Mustafa 2015

AUTREV-01733; No of Pages 22
Autoimmunity Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev
1 Review
2Q1 Oral mucosal manifestations of autoimmune skin diseases

3Q2 Mayson B. Mustafa a,b, Stephen R. Porter c, Bruce R. Smoller d, Cassian Sitaru a,e,⁎
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4 a
Department of Dermatology, University of Freiburg, Hauptstrasse 7, 79104 Freiburg, Germany
5 b
Oral medicine section, Department of Oral and Maxillofacial Surgery, University of Khartoum, Faculty of Dentistry, Khartoum, Sudan
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6 c
UCL, Eastman Dental Institute, London,United Kingdom
7 d
Department of Pathology, University of Rochester, School of Medicine and Dentistry, USA
8Q3 e
BIOSS Centre for Biological Signalling Studies
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9 a r t i c l e i n f o a b s t r a c t
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10 Article history: A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or 30
11
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Received 14 March 2015 tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces 31
12 Accepted 16 June 2015 and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, 32
13 Available online xxxx
these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those 33
where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. 34
14
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15
Keywords:
Autoantibodies
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Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal 35
16 Autoantigens surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical 36
17 manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by 37
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Autoimmune blistering diseases
18 Basement membrane various methods including histological examination, direct and indirect immunofluorescence microscopy, 38
19 Ulcers immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency 39
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20 ELISA of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practi- 40
21 Immune-mediated tioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatoses with oral 41
22 Immunofluorescence microscopy
involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity 42
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23 Corticosteroids
with a specific emphasis on their differential diagnosis and current management approaches. 43
24 Erythema multiforme
25 Desquamative gingivitis © 2014 Published by Elsevier B.V. 44
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26 Epidermolysis bullosa
27 Lichen planus
28 Pemphigoid
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29 Pemphigus
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50
49 Contents
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51 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
52 2. Clinical phenotypes of oral involvement in autoimmune disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
53
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3. Diagnostic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
54 4. Pemphigus diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
55 4.1. Pemphigus vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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56 5. Pemphigoid diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
57 5.1. Mucous membrane pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
58 5.2. Linear IgA disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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59 6. Epidermolysis bullosa acquisita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

60 7. Other autoimmune skin diseases with oral manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
61 8. Chronic ulcerative stomatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
62 9. Lichen planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
63 10. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
64 11. Lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Abbreviations: BP, bullous pemphigoid; DH, dermatitis herpetiformis; EBA, epidermolysis bullosa acquisita; ELISA, enzyme-linked immunosorbent assay; IF, immunofluorescence;
LAD, linear IgA disease; MMP, mucous membrane pemphigoid; PF, pemphigus foliaceus; PNP, paraneoplastic pemphigus; PV, pemphigus vulgaris.
⁎ Corresponding author at: Department of Dermatology, University of Freiburg, Hauptstrasse 7 D-79104 Freiburg, Germany. Tel.: +49 761 27067690; fax: +49 761 27068290.
E-mail addresses: cassian@mail.sitaru.eu, cassian.sitaru@uniklinik-freiburg.de (C. Sitaru).
http://dx.doi.org/10.1016/j.autrev.2015.06.005
1568-9972/© 2014 Published by Elsevier B.V.
Please cite this article as: Mustafa MB, et al, Oral mucosal manifestations of autoimmune skin diseases, Autoimmun Rev (2014), http://dx.doi.org/
10.1016/j.autrev.2015.06.005
2 M.B. Mustafa et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
65 12. Therapeutic approaches in autoimmune diseases with oral involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

