SEMINAR

ON

AUTOIMMUNE DISEASES OF ORAL

CAVITY

-by

Dr. Lakshmi S Anand

JR – III
Oral Pathology & Microbiology
INTRODUCTION

Immunity is the resistance offered by the host towards injury caused by microorganisms
and their products. Autoimmunity is the failure of an organism to recognize its own constituent
parts as self, which allows an immune response against its own cells and tissues. Any disease that
results from such an aberrant immune response is termed an autoimmune disease. The
misconception that an individual's immune system is totally incapable of recognizing self
antigens is not new. Thus, any autoimmune response was perceived to be abnormal and
postulated to be connected with human disease. Now, it is accepted that autoimmune responses
are an integral part of vertebrate immune systems, normally prevented from causing disease by
the phenomenon of immunological tolerance to self-antigens.
Ideally, at least three requirements should be met before a disorder is categorised as
truly due to autoimmunity-
1. The presence of an autoimmune reaction
2. Evidence that such a reaction is not secondary to tissue damage, e.g. resulting from
infection, but is of primary pathogenic significance; and
3. The absence of another well-defined cause of the disease.
Autoimmune disorders may result from tissue injury caused by T cells or antibodies that
reacts against self-antigens. The autoimmune disorders from a spectrum, on one end of which are
conditions in which the immune response is directed against a single organ or tissue, resulting in
organ specific disease, and on the other end are diseases in which the autoimmune reaction is
against widespread antigens resulting in generalized or systemic disease.
Immunologic Tolerance:

Immunologic tolerance is a state in which the individual is incapable of developing an

immune response to a specific antigen. Self-tolerance refers to lack of responsiveness to an
individual's own antigens, and it underlies our ability to live in harmony with our cells and
tissues. Several mechanisms, albeit not well understood, have been postulated to explain the
tolerant state. They can be broadly classified into two groups: central tolerance and peripheral
tolerance.
Central Tolerance: This refers to death (deletion) of self-reactive T- and B-lymphocyte clones
during their maturation in the central lymphoid organs (the thymus for T cells and the bone
marrow for B cells). T lymphocytes that bear receptors for self-antigens undergo apoptosis
within the thymus during the process of T-cell maturation. A protein called AIRE (autoimmune
regulator) is thought to stimulate expression of many "peripheral" self-antigens in the thymus
and is thus critical for deletion of immature self-reactive T cells. Mutations in the AIRE gene
(either spontaneous in humans or created in knockout mice) are the cause of an autoimmune
polyendocrinopathy.
 The developing T cells that express high-affinity receptor for such self-antigens are
negatively selected or "deleted, and therefore peripheral T cell pool is lacking or deficient in self
reactive cells. What triggers apoptosis in self-reactive T-cell clones is not entirely clear. Some
immature T cells that encounter self-antigens in the thymus develop into regulatory T cells. As
with T cells, clonal deletion is also operative in B cells. When developing B cells encounter a
membrane-bound antigen within the bone marrow, they undergo apoptosis.
Peripheral Tolerance: Those-self-reactive T cells that escape intrathymic negative selection can
inflict tissue injury unless they are deleted or muzzled in the peripheral tissues. Several "back-
up" mechanisms that silence such potentially autoreactive T cells are known to exist.
Anergy: (proposed by Nossal ) This refers to prolonged or irreversible func-tional inactivaion of
lymphocytes induced by encounter with antigens under certain conditions. Activation of antigen-
specific T cells requires two signals: recognition of peptide antigen in association with self-MHC
molecules on the surface of antigen-presenting cells and a set of costimulatory signals ("second
signals") provided by antigen-presenting cells. To initiate second signals, certain T cell
associated molecules, such as CD28, must bind to their ligands (costimulators B7-1 and B7-2). If
antigen is presented by the cells which do not bear costimulators, a negative signal is delivered
and the cell become anergic. Once the lymphocyte become anergic, they can not be activated
even if a relevant antigen is presented by competent antigen presenting cell like dendritic cell,
that can deliver costimulation. Because costimulatory molecules are not expressed or weakly
expressed on most normal tissues, the encounter between autoreactive T cell and their specific
self-antigen may lead to anergy. In some situations, T cells that recognize self-antigens receive
an inhibitory signal from a receptor called CTLA-4 that also binds to B7 molecules. Anergy
affects B cells in the tissues as well. It is believed that if B cells encounter antigen in the absence
of specific helper T cells, the B cells become unable to respond to subsequent antigenic
stimulation and may be excluded from lymphoid follicles.
Suppression by regulatory T cells: Regulatory T cell may develop in thymus, as a result of
antigen recognition or they may be induced in periphery. The best defined regulatory T cells are
CD4+ cells that constitutively express CD25 α chain of the IL2 receptor, but some cells lacking
the CD25 do the same job. The mechanisms by which these regulatory cells suppress immune
responses are not fully defined. A transcription factor of forkhead family, called foxp3, is
required for the development and functioning of CD4+ CD25+ regulatory T cells. Mutations in
foxp3 leads autoimmune diseases in humans.
Clonal deletion by activation-induced cell death: (proposed by Burnet ) CD4+ T cells that
recognize selt-antigens may receive signals that promote their death by apoptosis. This process
has been called activation-induced cell death, because it is a consequence of T-cell activation.
One mechanism of activation-induced death of CD4+ T cells involves the Fas-FasL system.
Lymphocytes as well as many other cells express Fas(CD95), a member of the TNF-receptor
family. FasL is a membrane protein that is structurally homologous to the cytokine TNF, is
expressed mainly on activated T lymphocytes. The engagement of Fas by FasL induces apoptosis
of activated T cells and may underlie the peripheral deletion of the autoreactive T cells. It is
believed that those self antigens that are abundant in peripheral tissues cause related and
persistent stimulation of self antigen specific T cells, leading eventually to their elimination via
Fas-mediated apoptosis. Self-reactive B cells may also be deleted by FasL on T cells engaging
Fas on the B cells.
Antigen sequestration: Some antigens are hidden from the immune system because the tissues in
which these antigens are located do not communicate with the blood and lymph. This is believed
to be the case for the testis, eye, and brain, all of which are also called immune-privileged sites
because it is difficult to induce immune responses to antigens in these sites. If the antigens of
these tissues are released, (or example, as a consequence of trauma or infection, the result may
be an immune response that leads to prolonged tissue inflammation and injury. This is the pos-
tulated mechanism for post-traumatic orchitis and uveitis.

