
between the neuronal (BP230) and epithelial isoforms of BP Ag1 which are both
encoded by dystonin gene. Recently, psychiatric comorbidities, such as schizophrenia and bipolar disorder, as well as personality disorders have been reported in BP
Skin Blister Formation and Subepidermal Bullous Disorders DOI:http://dx.doi.org/10.5772/110472
patients [17, 21]. A significant association with hematological malignancies between
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BP was revealed in the pooled analysis of cross-sectional studies while no association
between BP and overall cancer was found in any of the study designs in the results of
a meta-analysis [17]. Additionally, in BP risk of developing a thromboembolic disease
is 15-fold higher [22].
A geographic or ethnic predilection of the disease is defined recently. Certain HLA
class II alleles are more prevalent in patients with BP than in the general population.
In Caucasians, a significant association with DQB1*0301 and in the Japanese population DRB1*04, DRB1*1101, and DQB1*0302 alleles have been found [17, 23].
It is associated with a humoral and cellular immune response directed against the
components of the skin BM zone (BMZ). There are two self-antigens that are components of the hemidesmosomes: BP230 and BP180 [24]. In vitro studies have shown
that human BP180 antibodies play a key role in the pathogenesis of the disease and
are responsible for dermal-epidermal separation and subsequent subepidermal blister
formation in patients with BP [18, 25]. In DIF, IgG-type antibodies are observed in
90–95% of cases and C3 accumulation is observed in 100% of cases, and this is a critical test for diagnosis. In a smaller group of patients, accumulation of IgE, IgA, and IgM
can also be detected [26]. Those that are associated with pathogenesis are IgG and IgEtype antibodies. In particular, IgG1-type antibodies through complement activation,
and IgE-type antibodies through mast cell degradation; cause neutrophil and eosinophil chemotaxis. Proteolytic enzymes released from these cells also cause separation
at the dermo-epidermal junction. IgG4-type antibodies can also cause degradation
by complement-independent antibody-dependent pathways. IgE-type antibodies are
responsible for pruritic urticarial plaques, especially in the prebullous stage [27, 28].
The disease usually first presents with pruritus accompanied by localized or gener
alized excoriated lesions, eczematous, papular, and or urticarial lesions [29]. Blisters
may accompany the first lesions or occur a few weeks up to months after the development of the first cutaneous signs [22]. Tense bullae can arise on an erythematous base
or normal skin [29]. Blisters most commonly disperse symmetrically and predilection
sites are the lower abdomen, flexor surfaces of the limbs, groin, and axilla [30]. The
disease heals without scarring, but postinflammatory hypo-hyperpigmentation
and milia can be seen [18]. Oral mucosal involvement is seen in 10–20% of affected
patients [31–33].
The disease has a non-bullous phase in which typical clinical signs have not yet
appeared. Classical bullous lesions are not seen in 20% of patients diagnosed with BP
at the time of diagnosis [22, 30]. In this prodromal phase, patients may have only mild
to severe pruritus. In an elderly patient who had especially neurological disorders,
excoriations accompanied by severe pruritus should cause BP suspect. While eczematous patches can persist for months to years before the development of bullae progression from urticarial pemphigoid to bullous form is seen more quickly in approximately
6weeks [22]. Another presentation form of BP are Prurigo nodularis-like lesions. Most
Pemphigoid nodularis patients develop bullae within years but it is not necessary [22].
There is currently no standardized classification of BP. However, it is possible
to recognize distinct variants of the disease according to the age of onset, clinical
presentation, location of the lesions, and triggering factors [34]. The presence of
concomitant lichen planus with BP is defined as lichen planus pemphigoid. Bullae that
demonstrate classic immunopathologic findings of BP develop both on lichen planus
lesions and on normal skin [22]. Pemphigoid vegetans is a form of BP in which clinical
findings are similar to pemphigus vegetans but histopathology and immunofluorescence findings are identic with BP. BP rarely may manifest as exfoliative erythroderma
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