66 12.1. Principles of therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
67 12.2. Topical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
68 12.3. Systemic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
69 Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
70 Uncited reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
71 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
72 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
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74 1. Introduction focal contacts (Fig. 1) [4]. Desmosomes are anchoring complexes that 94
link epithelial cells to each other and attach the keratin filaments to 95
75 Oral mucosa and skin are composed of highly specialized stratified the cell surface. Desmosomes consist of calcium-dependent adhesion 96
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76 epithelium that functions as a first-line barrier against physical and molecules called cadherins, including desmogleins and desmocollins, 97
77 chemical damage. The integrity of this epithelial barrier is essentially which are transmembrane proteins that extend across the plasma 98
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78 dependent on structures maintaining cell-cell and cell-matrix adhesion membrane and mediate cell-cell adhesion by homo- or heterophilic in- 99
79 [1]. Autoimmune bullous diseases are associated with autoantibodies teractions between their extracellular protein domains. An additional 100
80 directed against structures that mediate cell-cell and cell-matrix group of intracellular proteins resides on the cytoplasmic face of desmo- 101
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81 adhesion in skin and mucous membranes [2]. In pemphigus diseases somes and constitutes the desmosomal plaque. Desmosomal plaque is 102
82 tissue injury is mediated by autoantibodies against the cell-cell junction associated with different types of proteins include plakoglobin, the 103
83 causing intra-epithelial blistering, whereas in subepidermal autoim- desmoplakins, the plakophilins, envoplakin, and periplakin. It provides 104
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84 mune diseases autoantibodies are directed against the epithelial – adhesion by linking the desmosomal transmembrane cadherin proteins 105
85 connective tissue junction at the basement membrane zone (BMZ) [3]. to the cytoplasmic keratin filaments [1,5]. 106
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86 Primary or extensive oral involvement is the hallmark of further inflam- Hemidesmosomes are specialized junctional complexes on the 107
87 matory autoimmune conditions, including lichen planus (LP), erythema ventral surface of the basal keratinocytes that maintain the epithelial 108
88 multiforme (EM), lupus erythematosus (LE) and chronic ulcerative cell attachment to the underlying basement membrane. In the oral cav-
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89 stomatitis (CUS). ity they can also be found in the junctional epithelium in contact to the 110
90 Skin and oral mucosa are stratified epithelia, in which the cell-cell tooth surface [6]. The basement membrane zone (BMZ) comprises the 111
91 adhesion is mainly mediated by desmosomes and adherens junctions, basal cell plasma membrane, the lamina lucida, the lamina densa and 112
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92 whereas the adhesion of basal epithelial cells on the underlying the sublamina densa. Anchoring filaments traverse the lamina lucida 113
93 basement membrane essentially depends on hemidesmosomes and perpendicularly from the basal cell membrane to the underlying lamina 114
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Fig. 1. Schematic representation of major autoantigens found in the skin and mucous membranes. The autoantigens are molecules that maintain the cell-cell and cell-matrix adhesion.
Desmosomes consist of cadherins, including desmogleins and desmocollins, which are transmembrane proteins that extend across the plasma membrane and confer adhesion by calci-
um-dependent interactions between their extracellular protein domains. On the cytoplasmic sides of desmosomes, reside the desmosomal plaque, through which the carboxy-terminal
regions of cadherins are rooted and composed of different types of proteins such as plakoglobin and desmoplakins which provide adhesion by linking the desmosomal transmembrane
cadherin proteins to the cytoplasmic keratin filaments. Hemidesmosomes have an important role in cell-basement membrane adhesion and are organized in three classes of proteins.
The first class is the cytoplasmic plaque proteins which connect the intermediate filament cytoskeleton to the plasma membrane. These include bullous pemphigoid antigens BP230
(BPAG 1) and plectin. The second class includes α6β4 integrin and BP180 (also termed BPAG 2 or type XVII collagen), which are transmembrane proteins involved in the assembly of
hemidesmosomes, connecting the cell interior to the extracellular matrix and serving as cell receptors. The final class of proteins consists of basement membrane associated proteins
of the extracellular matrix, which include different laminin isoforms and type IV collagen. Laminin (Ln) 332 is a major component of the lamina densa, Laminin γ1 chain, present in
the vessel walls and as in laminin 511, may function as autoantigen. Laminins interact with different subsets of integrins such as α6β1, α3β1 or α6β4 and regulates not only epithelial
cell adhesion to the BMZ but also normal cellular functions such as proliferation, polarity and differentiation. Collagen VII is the main constituent of the anchoring fibrils, which connect
lamina densa to the collagen fibers of the upper dermis.
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115 densa [3]. At molecular levels, the BMZ contains a mixture of structural Table 1 t1:1
116 components and antigens including collagen VII, which is the major Prevalence of oral mucosal involvement in immune-mediated disorders. t1:2
117 structural component of anchoring fibrils, and collagen IV, which is a Disease No. of cases Reference t1:3
118 major ubiquitous component of vertebrate basement membranes. Lichen planus (65%) 82 Carvalho et al. 2011 [20] t1:4
119 Laminins, which exist in various molecular forms as abundant non- Pemphigus vulgaris (26.8%) t1:5
120 collagenous glycoproteins of basement membranes, are heterotrimers Pemphigoid (7.3%) t1:6
121 consisting of alpha, beta and gamma chains [3,6]. Lichen planus (70.2%) 309 Jaafari-Ashkavandi et al. 2011 [22] t1:7
Pemphigus vulgaris (24.9%) t1:8
122 Hemidesmosomes, together with the anchoring filaments, form
Pemphigoid (3.3%) t1:9
123 the hemidesmosomes anchoring filament complex, which plays an im- Erythema multiforme (I.3%) t1:10
124 portant role in cell-basement membrane adhesion. The molecular organi- Lupus erythematosus (0.33%) t1:11
125 zation of hemidesmosomes is based on three classes of proteins. The first Lichen planus (51%) 88 Goncalves et al. 2010 – [21] t1:12
126 class is the cytoplasmic plaque proteins, which connect the intermediate Lupus erythematosus (20%) t1:13
Erythema multiforme (20%) t1:14
127 keratin filament cytoskeleton to the plasma membrane. These include Pemphigus vulgaris (9%) t1:15
128 bullous pemphigoid antigens BP230 (BPAG 1) and plectin. BP230 was Lichen planus (76.56%) 64 Arisawa et al. 2008 – [19] t1:16
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129 the first recognized targeted antigen in patients with bullous pemphigoid. Pemphigoid (9,37%) t1:17
130 The second class consists of transmembranous proteins, including α6β4 Erythema multiforme (7.82%) t1:18
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Pemphigus vulgaris (6.25%) t1:19
131 integrin and collagen XVII/BP180 (also termed BPAG2), which connect
Lichen planus (70.5%) 187 Leo et al. 2008 – [23] t1:20
132 the hemidesmosomal plaque to the extracellular matrix and may serve Pemphigoid (14%) t1:21
133 as cell receptors [7]. The extracellular domain of α6β4 integrin is crucial Pemphigus vulgaris (13%) t1:22
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134 for cell adhesion and acts as a receptor for various laminin types with linear IgA disease (1.6%) t1:23
135 particular high affinity to laminin 332. BP180 is a collagenous molecule
that can interact with α6β4 integrin. A further main class of proteins of
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137 the epidermal basement membrane are components of the extracellular 2. Clinical phenotypes of oral involvement in autoimmune disorders 181
138 matrix and include different laminin isoforms and collagen IV. Laminins
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139 are large family of glycoproteins serving as major cell adhesion substrates Autoimmune diseases may manifest on oral mucous membrane as 182
140 at the basement membranes. They interact with different subsets of erythema, blisters, erosions, and ulcerations. By far, oral blisters and 183
141 integrins such as α6β1, α3β1 or α6β4. Such an interaction at the cell ulcerations are the most common presenting features of immune-
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142 surface regulates not only epithelial cell adhesion to the basement mediated disorders in the oral cavity. Oral blisters erode rapidly and 185
143 membrane zone but also further physiological cellular functions such as leave behind ulcers associated with moderate to severe pain and 186
144 proliferation, migration polarity and differentiation [6,7]. discomfort that may interfere with speaking, eating and swallowing. A 187
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145 Various autoimmune diseases may involve oral epithelium, includ- variety of local and systemic factors and conditions may trigger mucosal 188
146 ing pemphigus vulgaris, mucous membrane pemphigoid, epidermolysis ulceration such as trauma, recurrent aphthous stomatitis, haematologi- 189
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147 bullosa acquisita, lichen planus, erythema multiforme, lupus erythema- cal diseases, gastrointestinal disorders and malignant conditions. 190
148 tosus and chronic ulcerative stomatitis. Affected individuals present Patients with immune-mediated disorders usually present with multi- 191
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149 with variable degrees of oral mucosal lesions associated with extraoral ple ulcers or erosions, which may have an acute onset or develop slowly 192
150 manifestations due to involvement of the skin and/or further mucosal over a period of time. Erosions and ulcerations appear variable in 193
151 surfaces, including nasal mucosa, pharyngeal mucosa or the conjunctiva size with irregular shape and are preceeded by superficial blisters 194
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152 [8,9]. The clinico-epidemiological features of autoimmune diseases have (Table 2). Further mucosal lesions, including white striae or plaques 195
153 been studied in different populations worldwide. However, the majority may be also identified upon clinical examination. Extra-oral examina- 196
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154 of existing reports focus on the epidemiology of a single disease or a tion is important and may reveal lesions of the skin and of other mucous 197
155 group of diseases and only a few describe the epidemiological features membranes including the nose, eyes or genitalia. These lesions may ap- 198
156 of the whole spectrum of autoimmune diseases in particular population. pear concomitantly with oral lesions or may precede or arise later in the 199
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157 Studies from Eastern Europe show that pemphigus is the most common course of the disease. 200
158 autoimmune blistering disease with an estimated incidence and preva-
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159 lence of 4 and 24.8 per 100 000 inhabitants, respectively [10]. Similar
160 results also emerged in studies conducted in Western Asia, East Asia Table 2 t2:1
161 and Africa, where pemphigus was also found to be the most prevalent Major autoantigens in immune-mediated disorders affecting the oral mucosa. t2:2
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162 autoimmune bullous dermatose [11–13]. In contrast, in Western Disease Autoantigen t2:3
163 Europe and North America, bullous pemphigoid was found to be the
Pemphigus Diseases t2:4
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164 most common autoimmune blistering disease with an incidence Pemphigus vulgaris Desmoglein 3, Desmoglein 1 t2:5
165 ranging from 0.6 to 4.3 cases per 100 000 inhabitants [14–16]. Several Paraneoplastic pemphigus Desmoglein 3, Desmoglein 1, Desmoplakin, t2:6
166 descriptive epidemiological studies on lupus erythematosus have been Periplakin, Envoplakin, Plectin, Desmocollins
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167 also conducted worldwide. The most extensive available data come 1-3, BP230,
Alpha-2-macroglobuline-like -1 t2:7
168 from the European Union and the United States of America. The inci- Pemphigus vegetans Desmoglein 3, Desmoglein 1 t2:8
169 dence rate of SLE in Europe is 3.3–4.8 cases per 100,000 population Pemphigus foliaceus Desmoglein 1 t2:9
170 and year and in the USA 2.0–7.6 [17,18]. t2:10
Pemphigoid Diseases t2:11
171 The prevalence of oral mucosal involvement in immune-mediated Mucous membrane pemphigoid Collagen XVII/BP180, BP230, Laminin 332, α6β4 t2:12
172 disorders varies according to the type of disease. Studies show that integrin
173 oral lichen planus is the most common immune-mediated disorder Linear IgA disease LAD-1 (120 kDa), LABD97(97 kDa), 285 kDa, t2:13
174 affecting the oral cavity, followed by pemphigus vulgaris and mucous 180 kDa
Epidermolysis bullosa acquisita Collagen VII t2:14
175 membrane pemphigoid [19–23] (Table 1). Moreover, oral mucosa can
Bullous pemphigoid Collagen XVII/BP180, BP230 t2:15
176 be the first affected mucosal surface in many of these conditions, a fact Dermatitis herpetiformis Tissue/epidermal transglutaminase t2:16
177 that emphasizes the need for better understanding of clinical features Chronic ulcerative stomatitis deltaNp63alpha t2:17
178 and diagnostic tools for autoimmune diseases among practitioners. Lichen planus Not known t2:18
179 Precise and early diagnosis greatly facilitates timely, effective and Erythema multiforme Not known, Desmoplakin I and II (?) t2:19
Systemic lupus erythematosus Nuclear antigens t2:20
180 specific treatment [19].
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201 Several immune-mediated disorders share a common clinical used. With the identification of target antigens and advancement of 265
202 feature in the oral cavity, the so-called “desquamative gingivitis”. This molecular biology and recombinant technology, antigens have been 266
203 term was introduced to describe the presence of erythema, localized produced in bacteria and eukaryotic cells. These recombinant, cell- 267
204 or generalized desquamation and /or erosion on the buccal aspect of derived forms of the target antigens have been utilized in the develop- 268
205 attached gingiva mainly of the anterior teeth. In some cases, marginal ment of sensitive and specific ELISA kits for detection of circulating 269
206 gingiva may also be affected. Gingival desquamation has a subacute autoantibodies. ELISA using recombinant antigens has several 270
207 or chronic onset in the majority of cases, with variable degrees of advantages over indirect IF techniques on tissue sections. It provides in- 271
208 extension and distribution [24]. Desquamative gingivitis thus may be a formation on the molecular specificity of autoantibodies, it is easy to 272
209 common clinical phenotype occurring in a variety of disorders such perform and readily amenable to standardization, and, importantly 273
210 as chronic ulcerative stomatitis, lichen planus, mucous membrane gives quantitative results. Therefore, these are exquisite parameters 274
211 (cicatricial) pemphigoid, pemphigus vulgaris, erythema multiforme, for monitoring diseases, in which levels of serum autoantibodies have 275
212 plasma cell gingivitis and graft-versus-host disease [24]. Epidemiologi- been shown to correlate with disease activity. Several commercially 276
213 cal data shows that desquamative gingivitis is associated with available ELISA kits are now used for the diagnosis and monitoring of 277
214 immune-mediated disorders in about 88% to 98% of the cases [25]. immune-mediated diseases (Table 3) [32,33]. 278
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215 Mucous membrane pemphigoid has been reported in many published
216 series to be the most common cause of desquamative gingivitis, respon-
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217 sible for 35% to 48% of the cases [24,26,27]. However, more recent data 4. Pemphigus diseases 279
218 showed a predominance of oral lichen planus over mucous membrane
219 pemphigoid as a cause for desquamative gingivitis (75% vs 9%) [25]. Pemphigus diseases represent a group of immune-mediated disor- 280
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ders characterized by widespread blistering and ulceration affecting 281
220 3. Diagnostic approach the skin and mucous membranes. The term pemphigus is the latinised 282
form of the Greek Pemphix (meaning bubble or blister). In 1964, it was 283
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221 The specificity of the clinical features as a diagnostic parameter tend Beuter and Jorden who found that patients with pemphigus diseases ex- 284
222 to vary among different autoimmune disorders. A significant overlap hibit circulating autoantibodies against calcium-dependant adhesion 285
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223 exists in their clinical presenting features, which makes accurate diag- molecules (desmosomes), which maintain keratinocytes adhesion 286
224 nosis extremely difficult based on clinical features alone. Therefore, for [34]. Binding of autoantibodies to desmosomal components results in 287
225 initiating an adequate differential diagnosis, observation of the clinical cell-cell detachment (acantholysis) and formation of intra-epithelial
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226 features must be accompanied by histopathological examination of blisters [35]. 289
227 the skin or mucosal biopsy [28]. Biopsies that are taken from fresh ves- Main diseases of the pemphigus group include pemphigus vulgaris, 290
228 icles/blisters are helpful in revealing the pathological pattern of tissue pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, 291
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229 damage regarding the site of vesicles formation as well as the presence, paraneoplastic pemphigus and IgA pemphigus [36,37]. Oral mucosa 292
230 intensity, and composition of the inflammatory cells infiltrate [29]. can be involved to variable degrees in different pemphigus conditions, 293
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231 However, the definitive, accurate diagnosis of autoimmune diseases however, pemphigus vulgaris and paraneoplastic pemphigus are the 294
232 requires the detection of immunoreactant deposits in the tissues and most common variants of the pemphigus group that consistently 295
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233 the circulating autoantibodies by direct and indirect immunofluores- show oral lesions during the course of disease. 296
234 cence (IF) microscopy, respectively. Direct IF microscopy helps to detect Paraneoplastic pemphigus, sometimes also termed paraneoplastic 297
235 molecules such as immunoglobulins and complement within biopsy autoimmune multi-organ pemphigus (PAMS), is usually associated 298
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236 specimens. Selection of the site for the biopsy specimen is important. with malignant tumours such as lymphomas, leukaemia and malignant 299
237 Direct IF microscopy is performed on non-bullous or non-eroded skin melanoma. The disease arise as a result of several autoantibodies against 300
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238 or mucosa (i.e. erythematous or normal appearing tissue adjacent to several keratinocyte proteins such as desmoglein 1, desmoglein 3, 301
239 blisters or erosions), because immune deposits maybe degraded in the desmoplakin 1, envoplakin, periplakin and BP230 [38]. Patients develop 302
240 area where the dermal-epidermal separation occurs, leading to false intractable mucosal ulceration of the oropharynx and severe crusting of 303
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241 negative results. False negative results may also occur as a result of the lips along with the typical cutaneous eruptions of pemphigus 304
242 improper handling or faulty preservation of the biopsy, which must be diseases [39]. 305
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243 frozen immediately and stored at temperatures below −70 °C or placed Pemphigus vegetans is a rare variant of PV, that constitute only 1–2% 306
244 in a saline or a special Michel's medium for transport for no longer than of all pemphigus cases. The main antigenic targets of pemphigus 307
245 48 hours for subsequent immunofluorescence testing [29,30]. vegetans are the same as for pemphigus vulgaris, namely Dsg3 and 308
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246 Indirect IF microscopy, is a test in which patient’s serum is examined Dsg1. Pemphigus vegetans usually affects intertriginous areas such as 309
247 for the presence of circulating autoantibodies to a defined antigen. Sub- the axilla and the groin and give rise to vegetating skin lesions and ves- 310
icles. Long-standing disease may produce hyperkeratotic and fissured
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248 strates used in this technique include frozen sections of normal tissues 311
249 such as human skin and monkey oesophagus. These sections are then vegetations [40]. More than 50% of the patients show oral manifesta- 312
250 incubated with serum samples and the binding of serum autoantibodies tions preceding cutaneous lesions and those with cutaneous lesions 313
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251 to their corresponding antigens in the tissues is detected by using eventually develop oral manifestations. Oral lesions appear as irregular 314
252 fluorescent-labeled anti-immunoglobulin antiserum [31]. For further ulceration that may have a vegetative appearance with occasional 315
253 characterising the binding sites of autoantibodies against the basement
254 membrane, the sensitivity of this technique may be increased by using Table 3 t3:1
255 salt-split skin as a substrate. This substrate is generated by incubating Commercially available quantitative immunoassays for the detection of autoantibodies in t3:2
256 normal human skin in 1 M NaCl until splitting occurs within the lamina patients with oral manifestations of autoimmune blistering diseases. t3:3
257 lucida of the basement membrane. This test allows the differentiation
Disease Autoantigen Epitope(s) References t3:4
258 between serum autoantibodies that bind to the roof and those that
Pemphigus Desmoglein 1 Ectodomain [215,216] t3:5
259 stain the floor of the artificial split reflecting the molecular difference
Pemphigus Desmoglein 3 Ectodomain [215,216] t3:6
260 in autoantibody specificity [30]. Paraneoplastic pemphigus Envoplakin Full-length [217] t3:7
261 A number of other immunoassays, including enzyme-linked immu- Pemphigoid (IgG, IgE) BP180 NC16A domain [218,219] t3:8
262 nosorbent assay (ELISA), immunoblot or immunoprecipitation are Pemphigoid (IgG) 4xNC16A domain [220] t3:9
263 available to facilitate the characterization of the molecular specificity Epidermolysis bullosa Collagen VII NC1 domain [221,222] t3:10
acquisita (IgG) NC1, NC2 domains [223] t3:11
t3:12
264 of autoantibodies. Of these techniques, the ELISA is most commonly
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316 pustules formation. The tongue may acquire a cerebriform appearance Exogenous factors in genetically predisposed individuals have been 380
317 with numerous sulci and gyri [38,41]. suggested such as drugs (e,g. penicillamine and angiotensin-converting 381
318 Pemphigus foliaceus is a rare type of pemphigus with both sporadic enzyme inhibitors), diet and viral infections. Also, endogenous factors, 382
319 and endemic forms occurring mainly in children and young adults. including emotional stress and increased levels of oestrogen hormones 383
320 Pemphigus foliaceus is characterized by the presence of IgG4 antibodies have been implicated [46,53]. 384
321 directed against Dsg1 that give rise to acantholysis in the upper spinous Clinically, pemphigus vulgaris usually begins with mucosal involve- 385
322 layer. Resulted vesicle and bulla are therefore very superficial and ment with or without skin lesions. Mucosal lesions are usually located in 386
323 extremely fragile [42]. Pemphigus foliaceus can occur at almost any the oral and pharyngeal mucosa, although conjunctiva, larynx, nasal 387
324 cutaneous surface, however, the skin of the chest, back and shoulders mucosa and vagina may also be involved [59]. Oral mucosa is the most 388
325 are most commonly affected. Presumably, because of the absence of commonly affected mucosal surface in patients with pemphigus 389
326 anti-Dsg1 antibodies, the oral mucosa and gingivae are rarely affected vulgaris. Oral lesions are hallmark of PV and occur in almost all the 390
327 in patients with pemphigus foliaceus and when present are similar to cases usually at the onset of the disease [10,19,20,60–63]. The preva- 391
328 those of pemphigus vulgaris [43]. lence of oral involvement as the initial site varies in different population 392
329 Other rare forms of pemphigus foliaceus include pemphigus erythe- studies, ranging between 37% and 77.5% [60,61,64–66]. Importantly, the 393
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330 matosus (Senear-Usher type), pemphigus herpetiformis, and drug- high frequency of initial isolated oral mucosal involvement may result 394
331 induced pemphigus vulgaris [2]. in delayed diagnosis despite the fact that patients seek medical help at 395
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an early stage due to pain and discomfort associated with mastication, 396
332 4.1. Pemphigus vulgaris swallowing and speech [67,36]. 397
Oral lesions of pemphigus vulgaris may present as multiple chronic 398
O
333 Pemphigus vulgaris (PV) is a life-threatening organ-specific human ulcers involving any part of the oral mucosa, with sites subjected to fric- 399
334 autoimmune disease. This variant represents the most frequent and rep- tion trauma. The buccal mucosa, palate, lips and gingiva, are particularly 400
affected [68]. Oral lesions start initially as fluid-filled blisters which may
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335 resentative form of the pemphigus group, corresponding to about 70% of 401
336 the ceases. Pemphigus vulgaris has a wide range of incidence across be localized or diffuse with tendency to spread. Blisters are usually thin- 402
337 worldwide geographic locations and ethnic groups, ranging between walled and easily rupture, giving rise to painful, multiple ulcerations. 403
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338 0.76 and 16 cases per million per year [44,45]. The disease is more com- New blisters keep developing as the older ones rupture and ulcerate. 404
339 mon among Jewish populations, in particular of Ashkenazi origin and in Ulcerations are initially superficial, irregular in shape, with a red base 405
340 Eastern countries such as India, Malaysia, China and Japan. It affects both and ragged whitish margins, but as infection supervenes, a yellowish
D 406
341 males and females with a mean age between 40 and 60 years [46]. slough may develop (Fig. 2a). These ulcers heal slowly without scaring 407
342 Pemphigus vulgaris is a potentially lethal disease. Before the advent [36]. Gingival pemphigus lesions are less common and at onset appear 408
343 of corticosteroid therapy the mortality was about 90%. Detailed data on as isolated blisters and erosions located on free gingiva. In longstanding 409
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344 the real incidence of pemphigus vulgaris mortality is not available, how- disease, erosive or desquamative gingivitis may develop [69]. Oral le- 410
345 ever, recent studies show that patients with pemphigus has a 2.36-fold sions in pemphigus vulgaris may persist for months before progressing 411
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346 increase in mortality compared with the general population. Pemphigus to the skin and other mucosal surfaces. Cutaneous involvement may be 412
347 vulgaris is still associated with high mortality rate ranging in the litera- localized or generalized. Skin lesions have a predilection for the trunk, 413
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348 ture from 5 to 30% during various lengths of follow-up [44]. groins, axillae, scalp, face, and pressure points. Flaccid blisters develop 414
349 Tissue damage in pemphigus vulgaris results from binding of on these sites and may coalesce; these blisters eventually rupture and 415
350 autoantibodies to the intercellular junctions within the epidermis. result in painful erosions [59]. 416
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351 Tissue-bound antibodies are generally of IgG type, but IgA and comple- Extra-oral mucosal sites may be also affected in patients with 417
352 ment deposits may also be detected by direct immunofluorescence of pemphigus vulgaris. In a recent study conducted in 38 patients, 87% of 418
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353 perilesional biopsy [47,48]. Pemphigus vulgaris may manifest clinically the patients with pemphigus vulgaris were found to have blisters 419
354 with mucosal or mucocutaneous involvement. The clinical features of and erosions involving the ear, nose and throat (ENT) mucosae upon 420
355 each type roughly correlates with anti-Dsg autoantibody profile in the endoscopic examination [70]. Involvement of the mucosa of the eye, 421
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356 patients serum as well as the difference in Dsg expression between nose and larynx are associated with pain or discomfort and may cause 422
357 the skin and mucous membranes. The so called desmoglein compensa- multiple dysfunctions affecting swallowing, phonation, respiration and 423
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358 tion hypothesis has been advanced to explain this phenomenon and is olfaction. Endoscopic findings show greater frequency of clinically 424
359 reviewed in details elsewhere [46,49]. Dsg1 and Dsg3 are considered active pemphigus vulgaris lesions than the ENT symptoms reported by 425
360 the main target antigens in pemphigus diseases. Several lines of clinical affected patients. These findings highlight the need for endoscopic 426
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361 and experimental evidence support the pathogenic role of Dsg-specific assessment for patients with pemphigus vulgaris [68,70]. 427
362 autoantibodies [8]. Thus titres of anti Dsg1 and anti Dsg3 antibodies A number of scoring systems have been developed in recent years to 428
N
363 correlate well with clinical severity of the disease and injection of provide objective and standardized values for disease severity and pro- 429
364 these antibodies into neonatal mice leads to acantholytic blistering gression (Table 4). Presently, the pemphigus disease area index (PDAI) 430
365 [50]. In addition, autoantibodies to several non-desmoglein antigens and autoimmune bullous skin disorder intensity score (ABSIS) are the 431
U
366 have been detected in patients with pemphigus vulgaris, including most established tools to assess disease activity in pemphigus [71–73]. 432
367 those against E-cadherin, desmoplakin and the alpha9 acetylcholine Pemphigus vulgaris must be differentiated from other blistering 433
368 receptor [51–53]. As with other autoimmune diseases, pemphigus disorders such as lichen planus, mucous membrane pemphigoid, linear 434
369 vulgaris may associate clinically or serologically with other autoimmune IgA disease and erythema multiforme (Table 5). It is crucial to establish 435
370 disorders, such as myasthenia gravis, ulcerative colitis, rheumatoid an early diagnosis for patients with PV, so that adequate treatment can 436
371 arthritis, lupus erythematosus or vitiligo [54–56]. be commenced. The informed practitioner will suspect pemphigus 437
372 The initiating stimulus for the production of pemphigus autoanti- vulgaris in a patient with non-scarring, fragile blisters and erosions 438
373 bodies remains unclear, however, predisposing factors have been involving the mucosa with varying degree of cutaneous involvement, 439
374 suggested. Genetic association between HLA class II genes and pemphi- especially when suprabasilar acantholytic cleavage is documented 440
375 gus vulgaris is well documented. Additional support for a genetic basis as the histopathological correlate in lesional skin. The diagnosis of 441
376 comes from the observation that PV is increased in certain ethnic groups pemphigus vulgaris is confirmed by the detection of tissue-bound and 442
377 and that only sporadic cases involve first-degree relatives [57,58]. circulating autoantibodies against the intercellular junctions in the 443
378 However, genetic predisposition is not sufficient by itself to initiate epidermis, by direct and indirect immunofluorescence microscopy, 444
379 the pathogenic autoimmune mechanism resulting in tissue damage. respectively. In addition the molecular specificity of pemphigus 445
10.1016/j.autrev.2015.06.005
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Fig 2. Pemphigus vulgaris (PV). (a) Oral lesions in a patient with pemphigus vulgaris showing generalized ulceration and erosions. (b) Histopathological examination shows typical intra-
epithelial suprabasal acantholysis with moderate inflammatory infiltrate. A “row of tombstones” appears as a single layer of basal keratinocytes remains attached to the basement
membrane. (c) Direct immunofluorescence microscopy of a perilesional biopsy shows interceluular deposition of IgG in epidermis. (d) Serum IgG autoantibodies binding with an
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intercellular pattern are detected by indirect immunofluorescence microscopy on monkey oesophagus.