Determinants of Autoimmune Disease

• Genetic predisposition
• Environmental triggers
• Hormonal influences
• Regional/ethnic differences

Genetic predisposition
Due to their direct involvement in T cell responses, the most important genes that predispose
both humans and animals to Autoimmune disease(AD) are the MHC genes
Mutations and polymorphisms in Fas, AIRE, CTLA-4 & foxp3
Most human autoimmune disorders have complex, multigenetic pattern of susceptibility and
are not attributable to single gene mutations.
Perhaps the best illustration of AD-HLA association in humans can be found in ankylosing
spondyliitis (AS). Over 90% of Caucasians with AS express an allele belonging to the HLA-
B27 family.

Environmental triggers
Environmental stimuli, including chemical agents and pathogens, show significant links to
AD onset or flare-ups in both humans and animal models.Certain chemical and
pharmaceutical agents have been linked to the onset of particular systemic AD symptoms.
For example, toxins such as the heavy metal mercuric-chloride or polyvinylchloride can
precipitate immune complex nephritis, systemic sclerosis, or the development of
autoantibodies. Smoking, use of hair dyes (which contain aromatic amines), glue-sniffing, or
exposure to silica dust (as occurs in many types of manufacturing and mining jobs) or other
toxins can bring on an episode of RA, SLE, Graves’ disease (GD), or scleroderma. Workers
in industries such as furniture re-finishing, spray-painting, perfume or cosmetic
manufacturing also have a slightly increased risk of developing AD.
Exposure to UV radiation, particularly UV-B rays, has been linked to a physical insult that
results in flare-ups of SLE.
The mechanism by which these environmental factors induce autoimmunity includes
epigenetic changes (DNA methylation and histone modification), reaction with the self
component to generate novel antigens, aberrant cell death releasing cellular material that can
lead to inflammasome activation and production of pro-inflammatory cytokines and
molecular mimicry
Infections with certain viruses, bacteria, and mycoplasma appear to provoke the initiation of
systemic AD in genetically predisposed individuals

Hormonal influences
Females are more susceptible than males.More than 85 percent of patients with thyroiditis,
scleroderma, lupus, and SS are females .In addition to genetic factors such as X-chromosome
abnormalities, sex hormones such as estrogens and androgens are believed to play a
significant role in the sex-based susceptibility to many Autoimmune diseases.
Estrogen metabolism is often abnormal in SLE patients, and flare-ups of SLE may on
occasion be associated with changes in hormonal status, such as during pregnancy or the
initiation of hormone replacement therapy.