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446 autoantibodies may be characterized by quantitative immunoassays epidermis (Fig. 2c). Pemphigus autoantibodies predominantly belong 459
447 using recombinant Dsg 1 and 3, which may be used as monitoring to the IgG4 subclass, however autoantibodies belonging to the IgA and 460
448 tools for the follow-up. IgE isotypes have also been detected [74,75]. Indirect IF microscopy 461
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449 Histopathological examination is typically characterized by suprabasal reveals the presence of serum autoantibodies binding with an intercel- 462
450 loss of adhesion (acantholysis), leaving a single layer of basal lular fluorescence (net-like) pattern within epithelia of suitable 463
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451 keratinocytes attached to the dermal-epidermal basement membrane substrates such as monkey esophagus (Fig. 2d) [30]. 464
452 (tombstone pattern) (Fig. 2b). This characteristic feature differentiates Enzyme-linked immunosorbent assay (ELISA) provide higher sensi- 465
453 pemphigus vulgaris from pemphigus foliaceus, which is associated with tivity and specificity in making the diagnosis of pemphigus subtypes. 466
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454 a more superficial, subcorneal split formation [30,59]. ELISA tests provide a quantitative method for measuring Dsg-specific 467
455 By direct IF microscopy, IgG or C3 binding to the intercellular autoantibody levels, and are currently used for the diagnosis of pemphi- 468
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456 adhesion substance in the mid-lower or entire epidermis of perilesional gus [32,76]. The severity of skin and oral mucous membrane lesions in 469
457 skin or mucosa, is characteristic. Tissue-bound IgG, C3, IgM, or IgA will pemphigus was found to correlate well with the levels of autoantibodies 470
458 appear in a characteristic net-like intercellular pattern within the to Dsg1 and Dsg3 , respectively [77,78]. 471
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t4:1
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Table 4
t4:2 Scoring systems for pemphigus diseases involving oral mucosa.
t4:3 Scoring System Description References

U
(Advantages / Limitations)
t4:4 Pemphigus Disease Activity Index Integrates cutaneous with mucosal diseases in well defined anatomical locations. [71,224]
(PDAI) Asses numbers and sizes of the lesions. Scores post-inflammatory hyperpigmentation of resolving lesions
t4:5 Autoimmune Bullous Skin Disorder Is a quality and quantity based score for cutaneous and oral mucosal lesions [73]
t4:6 Intensity Score (ABSIS) Monitors clinical status of individual patients overtime. Oral involvement scores comprise both objective and subjective
information
t4:7 Pemphigus Area and Activity Score Scores are based on the body surface area, number of new blisters, peripheral extension of lesions and Nikolsky's sign [225]
(PAAS) Severity description is subjective. Does not incorporate size of the lesions. Large changes in the body surface area are
required to reflect change in severity score
t4:8 Saraswat's oral pemphigus scoring A scoring system for oral pemphigus [226]
Assess both the extent of lesions on different oral sites and the their severity. May be used for assessing MMP, herpetic
gingivostomatitis and Steven's Johnson's Syndrome.
t4:9 Pemphigus Activity Score Introduces intensity of steroid and immunosuppressive therapy along with the extent of disease. Lacks the differential [227]
clinical involvement of mucosal and cutaneous lesions
t4:10 Mahajan's Scoring System Assesses severity of pemphigus by the degree of body surface area involved. [228]
t4:11 Harman's Pemphigus grading Scores the severity of oral and skin lesions. Incorporates the antibody titer as assessed by ELISA [78]
10.1016/j.autrev.2015.06.005
t5:1 Table 5 anti-epiligrin cicatricial pemphigoid (AECP), is characterized by oral and 519
t5:2 Diagnostic criteria for pemphigus vulgaris. ocular mucosal involvement and autoantibodies against laminin 332. 520
t5:3 Diagnostic criteria Findings Clinical evidence suggests that patients with AECP have increased risk 521
of developing solid cancers early on during the course of disease, such 522
t5:4 Clinical features
t5:5 Oral lesions First manifestation in (50–70%) of the patients as adenocarcinomas and non-Hodgkin's lymphoma [89,90]. 523
Multiple ulcerations / erosions resulting from blisters Clinically, mucous membrane pemphigoid most commonly affects 524
Desquamative gingivitis the oral mucosa, followed by the conjunctiva, nasal cavity, nasopharyn- 525
t5:6 Skin lesions Skin blistering, erosions
geal mucosa, anogenital area, skin, larynx and esophagus in a descending 526
t5:7
t5:8 Laboratory investigations order of frequency [81,91]. The disease has a relapsing and remitting 527
t5:9 Histology Intraepithelial suprabasal cleavage with acantholysis course, with symptoms and signs typically that develop progressively 528
t5:10 Direct IF microscopy Intraepidermal deposition of IgG/C3 with an
over several weeks, and persist for many years with intermittent periods 529
intercellular pattern
t5:11 Indirect IF microscopy IgG autoantibodies binding to epithelial cells with an of activity and remission. Clinical severity is variable and ranges from 530
intercellular pattern mild oral and conjunctival lesions to severe and painful generalized mu- 531
t5:12 ELISA / Immunoblotting IgG autoantibodies to Desmoglein (Dsg)3 and Dsg1 cosal involvement [80]. In all the affected mucosal surfaces, ulcers and 532
F
erosions have a pronounced tendency to heal with scaring and hence 533
compromise the function of the affected mucosa. Sequelae and complica- 534
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472 5. Pemphigoid diseases tions such as strictures of larynx or oesophagus may develop and could 535
be fatal [92]. However, in the oral mucosa re-epithelialization of the 536
473 Pemphigoid diseases represent a family of chronic, subepithelial affected sites without scaring may also occur. 537
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474 blistering disorders, characterized by autoantibodies against structural Oral lesions may be the first and only manifestation of the disease. 538
475 components of the dermo-epidermal junction. Pemphigoid diseases Patients present with complaints of pain and dysphagia associated 539
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476 are heterogeneous with respect to the clinical presentation, degree of with peeling of the mucosa. Lesions initially appear as tense vesicles, 540
477 skin and / or mucosal involvement, target antigens and autoantibody with serous and/or hematic contents, that progress quickly to irregular- 541
478 isotypes. Diseases of the pemphigoid group include bullous pemphi- ly shaped erosions, covered with yellowish pseudomembranes and 542
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479 goid, mucous membrane pemphigoid, pemphigoid gestationis, linear surrounded by inflammatory halos (Fig. 3a) [93]. Oral lesions most 543
480 IgA-disease, anti-p200 pemphigoid and lichen planus pemphigoides commonly affect the gingivae, buccal mucosa, and palate; they may 544
481 [79,80] also occur on the alveolar ridge, tongue, and lower lip. Gingival lesions
D 545
may represent the onset of the diseases in the oral cavity and appear 546
482 5.1. Mucous membrane pemphigoid clinically as a desquamative gingivitis. In a recently conducted large 547
cohort study of patients with desquamative gingivitis, mucous mem- 548
E
483 Mucous membrane pemphigoid is an autoimmune subepithelial brane pemphigoid was found to be the second most common cause, fol- 549
484 blistering disease that predominantly affects mucous membranes with lowing lichen planus, representing more than 25% of the patients [94]. 550
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485 varying degrees of severity, such as the oral mucosa, ocular mucosa, Several studies have shown that mucous membrane pemphigoid affects 551
486 laryngeal mucosa and genital mucosa. Previously, different terms such the periodontal health status, especially with regard to the development 552
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487 as cicatricial pemphigoid and benign cicatricial pemphigoid were used of supragingival dental plaque as well as worsening of periodontal 553
488 as a reference for this condition [81]. This rare disease predominantly parameters, including periodontal depth, clinical attachment level, 554
489 affects women with mean age of onset in the mid 60s [10,11,16]. mobility scores and bleeding [95–97]. 555
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490 Mortality associated with mucous membrane pemphigoid is usually Ocular involvement is a serious aspect of mucous membrane pemphi- 556
491 secondary to aero-digestive tract stricture and has been estimated as goid. Patients complain of dryness and burning sensation of their eyes. 557
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492 0.029 per 100 000 in the United States during 1992–2002 [82]. Subsequent erosions may result in scaring and symblepharon formation 558
493 Mucous membrane pemphigoid is associated with autoantibodies (fusion of the bulbar and palpebral conjunctiva) ankyloblepharon 559
494 directed against several components at the dermal-epidermal junction. (defined as full thickness fusion of the lid margins), entropion (inward 560
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495 Thus, in about 2/3 of patients, mucous membrane pemphigoid is associ- rolling of the eyelid), trichiasis (eyelashes rubbing on the eyeball), corneal 561
496 ated with autoantibodies targeting Kollagen XVII/BP180 [83,84]. neovascularization and scarring with end result of blindness (Fig. 3b). 562
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497 Approximately 25% of mucous membrane pemphigoid patients also Conjunctival lesions usually start in one eye but involve the other within 563
498 show reactivity to BP230. A subgroup of about 20% of patients with few years [98,99]. While nasolaryngeal lesions are less common, nasal 564
499 mucous membrane pemphigoid, show autoantibodies to laminin 332 discharge, epistaxis or crusting may develop, resulting in hoarseness, 565
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500 (also known as epiligrin). Studies coming mainly from one laboratory dysphonia, shortness of breath and stenoses of the upper airways in 566
501 also incriminated both subunits of α6β4 integrin as autoantigens in severe cases [100] 567
N
502 mucous membrane pemphigoid [81,85]. The autoantibodies targeting Mucous membrane pemphigoid must be differentiated form other 568
503 these antigens are of IgG class, but IgA deposition along the epidermal subepidermal blistering diseases, such as linear IgA disease and 569
504 basement membrane can also be detected [86,87]. Combined presence epidermolysis bullosa acquisita (Table 6). Histopathological examination 570
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505 of circulating IgG and IgA in the serum of patients with mucous mem- reveals subepidermal bullae and an inflammatory infiltrate consisting 571
506 brane pemphigoid is associated with more severe and persistent disease mostly of lymphocytes, with the possible presence of eosinophils and 572
507 than IgG autoantibody alone [88]. neutrophils (Fig. 4a). Plasma cells are frequently found in mucosal 573
508 The marked variability of targeted antigens have suggested the lesions, but are site specific and not related specifically to this disease. 574
509 existence of several subsets of mucous membrane pemphigoid. Mild to moderate degrees of fibrosis can also be detected [101]. 575
510 Each has distinct features regarding tissues affected, the pattern of Direct IF microscopy of perilesional mucosa or skin, shows linear 576
511 immnopathology and antigen specificity of autoantibodies. They deposits of IgG and C3 at the dermal-epidermal junction (Fig. 4b). Auto- 577
512 include the oral pemphigoid that predominantly affect the oral mucosa antibodies of the IgG4 subtype predominate in patients with mucous 578
513 with a significant autoantibody reactivity (46–75%) against BP180. An membrane pemphigoid, especially in the anti-epiligrin (laminin 332) 579
514 ocular variant is the second distinct subset of mucous membrane form [102]. Indirect IF microscopy in patients with mucous membrane 580
515 pemphigoid in which lesions are mainly affecting the conjunctiva. pemphigoid is often negative due to low serum reactivity. The indirect 581
516 Anti-BP180 mucosal pemphigoid is a subset of mucous membrane pem- IF microscopy on salt-split skin demonstrates binding of autoantibodies 582
517 phigoid characterized by a concomitant involvement of oral mucosal from mucous membrane pemphigoid patients to the epidermal (Fig. 4c) 583
518 and skin lesions, with or without other mucosal lesions. Similarly, the or dermal side of the artificial split largely reflecting their molecular 584
10.1016/j.autrev.2015.06.005
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Fig. 3. Clinical features of mucous membrane pemphigoid (MMP). (a) Oral ulceration and erosions on the buccal and labial mucosa of a 65 year-old female patient with mucous membrane
pemphigoid. (b) Ocular involvement in the same patient appears as conjunctival scarring with symblepharon.
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585 specificity to hemidesmosomal antigens such as BP180 or to laminin IgA autoimmune response against the epidermal basement membrane 613
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586 332, respectively [103,104]. by viral infections, drugs (e.g. vancomycin, diclofenac and captopril) 614
and malignancies have been hypothesised [109]. 615
587 5.2. Linear IgA disease Linear IgA disease shows a heterogeneous clinical presentation 616
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involving the skin and mucous membrane. Characteristically, lesions 617
588 Linear IgA disease (LAD), also known as linear IgA bullous dermato- tend to appear in a “cluster of jewels” pattern, where new lesions 618
P
589 sis, is an autoimmune subepidermal blistering disease characterized by arise at the periphery of old ones [107]. In adults, lesions predominantly 619
590 linear deposition of IgA at the epidermal basement membrane. The affect the trunk, extensor surfaces and face. Mucous membrane involve- 620
591 features of this disease were first described in 1901 in children who ment can be seen in up to 80% of the patients. Oral lesions appear as
D 621
592 were diagnosed as having dermatitis herpetiformis. However, it was multiple, painful ulcers that follow the rupture of blisters. They may 622
593 not until 1979, when the term linear IgA disease was coined and the sometimes exhibit in a form of erosive cheilitis or desquamative gingivi- 623
594 entity was formally separated from dermatitis herpetiformis [105]. tis [110,111]. 624
E
595 Linear IgA disease is a rare disease, and only limited and heteroge- Linear IgA disease may be difficult to differentiate on clinical grounds 625
596 neous data regarding its prevalence and incidence worldwide are from other autoimmune bullous diseases, particularly, mucous mem- 626
T
597 available. Linear IgA disease is the most common autoimmune bullous brane pemphigoid, bullous pemphigoid and dermatitis herpetiformis 627
598 disorder of childhood and usually appears in children under the age of (Table 7). Histopathological examination shows subepithelial blistering 628
C
599 5, while the adult-onset linear IgA disease generally appears after the with a predominant neutrophils infiltrate in the epidermis. Importantly, 629
600 age of 60 [16,106,107]. detection of tissue-bound and circulating IgA autoantibodies is mandato- 630
601 Patients with linear IgA disease produce IgA autoantibodies directed ry for diagnosis [107]. Direct IF microscopy reveals linear IgA deposition 631
E
602 against multiple autoantigens at the basement membrane zone. Most along the epidermal side of the basement membrane. Using indirect IF 632
603 patients with linear IgA disease develop IgA antibodies against a microscopy on salt-split skin, IgA antibodies from patients with linear 633
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604 97 kDa protein (LABD97) and a 120 kDa (linear IgA disease-1) antigens, IgA disease bind to the roof of the split. Furthermore, recombinant 634
605 which were both found to be generated as proteolytic cleavage products BP180 ectodomain or concentrated supernatant from cultured 635
606 of the BP180 ectodomain [2,108]. Therefore, a staining of the epidermal keratinocytes can be used in immunoblotting for the sensitive detection 636
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607 side of salt-split skin will appear upon examination using indirect IF of IgA autoantibodies against the BP180 ectodomain. ELISA systems 637
608 microscopy. On the other hand, staining of the dermal side of the skin using recombinant PB180 have also been used for measurement of IgA 638
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609 may also be detected in some patients where IgA autoantibodies react levels in patients' sera [112,113]. 639
610 with collagen VII and other dermal proteins [2].
611 The triggering factors for IgA autoantibody production in patients 6. Epidermolysis bullosa acquisita 640
C
612 with linear IgA disease are not clear. However, induction of patients
Epidermolysis bullosa acquisita (EBA) is a chronic blistering disease 641
N
of the skin and mucous membranes characterized by subepidermal blis- 642

t6:1 Table 6 tering associated with tissue-bound and circulating autoantibodies 643
t6:2 Diagnostic criteria for mucous membrane pemphigoid. against collagen VII. Epidermolysis bullosa acquisita is a rare disease 644
U
t6:3 Diagnostic criteria Findings with approximate prevalence of 0.2/million people and has no sex or ra- 645
cial predilection [16]. The disease has a variable age of onset, from early 646
t6:5 Oral lesions Multiple erosions/ulcerations resulting from blisters childhood to late adult life, however, most of the patients are between 647
Desquamative gingivitis fourth and fifth decades of life. 648
t6:6 Skin lesions Not common Epidermolysis bullosa acquisita is characterized by autoantibodies 649
Blisters, possible scarring
directed against collagen VII, the major constituent of the anchoring fi- 650
t6:7
t6:8 Laboratory investigations brils located at the dermal-epidermal junction. These autoantibodies, 651
t6:9 Histology Subepithelial cleavage, mixed leukocytic infiltrate, most often of IgG type, bind mainly to epitopes within the NC1 domain 652
mild-moderate fibrosis
of collagen VII. Subsequent complement activation and neutrophil 653
t6:10 Direct IF microscopy Linear deposition of IgG and C3 at the dermo-epidermal
junction recruitment by bound IgG at the dermal-epidermal junction results in 654
t6:11 Indirect IF microscopy Binding of the patient’s IgG/IgA to epidermal or dermal subepidermal blister formation [114]. 655
side of human salt-split skin Epidermolysis bullosa acquisita presents clinically with heteroge- 656
t6:12 ELISA / Immunoblotting IgG/IgA autoantibodies specific to Collagen XVII/BP180, neous clinical features that are difficult to differentiate form other auto- 657
Laminin 332, α6β4 integrin
immune diseases. However, patients may present with several clinical 658
10.1016/j.autrev.2015.06.005
Fig. 4. Histopathological and immunological findings in mucous membrane pemphigoid (MMP). (a) Histopathological examination reveals sub-corneal epithelial acantholysis with
F
adjacent neutrophil inflammatory infiltrate. (b) Direct immunofluorescence microscopy of perilesional mucosal biopsy shows a linear and continuous deposition of IgG and C3 at the
basement membrane zone. (c) By Indirect immunofluorescence microscopy using 1 M NaCl-split tissues, serum IgG autoantibodies appear to bind to the epidermal side of the split.
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659 forms, including a non-inflammatory and inflammatory phenotype. The artificial split in serum of patients with epidermolysis bullosa acquisita 694
660 non-inflammatory form (also called the classic, mechanobullous variant (Fig. 6c). These autoantibodies recognize the immunodominant region 695
O
661 of epidermolysis bullosa acquisita), occurs in about one-third of the pa- of the collagen VII, the NC1 domain, by immunoblotting with normal 696
662 tients and is characterized by skin fragility and tense blisters formation. human dermal extract. Furthermore, for the detection of circulating 697
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663 Lesions predominantly appear at sites subjected to trauma, such as anti-collagen VII IgG antibodies, different ELISA systems have been 698
664 elbows, knees and dorsal surfaces of the hands and feet. Lesions usually developed, of which two are commercially available [119] ( Table 3). 699
665 heals with scaring and post-inflammatory hyper and hypo pigmenta-
P
666 tion (Fig. 5a) [115]. This clinical phenotype shares further features
667 with the hereditary dystrophic epidermolysis bullosa, including loss of 7. Other autoimmune skin diseases with oral manifestations 700
668 the hair and nails, esophageal involvement and stenosis. Patients with D
669 inflammatory subtype of epidermolysis bullosa acquisita present clini- Oral lesions may less commonly manifest other autoimmune skin 701
670 cally with widespread bullous lesions that resemble other pemphigoid diseases such a bullous pemphigoid and dermatitis herpetiformis. 702
671 diseases. Brunsting–Perry cicatricial pemphigoid is a chronic recurrent Bullous pemphigoid is a subepidermal blistering disease characterized 703
E
672 bullous eruption localized to the head and neck, characterized by by autoantibodies directed against the BMZ and targeting a 230-kDa 704
673 residual scars, subepidermal bullae and modest mucosal involvement. protein (BPAG1) and a 180-kDa transmembrane protein (BPAG2). 705
T
674 IgG autoantibodies in this condition are heterogeneous with regard to Bullous pemphigoid is the most common autoimmune blistering 706
675 their molecular specificity, but were often reported to recognize colla- disease in North America and Western Europe, with a recent reported 707
C
676 gen VII [116,117]. In addition to bullous systemic lupus erythematosus, incidence of 4.3 cases per 100,000 person-years in the United 708
677 autoimmunity to collagen VII has been shown to associate with other Kingdom [2,15]. The clinical picture of bullous pemphigoid is dominated 709
678 systemic inflammatory diseases such as inflammatory bowel diseases. by polymorphic skin eruptions consisting of large, tense blood and/or 710
E
679 The oral mucosa shows multiple blisters and erosions and is most fluid filled blisters associated with eczematous papules and plaques. 711
680 commonly described in patients with the non-inflammatory form The lower trunk, thighs and flexor aspects of the arms are typical sites 712
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681 (Fig. 5b) [118]. of involvement [43]. Atypical pruritic erythematous or eczematous le- 713
682 The inflammatory type of epidermolysis bullosa acquisita may be sions may also coexist with typical bullae and may sometimes resemble 714
683 clinically and histologically indistinguishable from other subepidermal polycyclic, targetoid, nodular or lichenoid reactions [120]. The frequen- 715
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684 bullous diseases including bullous pemphigoid, mucous membrane cy of mucosal involvement in bullous pemphigoid appears to be low in 716
685 pemphigoid and linear IgA disease. Histopathological examination of comparison with other bullous diseases, such as pemphigus vulgaris 717
O
686 patients' lesional skin reveals subepidermal blisters typically infiltrated and mucous membrane pemphigoid. Oral bullous lesions are usually 718
687 by various inflammatory cells including neutrophils, eosinophils, asymptomatic and temporary in nature with consequent ulceration. Le- 719
688 and lymphocytes (Fig. 6a). Definitive diagnosis is achieved through sions are mostly located on the palate, buccal mucosa, lips, and tongue 720
C
689 detection of linear deposition of IgG autoantibodies at the epidermal [121]. Histopathological examination reveals subepithelial blistering 721
690 basement membrane by direct IF microscopy (Fig. 6b) and the detection with inflammatory infiltrate comprising lymphocytes and eosinophils. 722
N
691 of serum autoantibodies by indirect IF microscopy (Table 8). Indirect IF Direct IIF microscopy of the skin or perilesional mucosa shows linear 723
692 using 1 mol/L NACL-split normal human skin as a substrate demon- IgG and C3 deposits at the epidermal basement membrane, whereas 724
693 strates circulating IgG autoantibodies binding to the dermal side of the the indirect IIF microscopy shows IgG circulating autoantibodies in 725
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approximately 80% of patients [2]. 726