Regional/ethnic differences
Such data have been relatively hard to come by and are not consistent for all AD or countries.
May be due to the uneven prevalence of an HLA allele linked to a particular AD (due to
ethnic differences) or of a triggering pathogen or chemical agent (due to geographic or
environmental differences)
Decreasing incidence of infections in western countries and more recently in developing
countries is at the origin of the increasing incidence of both autoimmune and allergic diseases
including Crohn’s disease (CD), T1DM, and multiple sclerosis (MS)
Mechanisms of Autoimmune Diseases
The vast majority of Autoimmune Diseases stem from abnormalities in the mechanisms of
peripheral tolerance.
The mere presence of autoreactive lymphocytes in an individual’s repertoire is not enough to
trigger AD: it only predisposes that individual to developing AD.
For AD to develop, a stimulus that activates the autoreactive cells must be present, and
mechanisms designed to regulate autoreactive lymphocyte responses must fail
Although it would be attractive to explain all autoimmune diseases by a single mechanism, it
is now clear that there are a number of ways by which tolerance can be bypassed, thus
terminating a previously unresponsive state to autoanti-gens. More than one defect might be
present in each disease, and the defects vary from one disorder to the other. The development
of autoimmunity is related to the inheritance of susceptibility genes which may influence the
maintenance of self-tolerance, and environmental triggers, particularly infections, which
promote the activation of self-reactive lymphocytes.
• Role of Susceptibility Genes- Most autoimmune diseases show a strong genetic
predisposition. Among the genes known to be associated with autoimmunity, the best
defined are HLA genes. Although the association has been well established for many
years, the underlying mechanisms remain obscure. Mutations and polymorphisms in the
Fas, AIRE, CTLA-4, and foxp3 genes are also the cause of human autoimmune diseases.
it should be emphasized that most human autoimmune disorders have complex,multigenic
pattern of susceptibility and are not attributable to single gene mutations.
• Role of Infections- Many autoimmune diseases are associated with infections, and
clinical flare-ups are often preceded by infectious prodromes. Two mechanisms have
been postulated to explain the link between infections and autoimmunity. First, infection
may upregulate the expression of costimulators of antigen presenting cells. If these cells
are presenting self-antigens, the result may be a breakdown of clonal anergy and
activation of T cell specific for self antigens.
• Second, some microbes may express antigens that have the same amino acid
sequences as self-antigens, immune responses against the microbial antigens may result
in the activation of self-reactive lymphocytes. This phenomenon is called molecular
mimicry. A clear example of such mimicry is rheumatic heart disease in which antibodies
against streptococcal proteins cross reacts with myocardial proteins and cause
myocarditis.
• Once an autoimmune disease has been induced, it tends to be progressive,
sometimes with sporadic relapses and remissions, and the damage becomes inexorable.
An important mechanism for the persistence and evolution of autoimmune disease is the
 phenomenon of epitope spreading. Infections, and even the initial autoimmune response,
may release and damage self-antigens and expose epitopes of the antigens that are
normally concealed from the immune system, or cryptic The result is continuing
activation of new lymphocytes that recognize these previously cryptic epitopes; since
these epitopes were not expressed normally, the lymphocytes did not become tolerant to
them. Thus, regardless of the initial trigger of an autoimmune response, the progression
and chronicity of the autoimmune response may be maintained by continued recruitment
of autoreactive T cells that recognize normally cryptic self-determinants.