t7:1 Table 7 Dermatitis herpetiformis, is an autoimmune blistering disease that 727
t7:2 Diagnostic criteria for linear IgA disease. arise secondary to gluten hypersensitivity. The disease is characterized 728
by an inflammatory cascade following exposure to gluten, which 729
t7:3 Diagnostic criteria Findings
result in IgA autoantibodies formation directed against epidermal 730
transglutaminase [122]. It is a relatively rare disease, being more preva- 731
t7:5 Oral lesions Erosions/ulcerations resulting from blisters
t7:6 Skin lesions Erythema, blisters, erosions, crusts lent in Scandinavian countries and in the UK [123]. Dermatitis 732
t7:7 herpetiformis manifests as papulovesicular eruptions of the extensor 733
t7:8 Laboratory investigations
surfaces of the elbows and knees, back, scalp and buttocks. The disease 734
t7:9 Histology Subepithelial cleavage with inflammatory infiltrates
dominated by neutrophils rarely affects the oral cavity and when present, occurs especially in areas 735
t7:10 Direct IF microscopy Linear IgA deposition at the dermo-epidermal junction subject to trauma. All patients with dermatitis herpetiformis have intes- 736
t7:11 Indirect IF microscopy Binding of IgA autoantibodies to the epidermal side of tinal sensitivity to gluten, but only a small proportion of them (10%) will 737
salt-split skin present symptoms suggestive of celiac disease such as diarrhea, cramps, 738
t7:12 ELISA/Immunoblotting IgA against the shed ectodomain of PB 180 (LAD1)
and malabsorption [122,124]. 739
10.1016/j.autrev.2015.06.005
F
Fig. 5. Epidermolysis bullosa acquisita (EBA). (a) Multiple erosions and crusting affecting the skin. (b) Oral lesions present as diffuse, multiple ulceration, blisters and erosions.
O
740 Histopathological examination of skin lesions reveals an inflamma- CUS is indistinguishable clinically from other immune-mediated 769
O
741 tory infiltrate in the upper dermis and at the dermo-epidermal junction disease, such as mucous membrane pemphigoid, linear IgA disease, 770
742 dominated by collections of neutrophils and eosinophils. These pemphigus vulgaris, erythema multiforme and particularly lichen 771
743 granulocytes form typical papillary microabscesses that lead to blister planus (Table 9). Diagnosis of CUS should be considered in patients 772
R
744 formation in these areas [125]. Direct IF microscopy from biopsies of un- with prolonged oral ulceration. Histopathological examination of muco- 773
745 affected skin reveal granular deposits of IgA along the dermal-epidermal sal lesions show identical or very similar features to lichen planus 774
P
746 junction and on top of the dermal papillae. Indirect IF may be useful exhibiting partially atrophic epithelium with saw-toothed rete ridges 775
747 for the detection of IgA autoantibodies against endomysium, which formation. Interface stomatitis (leukocytic exocytosis) and a dense 776
748 specifically recognize the epidermal transglutaminase (TG3) and tissue band-like inflammatory infiltrate composed mainly of lymphocytes
D 777
749 transglutaminase (TG2) [2,122]. and a few plasma cells in the epithelium-connective tissue interface is 778
also noted [126]. 779
750 8. Chronic ulcerative stomatitis A goal standard in the diagnosis of CUS is the direct IF staining with 780
E
IgG of lesional and perilesional oral mucosal tissues, which reveal a 781
751 Chronic ulcerative stomatitis (CUS) is a rare mucocutaneous disease, speckled, finely granular pattern of IgG deposition in the nuclei of 782
T
752 involving the mucosal surfaces, particularly the oral mucosa, and some- keratinocytes. This stratified epithelial-specific antinuclear antibody 783
753 times the skin (39), occurring particularly at fifth and sixth decade of life (SES-ANA) signal is confined to the basal cells and the lower third of 784
C
754 with an average age of 59 years. Females represent the majority of the spinous layers. This pattern is generated because patients with 785
755 reported cases, of which 90% are white women [126]. CUS have autoantibodies that bind to specific protein, deltaNp63alpha, 786
756 The condition is characterized by ulcerative mucosal lesions that an antigen of the nuclei of the oral epithelium keratinocytes [129]. 787
E
757 show a distinctively unique direct immunofluorescence pattern. Furthermore, patients with CUS have circulating autoantibodies that 788
758 Patients present with persistent or recurrent painful erosive, ulcerative, show the SES-ANA pattern on indirect IF. The pathogenic role of these 789
R
759 vesicular lesions, predominately affecting the tongue, buccal mucosa autoantibodies has been investigated in a recent study using three- 790
760 and the gingiva. Labial mucosa and hard palate are less frequently dimensional in vitro tissues with a fully differentiated epithelium 791
761 affected. Gingival soreness is a main source of patients' discomfort and resembling the human counterpart. Incubation of these tissues with 792
R
762 many patients refer to periodontists regarding predominant areas of serum from patients with CUS causes tissue detachment, confirming 793
763 gingival desquamation that may display areas of white lichenoid striae the role of these autoantibodies in the pathogenesis of CUS [130]. 794
O
764 that mimics lichen planus [127,128]. Furthermore, the bilateral presen-
765 tation of the lesions on the buccal mucosa may also lead to a wrong 9. Lichen planus 795
766 diagnosis of lichen planus. Widespread lesions have been observed in
C
767 29% of the reported cases. In particular, oral lesions may present in Lichen planus is a chronic immune disease mediated by T lympho- 796
768 conjunction with skin lesions in 5.1% of the cases [128]. cytes that commonly involves the stratified squamous epithelium of 797
N
U
Fig. 6. Histopathological and Immunological features of epidermolysis bullosa acquisita (EBA). (a) Histopathological examination reveals dermal-epidermal separation associated with
inflammatory infiltrate. (b) Direct immunofluorescence microscopy shows IgG deposits at the basement membrane zone (c) By Indirect immunofluorescence microscopy using 1 M
NaCl-split tissues, serum IgG autoantibodies appear to bind to the dermal side of the split.
10.1016/j.autrev.2015.06.005
t8:1 Table 8 ulceration. Clinical manifestation of oral lichen planus is heterogenous 833
t8:2 Diagnostic criteria for epidermolysis bullosa acquisita. with reticular, plaque-like, papular, atrophic, erosive and bullous 834
t8:3 Diagnostic criteria Findings presentation. The white forms of oral lichen planus are reported to be 835
more prevalent (72.6%) than red forms (27.4%) [133]. Lesions are 836
t8:5 Oral lesions Erosions/ulcerations resulting from blisters multiple and symmetrically distributed bilaterally, most commonly on 837
t8:6 Skin lesions Inflammatory form: generalized eruption with the buccal mucosa (60–70% of the cases), followed by the dorsum and 838
tense blisters lateral borders of the tongue and the gingiva. The reticular appearance 839
Mechanobullouos form: skin and mucosal fragility,
is the most common form and appears clinically as intertwined white 840
trauma induced blistering
t8:7
striae, called “Wickham striae”. These lesions are usually asymptomatic 841
t8:8 Investigations with a preference bilateral location on the posterior buccal mucosa. The 842
t8:9 Histology Subepithelial cleavage with neutrophilic
plaque-like variant presents as a white homogeneous irregularity that 843
inflammatory infiltrate
t8:10 Direct immunofluorescence Linear IgG and C3 deposition at the mimics leukoplakia. Papular lichen planus is rarely observed and 844
t8:11 microscopy dermo-epidermal junction presents as small white papules with fine striae in its periphery [144]. 845
t8:12 Indirect immunofluorescence Binding of IgG or IgA autoantibodies at the dermal Atrophic lichen planus is characterised by areas of erythema and 846
F
t8:13 microscopy side of salt-split skin atrophy with or without white striae (Fig. 7a). Erosive lichen planus, is 847
t8:14 ELISA Collagen VII-specific IgG or IgA
the most significant form of the disease, associated with great pain 848
O
and discomfort. It appears clinically as irregular areas of ulceration 849
that maybe covered with a yellowish fibrin pseudomembrane. Areas 850
798 the skin, genitalia and oral mucosa. Oral lichen planus (OLP) is a com- of surrounded “Wickham striae” can be seen. Finally, is the bullous 851
O
799 mon condition that affects individuals mainly in their 4th–5th decade variant, which is the most unusual form in the oral mucosa, appearing 852
800 of life. The disease has variable reported prevalence, calculated in a as blisters that rupture leaving painful and ulcerative surfaces [133, 853
R
801 recent meta-analysis of approximately 1.27%, with predilection for 144,145]. Gingival lesions in oral lichen planus can occur in about 48% 854
802 women in up to 67% of the cases [131,132]. In 1978, the World Health of the cases (Fig. 7b). Furthermore, exclusive gingival involvement is 855
803 organization classified oral lichen planus as a potentially malignant observed in up to 10% of the patients with oral lichen planus [146,147]. 856
P
804 disorder due to its tendency to exhibit malignant changes over time Oral lichen planus can occur with minimal skin involvement in about 857
805 [133]. 15% of the cases. However, in 40–70% of the cases, patients may show 858
806 The exact antigen triggering oral lichen planus lesions is unknown, skin lesions. Apart from the skin, the genital, and anal mucous mem-
D 859
807 however, it is likely that multiple factors or antigens, of extrinsic or branes, scalp, nails, larynx and conjunctiva can also be involved [148]. 860
808 intrinsic origin, could explain the disease process. The role of autoimmu- The term oral lichenoid lesions (OLL) is used to describe a group of 861
809 nity in oral lichen planus is undermined by the lack of specific inducing oral lesions that have a similar clinical presentation to oral lichen 862
E
810 factors, however, supported on the other hand by many autoimmune planus, however, they are triggered by known aetiological factors. 863
811 features such as disease chronicity, adult onset, female predilection and They can present in reticular, atrophic or erosive forms with very few 864
T
812 it's association with other autoimmune diseases [134]. distinguishing features from oral lichen planus [149]. Oral lichenoid le- 865
813 Several reports have pointed out the role of viral and bacterial infec- sions include several clinical types. (1) Oral lichenoid contact lesions 866
C
814 tions in the aetiology of oral lichen planus. In particular, a positive asso- (OLCL) are contact allergy of delayed hypersensitivity reactions due to 867
815 ciation between hepatitis C virus infection (HCV) and lichen planus has direct relationship to dental restorative materials, most commonly 868
816 been reported in many studies across the world. [135–137]. A high amalgam. Lesions are typically localized to the area of amalgam contact, 869
E
817 prevalence of human papilloma virus (HPV) in oral lichen planus unilateral, with the lateral borders of tongue and buccal mucosa being 870
818 cases has also been found, ranging between 9.2% for HPV-16 and −18 the preference sites, due to their close contact to filling materials. 871
R
819 up to 42.6% for non-specific types. These findings suggest that HPV (2) Oral lichenoid drug reactions (OLDR) arise in temporal association 872
820 may not only play a role in the aetiology of oral lichen planus, but also with the taking of certain medications, e.g. oral hypoglycemic agents, 873
821 in the malignant progression of this disorder [138,139]. Psychological angiotensin-converting enzyme inhibitors, and non-steroidal anti- 874
R
822 disturbances such as depression, anxiety and stress as well as autoim- inflammatory agents. Lesions can occur any time during the course of 875
823 mune thyroid disease have been also linked to the aetiology of lichen drug intake with localized and asymmetrical distribution in the 876
O
824 planus [140–143]. oral mucosa. (3) Oral lichenoid lesions of graft-versus-host disease 877
825 The clinical features of oral lichen planus vary widely, from mild to (OLL-GVHD) occur in patients with acute, or more commonly, chronic 878
826 moderate or severe presentation. The disease is known for its chronic graft-versus-host disease (cGVHD). GVHD is a major complication that 879
C
827 nature and its tendency to persist for several years with periods of re- arises in recipients of allogeneic hematopoietic stem cell or bone mar- 880
828 mission and exacerbations. In many cases, oral lichen planus has a silent row transplantation. It is believed to be a result of donor T lymphocyte 881
N
829 onset and progression where patients are not aware of their condition, reaction to major tissue antigens expressed by recipient cells. Several 882
830 and their lesions are often detected upon routine dental examination. organs, such as the skin, liver, gastrointestinal tract and salivary glands 883
831 Other patients may report roughness of the oral mucosa, sensitivity can be involved. Keratotic oral lesions with areas of ulceration, predom- 884
U
832 to hot or spicy food, or intense pain and discomfort due to mucosal inantly arise at the chronic stage of the disease [150,149]. 885
t9:1 Table 9
t9:2 Diagnostic criteria for chronic ulcerative stomatitis.
t9:3 Findings Diagnostic criteria

t9:5 Oral lesions Chronic oral erosions/ulcerations
t9:6
t9:7 Laboratory investigations
t9:8 Histology Atrophic parakeratinized stratified squamous epithelium
Band-like interface of inflammatory cell infiltrate
t9:9 Direct IF microscopy Speckled, finely granular pattern of IgG deposition in the nuclei of keratinocytes stratified epithelial-specific antinuclear antibody (SES-ANA)
t9:10 Indirect IF microscopy Circulating autoantibodies which exhibit the SES-ANA pattern using an oesophagus substrate
t9:11 ELISA / immunoblotting IgG antibodies against the N-terminal and DNA-binding domains of deltaNp63alpha
10.1016/j.autrev.2015.06.005
Fig. 7. Major clinical and histopathological features of oral lichen planus (OLP). (a) Clinical picture of a 32 year-old female patient with atrophic oral lichen planus, showing areas of mucosal
atrophy and white plagues predominately on the lateral borders of the tongue. (b) Desquamative gingivitis is seen on the same patient as diffuse atrophic and erosive areas involving
F
both the marginal and attached gingiva. (c) Histopahological analysis of oral lichen planus, featuring the characteristic sub-epithelial band of lymphocytes associated with liquefaction
degeneration of basal cells.
O
886 Oral lichen planus must be differentiated from other immune- cell carcinoma (SCC). Many series of cases have been published in rela- 935
887 mediated disease, lupus erythematosus, leukoplakia and oral lichenoid tion to the malignant transformation of OLP and they reveal a highly 936
O
888 lesions. Biopsy may not be required in patients who present with classic variable rate of transformation ranging from 0.4–6.5% [157]. In a recent- 937
889 reticular lesions in a bilateral and symmetric distribution, while patients ly published systematic review, the overall rate of transformation was 938
890 with erosive or ulcerative lesions should undergo a biopsy for histopath- 1.09% for oral lichen planus and in a solitary study in which investigators 939
R
891 ological examination [151]. Furthermore, considerations should be evaluated OLL, the rate of transformation was 3.2% [158]. One of the 940
892 made for repeating the biopsy during the follow-up periods whenever major problems for evaluating the risk of malignant transformation of 941
P
893 clinical presentation is changing or dyplastic changes are suspected. OLP is that several studies have included cases with oral lichen planus 942
894 Histopathological features of oral lichen planus are highly variable and OLL with no differentiation between the two processes. Therefore, 943
895 and depend partially on whether the biopsied lesion is reticular, atro- data is insufficient to determine whether the rate of transformation of
D 944
896 phic, or erosive. A “sawtooth” pattern of the rete ridges, which is more these two types of lichenoid diseases is different [159]. The systematic 945
897 commonly seen in cutaneous lichen planus, can also be observed in review has also found that patients' average age at onset of SCC was 946
898 oral lichen planus. The epithelium may appear acanthotic or atrophic 60.8 years, with the tongue being the most common site for malignant 947
E
899 corresponding to the clinical presentation. Interface dermatitis is a transformation. Furthermore, the clinical presentation of the disease 948
900 hallmark of oral lichen planus. It is characterized by a superficial, was found to be of relevance to the potential malignancy, with the atro- 949
T
901 dense, band-like, lymphocytic inflammatory infiltrate, predominately phic, erosive and ulcerative forms having a higher risk of transformation 950
902 of T lymphocytes, which may obscure the junction of the epithelium than reticular, papular and plaque-like types [158]. 951
C
903 and lamina propria. Liquefaction degeneration and necrosis of basal

904 keratinocytes are also prominent. These degenerated keratinocytes 10. Erythema multiforme, Stevens-Johnson syndrome and toxic 952
905 form Civatte (colloid, hyaline, or cytoid) bodies that appear as homoge- epidermal necrolysis 953
E
906 nous eosinophilic globules in the lower epithelium and superficial

907 lamina propria (Fig. 7c). Perivascular inflammation in not generally Erythema multiforme (EM) is an acute, reactive, immune-mediated 954
R
908 noted [151,152]. Biopsies of erosive oral lichen planus may lack many disorder that affects the skin and mucosal surfaces. The disease is related 955
909 of these histological hallmarks and are not diagnostic. Furthermore, to a hypersensitivity reaction to various agents including drugs and in- 956
910 the histopathological aspects of various types of lichenoid reactions fections [160]. Erythema multiforme was considered to be a spectrum 957
R
911 are often indistinguishable from oral lichen planus, which may cause of clinical conditions with variable degrees of severity, including erythe- 958
912 a diagnostic dilemma for clinicians and pathologists. It has been ma multiforme minor, major, Stevens-Johnson syndrome (SJS), and toxic 959
O
913 suggested that in oral lichenoid drug reactions, a mixed subepithelial epidermal necrolysis (TEN) (also known as Lyell’s disease). However, it is 960
914 inflammatory infiltrate of eosinophils and lymphocytes is seen, in con- now recognized as a distinct condition with clinical and epidemiological 961
915 trast to the lack of eosinophils infiltrate in oral lichen planus [153]. characteristics separate from those of Stevens-Johnson syndrome and 962
C
916 The inflammatory infiltrate is also more diffuse and extends deeper toxic epidermal necrolysis [161]. The exact incidence of erythema 963
917 within the lamina propria and superficial submucosa than the band- multiforme is unknown, however, early reports show a possible 964
N
918 like infiltrate seen in oral lichen planus. Amalgam associated OLCR is incidence range between 0.01% and 1% [162]. The incidence of toxic 965
919 also characterized by a dense lymphocytic infiltrate forming tertiary epidermal necrolysis is estimated at 0.4–1.2 cases per million people 966
920 lymphoid follicles [152]. per year, and of Stevens-Johnson syndrome, at 1–6 cases per million 967
U
921 For the differential diagnosis of oral lichen planus, it is important to people per year [163]. Erythema multiforme affects healthy young adults 968
922 include the clinical and histopathological findings together with other with a peak age of onset between 20 and 40 years. Stevens-Johnson syn- 969
923 relevant factors such as the history of systemic disease, history of drug drome and toxic epidermal necrolysis occur in all age groups including 970
924 intake and dental health. A widely used definition for the diagnosis of children and infants, with 10–20% of reported cases involving children. 971
925 oral lichen planus was the criteria introduced by World Health Organi- The mortality rate of SJS is about 5% among affected adult patients and 972
926 zation in 1978. However, studies show that as many as 50% of oral lichen up to 30% in patients with toxic epidermal necrolysis [162]. 973
927 planus cases, lack the clinicopathological correlation in the diagnosis Lesions of erythema multiforme occur as a result of body reactivity 974
928 based on this criteria [154,155]. Therefore, in 2003 a set of revised to different antigens, particularly following exposure to infections or 975
929 criteria was proposed, based on the WHO definition, including clinical drugs (Table 10) [164]. The most common causative infectious agent 976
930 as well as histological aspects [154]. Substantial increase in clinicopath- is herpes simplex virus (HSV), which is responsible for about 70% of 977
931 ological correlation was observed when the modified WHO criteria the recurrent cases. Patients' medical history often reveals previous 978
932 were compared with the 1978 criteria [156]. infection with HSV within 2 weeks before the onset of erythema 979
933 Patients with oral lichen planus and OLL should be followed regular- multiforme [165]. Earlier studies using PCR for detection of HSV 980
934 ly and closely, as they exhibit an increased risk for developing squamous genome, identified HSV-1 in 66% and HSV-2 in 28% and both HSV1 981
10.1016/j.autrev.2015.06.005
t10:1 Table 10
Usually begins with prodromal symptoms

t10:2
Flaccid bullae with epidermal sloughing

Trigger factors associated with erythema multiforme.
Severe widespread oral ulceration with

Multiple internal and external mucosal
Starts on the trunk and spread distally
Oral involvement in 71–100% of the

t10:3 Drugs (strong evidence) Viral infections
of fever, anorexia and pharyngitis

Common, in 100% of the patients.
t10:4 Antibacterial HSV-1, HSV-2
Dusky atypical target lesions

t10:5 Sulfonamides (trimethoprin-sulfamethoxazole) HIV
Exfoliation of N30% of BSA

Epstein Barr virus
30–40% mortality rate

t10:6
Lesions are persistent

Anticoagulants Cytomegalo virus
t10:7
mucosal sloughing
Phenytoin, Carbamazepine, Valproic acid Varicella Zoster virus
surfaces involved
Adenoviruses
Poor prognosis
t10:8 Nonsteroidal anti-inflammatory drugs (NSAIDs) Enteroviruses: coxsackie B5
and necrosis
Hepatitis virus
patients
Influenza
TEN
Poliovirus
t10:9 Further drugs Bacterial infections
t10:10 Allopurinol Mycoplasma Pneumoniae
Lesions are mostly persistent and may continue

Affects N10% of the BSA but more severe than
t10:11 Barbiturates Corynebacterium diptheriae
Severe, widespread oral ulcers with mucosal
F
Confluent purpuric macules or atypical flat
t10:12 Chemotherapeutic agents Neisseria Meningitidis
t10:13
target lesions with blisters and erosion.

Cephalosporins Mycobacterium
30% of the patients develop prodromal
to erupt in crops as long as 1–3 weeks.

symptoms of fever, anorexia, myalgia.
Common, in 90–100% of the patients.
O
t10:14 Herbal remedies avium complex
t10:15 Lamotrigine Mycobacterium leprae
Multiple mucosal sites involved

t10:16 Penicillins Mycobacterium tuberculosis
t10:17 Progesterone Fungal infections
O asymmetrically distributed
Almost 10% mortality rate

t10:18 Protease inhibitors
Risks of mucosal scaring

t10:19 Antifungals Coccidiodomycosis
t10:20 Dermatophytes
R
t10:21 Histoplasmosis
t10:22 Sporotrichosis
t10:23
sloughing
EM major
Trichimononas
P
t10:24 Toxoplasma gondii
SJS
982 and HSV-2 in 6% of the patients [166]. However, a recent retrospective
D
Lesions can be, persistent (continuous), cyclical

mucosal sites in more than 50% of the patients.
Lesions usually revolve over 1–6 weeks with

983 study, conducted in Mayo clinic, found that only 23% of the cases
Multiple, large oral ulcers involving all oral

Diagnostic features of erythema multiforme (EM) minor, major, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).
Symmetrically distributed on extremities

984 could be confidently attributed to HSV infection [167]. Another well-
E
Face and trunk are sometimes involved

985 documented infectious cause is Mycoplasma pneumoniae, which appears
Typical/atypical raised target lesions
Common, in 25–60% of the patients.
(acute and self-limiting), recurrent

Multiple mucosal sites are affected
986 to have a particular importance in the development of erythema
T
987 multiforme among children [168]. Several drugs have also been implicat-
988 ed as offending agents triggering attacks of variable severity of erythema
C
989 multiforme such as non-steroidal anti-inflammatory drugs, sulfonamides,

Affects N10% of BSA
990 anti-epileptics and antibiotics [162].

991 The pathogenic mechanism by which these aetiological factors
E
992 induce lesions of EM is not clear. Genetic susceptibility as a predisposing
Uncommon
EM major
993 factor, has been suggested in patients with severe SJS and toxic epider-
R
994 mal necrolysis following drugs use [169]. Furthermore, a diversity

995 in pathogenesis is suggested among different subsets of erythema
996 multiforme, all of which commonly involving cell-mediated immunity.
R
Only one site is involved, most commonly the oral mucosa.
997 Most of the studies that investigate the pathogenesis of HSV-induced Lesions can be, persistent (continuous), cyclical (acute and
non-keratinized mucosa, labial ulceration and crusting.
Mild, superficial, irregular ulcers,affecting mainly the
998 erythema multiforme, found that HSV fragments in the skin induce a
O
999 delayed-type hypersensitivity reaction driven by interferon gamma Lesions usually resolve in 2 weeks without sequel
Less involvement of skin of the face and trunk
1000 (INFγ). By contrast, interferon gamma is lacking in drug-induced

1001 erythema multiforme, in which tumour necrosis factor alpha is predom-
Symmetrically distributed on extremities
C
1002 inant [170]. An autoimmune pathogenesis in erythema multiforme has

1003 also been advanced, but is matter of controversy. Circulating autoanti-
N
1004 bodies to desmoplakin I and II were describe in 6 reported cases with

1005 erythema multiforme and their level correlating with disease activity
self-limiting) or recurrent.
1006 was found in another case report [171,172]. However, in a more recent
Affects N10% of the BSA
No systemic symptoms
U
Typical target lesions
1007 study no significant association of erythema multiforme with autoanti-

1008 bodies against structural proteins of the skin was found [173].
1009 The clinical manifestations of erythema multiforme vary from one
Uncommon
EM minor
1010 patient to another and furthermore, lesions may change in their mor-
1011 phological appearance over the course of illness. Erythema multiforme
1012 has been classified into minor and a major types depending on the
1013 severity of the condition and the number of mucosal surfaces involve
1014 [160] (Table 11). Erythema multiforme minor is an acute, self-limiting
Systemic symptoms
Clinical course and
1015 disease that may be recurrent with frequent episodes over years. It is
Cutaneous lesions
Differential entity
Mucosal lesions
1016 characterized by the skin “target lesions”, that appear on cutaneous

prognosis
1017 surfaces of the palms, soles and extensors surfaces of extremities with
1018 less involvement of the face and neck. Lesions are symmetrically distrib-
Table 11
1019 uted affecting less than 10% of the body surface area (BSA) [174]. Typical
1020 target lesions begin as erythematous papules, expanding for 2–3 cm in
t11:3
t11:4
t11:5
t11:6
t11:7
t11:1
t11:2
10.1016/j.autrev.2015.06.005
1021 diameter to form 3 distinct zones, a dusky purple centre, a pale middle syndrome and toxic epidermal necrolysis are most often caused by a hy- 1068
1022 zone and an erythematous border. Central blistering or crusting may persensitivity reaction to medications such as sulfonamides, lamotrigine, 1069
1023 occur. Lesions typically appear over 3–5 days and resolve over 1–2 and carbamazepine [180]. 1070
1024 weeks [160,174]. Mucosal involvement in patients with erythema Erythema multiforme must be differentiated from other immune- 1071
1025 multiforme minor is uncommon or mild in severity, usually affecting mediated disease such as mucous membrane pemphigoid and pemphi- 1072
1026 single mucosal site, that is the most commonly the oral mucosa, in gus vulgaris and from toxic epidermal necrolysis and Stevens-Johnson 1073
1027 25–50% of the patients. Oral lesions initially manifest as erythematous syndrome. The abrupt clinical presentation, the associated aetiological 1074
1028 macules that develop rapidly into multiple vesicles with subsequent factors and histological features are the main diagnostic measures 1075
1029 ulceration and pseudomembrane formation [175]. Predominantly, the [165]. Histopathological findings include liquefaction degeneration of 1076
1030 lips and intra-oral non-keratinized mucosal surfaces are affected. the basal epidermal cells, necrotic keratinocytes, exocytosis of lympho- 1077
1031 Patients present with swollen blood-stained, crusted and erosive cytes and intense lymphocytic infiltration at the basement membrane 1078
1032 upper and lower lips with impairment in feeding and speaking. Intra- zone [164]. Biopsies from early stage papules or peripheral portions of 1079
1033 oral lesions located mainly the anterior parts of the oral mucosa, with the lesions show dermal changes such papillary oedema, vascular 1080
1034 the tongue and buccal mucosa being the most affected sites (Fig. 8). dilatation and perivascular mononuclear infiltrates, while those taken 1081
F
1035 The hard palate and gingiva are usually preserved in patients with ery- from central portions of the target lesions show more epidermal changes 1082
1036 thema multiforme minor [174]. Although lesions most frequently affect such as necrosis. The findings by direct and indirect immunofluorescence 1083
O
1037 the oral mucosa, involvement of the ocular, genital, upper respiratory, microscopy in erythema multiforme are non-specific, but may be 1084
1038 or pharyngeal mucosa may also occur (165). occasionally relevant for differential diagnosis [164]. 1085
1039 Erythema multiforme major shows a wider spectrum of clinical pre-
O
1040 sentation, with tendency for recurrence or persistence in some patients. 11. Lupus erythematosus 1086
1041 Skin lesions usually involve less than 10% of the body surface but are
1042 generally more severe than erythema multiforme minor. In addition Lupus erythematosus (LE) is a chronic, autoimmune multisystem 1087
R
1043 to typical target lesions, atypical raised targets, characterized by two disorder that features a broad spectrum of symptoms and is associated 1088
1044 central zones and ill-defined borders, may also be seen. Multiple with significant morbidity and mortality. The disease basically affects 1089
P
1045 involvement of at least 2 mucosal surfaces, which typically involve the the body's connective tissues and blood vessels, hence accordingly, it 1090
1046 oral mucosa, is a hallmark feature for the diagnosis of erythema has been classified into two forms, systemic lupus erythematosus 1091
1047 multiforme major [176]. Oral lesions are more extensive than erythema (SLE), which is a multiorgan disease with variable prognosis and cuta-
D 1092
1048 multiforme minor and in more than 50% of the cases, all the oral muco- neous lupus erythematosus (CLE) which is a more benign condition, 1093
1049 sal surfaces are involved. The presence of typical skin target lesions is limited to the skin and mucosal surfaces. However, the clinical differen- 1094
1050 necessary to consider the diagnosis of erythema multiforme minor or tiation between the 2 forms is not always clear and significant overlap 1095
E
1051 major [177]. However, a less recognized variant of erythema multiforme may occur between CLE and SLE at clinical, histo- and immunopatholog- 1096
1052 is termed oral erythema multiforme and characterized by oral lesions ical levels [181]. It may affect both sexes at any age, however, it is more 1097
T
1053 with the typical clinical features and aetiology of erythema multiforme, prevalent among women of childbearing age. The incidence rate of SLE 1098
1054 but without skin involvement. Oral erythema multiforme is also a in Europe is 3.3–4.8 and in the USA is 2.0–7.6 cases per 100,000 persons 1099
C
1055 chronically recurrent condition, with frequency of episodes varying per year [182]. 1100
1056 from every 3 weeks to once yearly [177,178]. The pathomechanisms of lupus erythematosus involve a complex 1101
1057 Stevens-Johnson syndrome and toxic epidermal necrolysis are con- interaction of multiple genetic and environmental factors. The hallmark 1102
E
1058 sidered clinically different disorders from erythema multiforme [179, pathological features of the disease are inflammation and blood vessels 1103
1059 180]. Stevens-Johnson syndrome and toxic epidermal necrolysis are abnormalities in a form of occlusive vasculopathy and vasculitis [183]. 1104
R
1060 characterized by diffuse, atypical flat target lesions, with bullous central Antinuclear antibodies are the most characteristic feature in the patho- 1105
1061 areas, severe mucosal erosions; and, commonly, a prodrome of flu-like genesis of lupus erythematosus and present in more than 95% of the 1106
1062 symptoms. The two conditions differ in the extent of epidermal detach- patients. Anti-double stranded DNA (ds-DNA) and anti-Sm antibodies 1107
R
1063 ment, with Stevens-Johnson syndrome limited to less than 10% of BSA, are specific findings in patients with SLE and their presence is included 1108
1064 10% to 30% of BSA for Stevens-Johnson syndrome/ toxic epidermal in the classification criteria of SLE [183,184]. 1109
O
1065 necrolysis overlap and 30–100% of BSA for toxic epidermal necrolysis. In- Initiation of the disease results from a number of environmental trig- 1110
1066 volvement of the oral, ocular and genital mucosa occur in 90–100% of the gers and exogenous factors such infections, vaccines, smoking, drugs 1111
1067 patients and are associated with severe morbidity. Stevens-Johnson and dietary factors [183]. Exposure to ultra-violet light is an important 1112
C
trigger in many patients with SLE as it has been recently found to induce 1113
apoptosis of human keratinocytes that results in the exposure of nuclear 1114
N
and cytoplasmic antigens. UV light also induces and modulates immune 1115
and inflammatory mediators by increasing levels of both IL-10 and IL-12 1116
[185]. Genetic inheritance is strongly reflected by the concordance of LE 1117
U
in identical twins and its increased frequency among first-degree 1118

relatives and siblings. Furthermore, the higher incidence of LE among fe- 1119
males at childbearing age suggests a role for endogenous sex hormones 1120
in disease predisposition [182]. 1121
Lupus erythematosus is a systemic autoimmune disorder that 1122
manifests with a wide range of clinical features, ranging from mild 1123
cutaneous lesions to life threatening visceral manifestations. Although 1124
many organs can be affected in patients with lupus, cutaneous lesions 1125
are seen in almost all the patients (Fig. 9a). Patients with SLE have a 1126
wide profile of autoantibodies and present with a complex range of 1127
clinical manifestations involving the mucocutaneous surfaces, musculo- 1128
skeletal, hematological and renal systems [182]. Bullous systemic lupus 1129
Fig. 8. Clinical feature of erythema multiforme. Clinical picture of a 9 year-old male patient
with multiple, severe ulcerations and haemorrhagic crusting involving the labial and erythematosus (BSLE) is a rare cutaneous condition manifestation of SLE 1130
buccal mucosa. characterized by autoantibodies against collagen VII (187). Cutaneous 1131
10.1016/j.autrev.2015.06.005
F
O
O
R
P
D
E
Fig. 9. Clinical and histological features of lupus erythematosus (LE). (a) a patient with skin lesions of LE (b) Erythematous gingival appearance in a patient with LE (c) Histopahological
examination reveals hyperkeratosis, basal layer degeneration and subepithelial lymphocytic infiltrate (d) Direct immunofluorescence microscopy shows band-like deposition of IgG at the
basement membrane zone.
T
C
1132 lupus erythematosus includes a variety of lupus-specific skin lesions (Fig. 9b). Different morphological presentations have been reported, 1149
1133 (lupus dermatitis) and has been subdivided into 3 categories, acute ranging from the classic plaques with central erythema surrounded by 1150
1134 cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus ery- a white rim with radiating keratotic striae and occasional telangiectasia 1151
E
1135 thematosus (SCLE) and chronic discoid lupus erythematosus (CDLE). In to varicose or bullous forms [190]. Ulcerations are usually associated 1152
1136 addition to the specific skin lesions, patients with SLE and CLE can also with SLE and are included in the American College of Rheumatology 1153
R
1137 demonstrate less specific skin lesions such as periungual telangiectases, (ACR) criteria for the diagnosis of SLE. Ulcers are asymptomatic in 50– 1154
1138 Raynaud syndrome, leukocytoclastic vasculitis and urticarial vasculitis 80% of the patients. They occur at the onset of the disease in 11% of 1155
1139 [187]. patients and in some patients they can be the early manifestation of 1156
R
1140 Oral manifestations of lupus erythematosus are frequent with a the disease. Due to the multisystem involvement, patients with SLE 1157
1141 higher prevalence of oral lesions reported in patients with SLE (9–54%) may present with a number of orofacial manifestations, such as the 1158
O
1142 compared to CLE (3–20%) [181,188]. Oral mucosal lesions are frequently malar (butterfly) rash and the well-circumscribed white lacy plaques 1159
1143 chronic with a reported mean duration of 4.2 years in one study [189]. with hyperkeratosis and erythema, on the palatal mucosa. Xerostomia, 1160
1144 Also, lesions can be asymptomatic in up to 50% of the patients. It due to minor salivary gland involvement, can also occur in patients 1161
C
1145 has been suggested that oral lesions represent the mucosal counterpart with SLE associated with symptoms of hematologiocal disturbances 1162
1146 to the cutaneous lesions and should be similarly classified (Table 12). such as mucosal pallor, angular cheilitis and oral candidosis [191]. 1163
N
1147 Oral lesions are usually multiple, asymmetrically distributed and most Lupus erythematosus with predominantly oral lesions should 1164
1148 commonly affect the buccal mucosa, hard plate, lips and the gingiva be differentiated clinically and histologically from oral lichen planus 1165
U
t12:1 Table 12
t12:2 Clinical manifestations of cutaneous lupus erythematosus.
t12:3 Cutaneous lupus erythematosus (CLE) Skin lesions Oral lesions
t12:4 Acute Cutaneous Lupus Erythematosus (ACLE) Localized: Classic butterfly rash in the centre of the face
Circumscribed red macules
Generalized : maculopapular rash Diffuse or palatal erythema
Purpuric macules
Symmetrically/ asymmetrically distributed ulcers and erosions
t12:5 Subacute Cutaneous Lupus Erythematosus (SCLE) Localized lesions on sun-exposed areas Intra-oral lesions are rare
well-demarcated round red patches
Diffuse erythematous labial plaques
t12:6 Chronic Cutaneous Lupus Erythematosus (CCLE) Classic discoid lesions (well-demarcated scaly macules), Oral discoid lesions: well-demarcated, round, irregular atrophic
develop into painful indurated plaques. or ulcerated areas, with radiating keratotic striae
Verrucous LE, intensely keratotic discoid lesions. Honeycomb plaques: intensely keratotic white lesions and linear
fissured ulcerated lesions.
10.1016/j.autrev.2015.06.005
1166 (Table 13). The main histopathological features of cutaneous and muco- mild diseases such as atrophic lichen planus, mucous membrane pem- 1210
1167 sal lupus erythematosus are interface mucositis with superficial and phigoid and erythema multiforme [199]. 1211
1168 deep perivascular lymphocytic inflammation. Additionally, epithelial Topical corticosteroids are generally used in a number of ways. First, 1212
1169 hyperkeratosis, atrophy of the rete pegs, oedema in the lamina propria they are used in a short course of therapy in order to accelerate remis- 1213
1170 and liquefaction degeneration of the basal epithelial cells, are prominent sion in diseases that have natural tendency to remit spontaneously, 1214
1171 features (Fig. 9c) [190]. such as erythema multiforme minor. Second, they can be used in 1215
1172 Direct IF microscopy is important for confirming the diagnosis of prolonged courses and for unpredictable durations to lessen discomfort 1216
1173 lupus erythematosus. Direct IF microscopy in oral lupus erythematosus in diseases that tend to be chronic or with a marked tendency to recur 1217
1174 is frequently positive. IgA, IgG, IgM as well as different complement such as atrophic lichen planus, mucous membrane pemphigoid and er- 1218
1175 components maybe found at the epidermal basement membrane in a ythema multiforme major. Third, topical corticosteroids may be used as 1219
1176 linear or granular deposition pattern [192]. However, IgM is the most a maintenance regimen in patients with mild to moderate autoimmune 1220
1177 commonly identified immunoreactant in oral lupus erythematosus diseases following a short course of systemic corticosteroids [200]. 1221
1178 (Fig. 9d) [181]. However, topical corticosteroids alone will likely not sufficiently control 1222
disease activity in patients with severe, multiple disseminated lesions 1223
F
1179 12. Therapeutic approaches in autoimmune diseases with oral and high levels of antibodies titers such as pemphigus vulgaris, 1224
1180 involvement Stevens-Johnson syndrome and toxic epidermal necrolysis [201,200]. 1225
O
Topical corticosteroids are available in different strengths and 1226
1181 12.1. Principles of therapy preparations. They can be classified according to their potency into 1227
high, mid and low potency [199]. Many factors affect the choice of a 1228
O
1182 Management of oral lesions in patients with immune-mediated particular topical corticosteroid for the management of oral lesions in 1229
1183 disorders can be challenging and requires a multidisciplinary approach. immune-mediated disorders. A successful choice depends on choosing 1230
1184 Early diagnosis is of extreme importance in order for proper management the adequate potency for the severity of the disease, using the appropri- 1231
R
1185 at early stages of disease. The aim of treatment is usually directed towards ate vehicle for drug administration, prescribing the right number of 1232
1186 diminution of pain and discomfort, control of disease progression and drug applications per day, and tapering timely so that the maximum 1233
P
1187 prevention of related complications [193]. Several therapeutic guidelines therapeutic effect with minimum of side-effects is achieved [199,202]. 1234
1188 exist in the literature for the management of immune-mediated Therefore, topical corticosteroids are mostly used in a form of adhesive 1235
1189 disorders, however, the lack of large randomized clinical trials makes ointments or aqueous solutions for the management of oral ulcers.
D 1236
1190 treatment optimization difficult [194–197]. Adhesive ointments are suitable for treatment of small isolated lesions 1237
1191 Treatment regimens are usually tailored according to clinical or when few, easily accessible lesions exist or when the lesions are 1238
1192 findings such as the age of the patient, the medical history, severity of located on the palate or the gingiva so that customized trays can be 1239
E
1193 the disease, and the rate of disease progression (Table 14). Triggering used to hold drugs in contact to lesions for longer durations. On the 1240
1194 factors such as antimicrobials and non-steroidal anti-inflammatory other-hand, aqueous solutions are used for the management of large 1241
T
1195 drugs should be identified and discontinued in collaboration with the and deep lesions. However, they have a wider contact with the mucosal 1242
1196 patient's physician. Involvement of the oral mucosa in patients with surfaces, a fact that increases drug systemic absorption and hence 1243
C
1197 immune-mediated disorders necessitates great attention to maintain complications may arise [199]. 1244
1198 oral hygiene, perhaps by regular visits to periodontists for oral hygiene Triamcinolone acetonide is a moderate-potency topical corticoste- 1245
1199 instructions and periodic full mouth scaling [95,198]. Efforts must also roid that comes in a range concentration between 0.05% and 0.5%. It 1246
E
1200 be directed towards prevention of local irritation by avoiding spicy has been found to be effective for the management of mild cases of 1247
1201 and hard food with cessation of smoking. Tooth brushing with soft oral lichen planus. The drug should be applied several times per day 1248
R
1202 brushes should be encouraged and antiseptic mouthwashes such as (3–10 times) and for a period of 3 to 5 minutes each time in order to 1249
1203 chlorhexidine gluconate 0.2% can be used. Topical analgesics such as achieve therapeutic effect. This is inconvenient and thus, it maybe 1250
1204 benzydamine hydrochloride 0.15% (rinse or spray) are useful to relieve difficult for many patients to comply with treatment. Fluocinonide is a 1251
R
1205 pain and discomfort particularly prior to eating or tooth brushing [193]. moderate to high potency corticosteroid that is used at concentration 1252
ranging between 0.025% and 0.05%. The drug has better effect on 1253
O
1206 12.2. Topical therapy lesional resolution, however, it is still used for the management mild 1254
to moderate oral lesions [203]. 1255
1207 Topical corticosteroids are unfold locally their anti-inflammatory Clobetasol propionate is a high-potency topical corticosteroid that is 1256
C
1208 and immunosuppressive effects thereby significantly reducing disease used in concentrations of 0.025% and 0.05%. Both in the aqueous solu- 1257
1209 activity and clinical morbidity, especially in patients with chronic or tion and adhesive orabase forms, clobetasol propionate has superior 1258
N
t13:1 Table 13
U
t13:2 Diagnostic features of oral involvement in systemic lupus erythematosus.
t13:3 Diagnostic features Findings

t13:5 Oral lesions Painless oropharyngeal ulceration (discrete with red/grey base and hyperkeratotic borders)
Honeycomb white plaques on palatal mucosa
t13:6 Skin lesions Malar (butterfly) rash on the face (fixed erythema, over the malar area sparing the nasolabial folds), discoid lesions, photosensitivity
t13:7 Other organs/systems Non-erosive arthritis, serositis (pleuritis or pericarditis) neurologic disorder (seizures, psychosis)
t13:8
t13:9 Investigations
t13:10 Clinical chemistry nephritis (persistent proteinuria, red blood cell casts), anemia, leuko- and thrombocytopenia, low complement factors, increased complement
turnover, positive Coombs test
t13:11 Histology interface mucositis with superficial and deep perivascular lymphocytic inflammation
t13:12 Direct IF microscopy deposits of immunoglobulin (Ig)G, IgA, IgM and C3 at the dermal-epidermal junction (lupus band)
t13:13 Indirect IF microscopy antinuclear antibodies (ANA)
t13:14 Immunoassays IgG autoantibodies against ds-DNA, Sm, cardiolipin, beta2-glycoprotein I, Ro-60/TROVE2, La/SS-B, ribosomal Protein P, U1 ribonucleoprotein (RNP)
complex
10.1016/j.autrev.2015.06.005
FPG: Fasting peripheral glucose, OGTT: Oral glucose tolerance test, FBC: Full blood count, BMD: Body mineral density, LFTs: Liver function tests, UE: Urea and electrolytes, HIV: Human immunodeficiency virus, HBV: Hepatitis B virus, HCV: Hepatitis C
therapeutic effects in comparison to other topical corticosteroids. The 1259
REF, LFTs, FBC,UE, lipids profile, blood

Weight, blood pressure, FBC, Glucose
drug is effective in rapidly controlling oral lesions following a few 1260
(FPG, OGTT), BMD, Lipids profile

daily applications. Clobetasol propionate can be used for management 1261
FBC weekly for first 8 weeks;

of more severe localized oral lesions in patients with oral lichen planus, 1262
mucous membrane pemphigoid and erythema multiforme. It can also 1263
LFTs every two weeks,

FB and LFTs monthly
be used as a supplement to systemic therapy in patients with pemphi- 1264
thereafter monthly
gus vulgaris [203,199]. 1265
Other topical corticosteroids preparations such as betamethasone 1266
RFP, FBC , UE
Monitoring
sodium phosphate tablets dissolved in water and used as mouthwash 1267
pressure
can be also used in patients with more diffuse and multiple oral lesions. 1268
Hydrocortisone in a form of lozenges or sprayed directly to the oral 1269
gain; increased susceptibility to infection; Cushing’s syndrome; cataracts lesions with an asthma inhaler can also be effective [204]. 1270
Diabetes; osteoporosis; adrenal suppression; peptic ulceration; weight
Acute myelosuppression, mucosal ulceration, gastrointestinal distress,

The use of topical corticosteroids in the management of oral lesions 1271
can often be complicated with a number of topical or systemic side ef- 1272
Gastrointestinal distress, anaemia, leukopenia, thrombocytopenia,
nephrotoxicity, cardiotoxicity, increased risk of cancer, infertility
F
fects. Oral candidosis is a common side effect of topical corticosteroids 1273
Gastrointestinal toxicity, hepatotoxicity, alopecia, pancreatitis,
Electrolyte abnormalities, renal toxicity, tremors, hirsutism,

that appears in 25–55% of the patients, particularly following the use 1274
Myelosuppression and nausea (related to TPMT activity);
O
of high potent topical corticosteroids for long duration. Furthermore, 1275
lymphoproliferative diseases, increased infection rates
the use aqueous mouthwash appears to be a greater risk factor for the 1276
hyperlipidemia, hypertension, gingival hyperplasia

development of oral candidosis, in comparison with adhesive pastes. 1277
Irritation, pruritus and erythema on application
O
Oral candidosis can be prevented or treated successfully with topical 1278
antifungals. Mucosal atrophy, burning sensation, nausea and refractory 1279
R
responses may also occur [202]. The presence of large erosive and 1280
atrophied areas treated with topical corticosteroids may increase the 1281
Oral candidosis, mucosal atrophy
Oral candidosis, mucosal atrophy
risk of drug's systemic absorption and hence complications such as, 1282
P
1283
increased risk of infections
adrenal suppression, Cushingoid appearance (moon face), hypertension

and hyperglycemia. Therefore, patients on topical corticosteroids 1284
should be closely monitored especially when high-potency corticoste-
D 1285
roids in aqueous solutions are applied three or more times a day for 1286
Adverse effect
the management of extensive oral lesions [202,205]. 1287

Topical calcineurin inhibitors, such as tacrolimus, pimecrolimus and 1288
E
ciclosporin, are microbially derived immunosuppressive agents that 1289
have been used in transplant medicine and the for the management of 1290
T
immune-mediated diseases. Calcineurin inhibitors bind to different 1291

FBC, blood pressure, LFTs, UA, HIV, HBV, HCV
FBC, blood pressure, LFTs, UE, HIV, HBV, HCV
FBC, blood pressure, LFTs, UE, HIV, HBV, HCV

Thiopurine methyltransferase (TPMT) assay
Weight, Blood pressure, FBC, Glucose (FPG,
cytoplasmic proteins of the T lymphocytes (cyclosporine to cyclophilin; 1292

(determines risk of bone marrow aplasia)
tacrolimus and pimecrolimus to mFK506-binding protein) to form 1293

complexes that in turn inhibit the phosphorylase enzyme calcineurin, 1294
leading to suppression of transcription and production of many inflam- 1295
E
Pre-therapeutic investigations
matory cytokines. Tacrolimus also inhibits histamine release and the 1296
OGTT), BMD, Lipids profile
synthesis of prostaglandin D2 from mast cells activated by IgE, whereas 1297

R
pimecrolimus can inhibit mast cell cytokines and serotonin [206]. 1298
Topical calcineurin inhibitors are important treatment options for 1299
patients where the use of topical corticosteroid has failed to control 1300
R
FBC, LFTs, UA
the symptoms or where painful refractory lesions occur following initial 1301
healing. The most frequently reported adverse side effects associated 1302
O
with the use of these drugs include, transient burning or stinging sensa- 1303
tion associated with application. Some patients also report a degree of 1304
Tacrolimus, Pimecrolimus
E.g., mometasone furoate,
skin rashes, local swelling dyspepsia and gastrointestinal upset [206]. 1305
triamcinolone acetonide,
C
Mycophenolate mofetil
Therapeutic options for autoimmune diseases with oral involvement.
A recently conducted double-blind controlled trial, comparing the 1306

clobetasol propionate
Cyclophosphamide
efficacy of topically applied pimecrolimus and tacrolimus in the treat- 1307

N
ment of atrophic-erosive lichen planus refractory to topical steroids, 1308

Prednisolone
Azathioprine
Cyclosporine
was undertaken. The study shows that both drugs are equally effective 1309
at inducing clinical improvement among those patients with limited 1310
U
Drugs
side effects. However, pimecrolimus showed a significantly better 1311

stability of therapeutic effectiveness throughout the study duration 1312
Can be used alone to maintain remission
Cornerstone therapy, effective, has rapid
Used in conjunction with corticosteroids

Second-line therapy, in patients who do
Maintenance therapy after short course
with a longer-term resolution of signs and symptoms, in comparison 1313

Slower in onset than steroids, so rarely
not respond to topical corticosteroids
First-line therapy for localized mild /
with tacrolimus [207]. 1314

for their steroid-sparing actions;
after corticosteroids withdrawal
Comparative studies of the efficacy of topical corticosteroids and 1315

used alone to induce remission.
topical calcineurin inhibitors in the management of oral lichen planus, 1316

of systemic corticosteroids
Immunosuppressant drugs
found no significant superiority of either of the treatment modalities 1317

Systemic corticosteroids
(Indications/Properties)
Topical corticosteroids
Calcineurin-inhibitors
in controlling the patient's symptoms. Therefore, for the reason of the 1318
higher cost of the calcineurin inhibitors, their use is recommended as 1319
chronic disease
a second-line treatment for symptomatic oral lichen planus that fails 1320
to respond to topical corticosteroids [208]. In contras to topical cortico- 1321
Therapy
steroids, tacrolimus does not affect collagen synthesis and hence dose 1322
onset
Table 14
not cause thinning of the skin or mucous membrane. Few reports 1323
virus.
have recently shown that topical tacrolimus 0.1% is a safe and effective 1324
t14:10
t14:11
t14:12
t14:13
t14:14
t14:15
t14:16
t14:17
t14:18
t14:22
t14:19
t14:20
t14:23
t14:21
t14:24
t14:25
t14:3
t14:4
t14:5
t14:6
t14:7
t14:8
t14:9
t14:1
t14:2
10.1016/j.autrev.2015.06.005
1325 agent in inducing full remission of lesions in patients with oral mucous considered in patients with severe pemphigus vulgaris or mucous 1389
1326 membrane pemphigoid [209]. membrane pemphigoid that fail to be controlled with combination of 1390
corticosteroids and azathioprine or mycophenolate mofetil or those 1391
1327 12.3. Systemic therapy with clinically significant side effects from these therapies. Side effects 1392
can be severe and include infections, nausea, vomiting, leukopenia, 1393
1328 Systemic corticosteroids are the first line treatment for patients with se- thrombocytopenia, cystitis and increased risk of lymphomas [213]. 1394
1329 vere and progressive mucosal lesions associated with immune-mediated Calcineurin inhibitors are drugs which inhibit the action of calcine- 1395
1330 diseases. Systemic corticosteroids exhibit an anti-inflammatory and im- urin, a protein phosphatase involved in activating the T-cells of the 1396
1331 munosuppressive effect due to inhibition of pro-inflammatory cytokine immune system. Calcineurin inhibitors such as cyclosporine, tacrolimus 1397
1332 production. They reduce the number of circulating T-cell lymphocytes or pimecrolimus are occasionally used for topic and systemic therapy in 1398
1333 and hence diminish their response to antigens. In addition, systemic autoimmune diseases, including pemphigus vulgaris. Their effects are 1399
1334 corticosteroids decrease antibody production and therefore, the reaction mediated by inhibition of calcineurine resulting in a blockade of inter- 1400
1335 with self-antigens is also decreased [210]. leukin 2 production and T cell activation. The main adverse reactions 1401
1336 Oral prednisolone is the most commonly used systemic corticoste- of ciclosporin are renal dysfunction, hypertension, tremor and gingival 1402
F
1337 roid that successfully suppresses diseases activity in patients with hyperplasia [214]. 1403
1338 severe oral ulceration. Its effectiveness has been proved by a number
O
1339 of randomized controlled trials, however, its optimal dosing and Concluding remarks 1404
1340 formulation remains unclear. In general, oral prednisolone is used at
1341 high doses first to arrest blister formation and achieve disease control. Oral lesions may be the first and occassionaly the only manifestation 1405
O
1342 Once this objective have been reached, a careful tapering of predniso- for a number of immune-mediated diseases that affect the skin and 1406
1343 lone according to the patient’s clinical and serological response is mucosal surfaces. Autoantibodies directed against structural com- 1407
1344 recommended [211]. The use of systemic corticosteroids is often associ-
R
pounds of the skin and oral mucosa and/or inflammatory infiltrates 1408
1345 ated with severe side effects such as hypertension, diabetes, glaucoma cause tissue damage. An accurate diagnosis can be reached by utilizing 1409
1346 and systemic infection, specially among elderly people. Therefore, it is a number of diagnostic tools such as direct immunofluorescence mi- 1410
P
1347 important to minimize the total dose and duration of therapy with croscopy of a perilesional biopsy and serological testing for circulating 1411
1348 systemic corticosteroids [210]. autoantibodies in conjunction with histopathological analysis. An early 1412
1349 Systemic corticosteroids are usually combined with other immuno- and precise diagnosis of the autoimmune and inflammatory diseases
D 1413
1350 suppressive agents to allow for rapid reduction of the corticosteroid with oral involvement is a prerequisite for their effective treatment. 1414
1351 dose. Most commonly used immunosuppressive agents include azathi-
1352 oprine, mycophenolate mofetil, cyclophosphamide, methotrexate and
E
1353 calcineurin inhibitors. These drugs are slower in onset than corticoste- Uncited reference 1415
Q5
1354 roids, so rarely used alone to induce remission. They are commonly
1416
T
1355 used in conjunction with corticosteroids for their steroid-sparing [186]

1356 actions and may also be used alone to maintain remission after cortico-
C
1357 steroids withdrawal [195]. Acknowledgements 1417

1358 Azathioprine is a pro-drug that is converted to 6-mercaptopurine
1359 in the body. 6-mercaptopurine is subsequently converted by several The work of the authors is supported by grants from the Deutsche 1418
E
1360 enzymatic metabolites to into 6-tioguanine nucleotides that function Forschungsgemeinschaft SI-1281/5-1 (CS), from the European 1419
1361 as nucleotide analogs and lead to eventual lymphocyte impairment Community's Seventh Framework Program [FP7-2007-2013] under 1420
R
1362 [211]. Azathioprine is the first choice adjuvant drug for the manage- grant agreement No. HEALTH-F4-2011-282095 (CS). 1421
Q7
1363 ment of severe immune-mediated diseases such as pemphigus vulgaris.
1364 Myelosuppression, with marked reduction of white blood cells, is the
R
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1366 of myelosuppression is related to the level of thiopurine methyltransfer- [1] Presland RB, Jurevic RJ. Making sense of the epithelial barrier: what molecular 1423
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1368 metabolites. Patients with low levels of TPMT have increased suscepti- [2] Otten JV, Hashimoto T, Hertl M, Payne AS, Sitaru C. Molecular diagnosis in 1426
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1370 should also be monitored for other side effects such as cytopenia, [3] Challacombe SJ, Setterfield J, Shirlaw P, Harman K, Scully C, Black MM. Immunodi- 1428
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1371 hepatitis, pancreatitis and increase risk of infections [210,211]. 226–34. 1430
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1378 be successful in controlling disease activity, although it is typically Than Simple Adhesion Complexes. J Investig Dermatol 1999;112:411–8. http:// 1439
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[8] Sitaru C, Zillikens D. Mechanisms of blister induction by autoantibodies. Exp 1441
1380 effect [212]. Mycophenolate mofetil is generally well tolerated. The Dermatol 2005;14:861–75. 1442
1381 drug most common side effects include gastrointestinal symptoms [9] Schifter M, Yeoh SC, Coleman H, Georgiou A. Oral mucosal diseases: the inflamma- 1443
1382 such as nausea, vomiting, diarrhoea and abdominal pain. Patients tory dermatoses. Aust Dent J 2010;55:23–38. 1444
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AUTREV-01733; No of Pages 22

Autoimmunity Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/autrev

2Q1 Oral mucosal manifestations of autoimmune skin diseases

59 6. Epidermolysis bullosa acquisita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

65 12. Therapeutic approaches in autoimmune diseases with oral involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

intercellular pattern are detected by indirect immunoﬂuorescence microscopy on monkey oesophagus.

t4:3 Scoring System Description References

of the skin and mucous membranes characterized by subepidermal blis- 642

approximately 80% of patients [2]. 726

t9:3 Findings Diagnostic criteria

t9:4 Clinical features

903 and lamina propria. Liquefaction degeneration and necrosis of basal

906 nous eosinophilic globules in the lower epithelium and superﬁcial

Usually begins with prodromal symptoms

Flaccid bullae with epidermal sloughing

Severe widespread oral ulceration with

Oral involvement in 71–100% of the

of fever, anorexia and pharyngitis

Dusky atypical target lesions

Exfoliation of N30% of BSA

30–40% mortality rate

Lesions are persistent

Lesions are mostly persistent and may continue

Severe, widespread oral ulcers with mucosal

target lesions with blisters and erosion.

30% of the patients develop prodromal

to erupt in crops as long as 1–3 weeks.

Multiple mucosal sites involved

Almost 10% mortality rate

Risks of mucosal scaring

Lesions can be, persistent (continuous), cyclical

Lesions usually revolve over 1–6 weeks with

Multiple, large oral ulcers involving all oral

Symmetrically distributed on extremities

Face and trunk are sometimes involved

Common, in 25–60% of the patients.

(acute and self-limiting), recurrent

989 multiforme such as non-steroidal anti-inﬂammatory drugs, sulfonamides,

990 anti-epileptics and antibiotics [162].

992 induce lesions of EM is not clear. Genetic susceptibility as a predisposing

994 mal necrolysis following drugs use [169]. Furthermore, a diversity

Only one site is involved, most commonly the oral mucosa.

1000 (INFγ). By contrast, interferon gamma is lacking in drug-induced

1002 inant [170]. An autoimmune pathogenesis in erythema multiforme has

1004 bodies to desmoplakin I and II were describe in 6 reported cases with

Typical target lesions

1007 study no signiﬁcant association of erythema multiforme with autoanti-

Clinical course and

1016 characterized by the skin “target lesions”, that appear on cutaneous

in identical twins and its increased frequency among ﬁrst-degree 1118

t12:3 Cutaneous lupus erythematosus (CLE) Skin lesions Oral lesions

t13:2 Diagnostic features of oral involvement in systemic lupus erythematosus.

t13:3 Diagnostic features Findings

t13:4 Clinical features

REF, LFTs, FBC,UE, lipids proﬁle, blood

(FPG, OGTT), BMD, Lipids proﬁle

FBC weekly for ﬁrst 8 weeks;

LFTs every two weeks,

sodium phosphate tablets dissolved in water and used as mouthwash 1267

Acute myelosuppression, mucosal ulceration, gastrointestinal distress,

Gastrointestinal distress, anaemia, leukopenia, thrombocytopenia,