Classification - 1
By Ferguson A 1995
Organ specific Autoimmune Diseases
1. Hashimotos thyroiditis
2. Primary myxedema
3. Thyrotoxicosis
4. Pernicious anemia
5. Addison’s disease
6. Type I – Diabetes mellitus
7. Myasthenia gravis
8. Good Pasteur syndrome
9. ITP
10. Sjogren’s syndrome
Non Organ Specific
1. Rheumatoid arthritis
2. Systemic sclerosis
3. SLE
Classification-2
1. Vesiculo-bullous diseases
Pemphigus vulgaris
Cicatricial pemphigoid
Bullous pemphigoid
Epidermolysis bullosa acquisita
Dermatitis herpetiformis
2. Ulcerative conditions
Aphthous ulcers
Behcet’s syndrome
Reiter’s syndrome
Erythema multiforme
Lupus erythematosus
3. Salivary gland diseases - Sjogren’s syndrome, Mikulicz disease
4. Joint disorders – Rheumatoid arthritis
5. Miscellaneous
Lichen planus
Graft versus host disease
Psoriasis
Systemic sclerosis
PEMPHIGUS

• Pemphix (Greek) = bubble/blister

• Originally named by Wichman in 1791
Pemphigus is a serious chronic skin disease characterized by the appearance of vesicles and
bullae, small or large fluid-filled blisters that develop in cycles.Pemphigus includes a group
of autoimmune blistering diseases of the skin and mucous membranes characterized
histologically by intradermal blisters and immunologically by the finding of circulating
immunoglobulin G (IgG) antibody directed against the cell surface of keratinocytes
• The three primary subsets of pemphigus - pemphigus vulgaris (PV), pemphigus foliaceus,
and paraneoplastic pemphigus.

Etiology
• Abnormal production of autoantibodies directed against epidermal cell surface
glycoproteins – desmoglein 1 & desmoglein 3 (components of desmosomes), that
attaches to them and inhibits the molecular interaction responsible for adherence
• Patients with the active disease have circulating and tissue-bound autoantibodies of both
the immunoglobulin G1 and G4 subclasses
• Due to the immunological attack on desmosomes, a split develops within the epithelium,
causing a blister to form
• Desmoglein 3 : parabasal region of epidermis & oral epithelium
• Desmoglein 1 : superficial portion of epidermis , minimal in oral epithelium
• Hence those who develop autoantibodies against desmoglein 3 – intraepithelial clefting
histopathologically just above the basal layer &clinically oral mucosal blisters of
Pemphigus vulgaris
• Those against desmoglein 1 – superficial intra-epithelial clefting histopathologically but
oral mucosa not affected. Clinically fine scaly red lesions of pemphigus foliaceus /
erythematosus will be evident
Pemphigus Vulgaris (PV)
Clinical Features
• All races
• Males = females
• Mean age : 50–60 years ; in India : younger patients
Rapid appearance of vesicles and bullae, varying in diameter from a few millimeters to
several centimeters .These lesions contain a thin, watery fluid shortly after development, but
this may soon become purulent or sanguineous. When the bullae rupture, they leave a raw
eroded surface identical with that seen when focal areas of epithelium slide off either under
oblique pressure or spontaneously without the prior formation of a vesicle or bulla.Bullae can
be induced on normal appearing skin if firm lateral pressure is exerted - +ve Nikolsky sign. It
is caused by prevesicular edema which disrupts the dermal-epidermal junction
• C/O : Oral soreness
• O/E : superficial, ragged erosions, and ulcerations distributed haphazardly on the oral
mucosa. Palate, labial & buccal mucosa, ventral tongue & gingiva are often involved
Intraorally, patient seldom report bullae/ vesicle formation as they rupture early .Oral lesions
appear early in > 50% of patients by as much as 1 yr.Infrequently ocular involvement may be
seen as bilateral conjunctivitis (No scarring / symblepharon formation as in Cicatritial
Pemphigoid)
No treatment – oral & skin lesions involve more surface area
Histologic Features
Formation of a vesicle or bulla entirely intraepithelially - suprabasilar ‘split’
‘Row of tombstones’ appearance : when only basal layer is left behind
Acantholytic and rounded cells with swollen & hyperchromatic nuclei: Tzanck cells
(Due to prevesicular edema weakening the junction between cells)
Obvious in cytologic smears taken from early, freshly opened vesicles
The fluid in most vesicles, particularly those more than a day or two old, contains variable
numbers of polymorphonuclear leukocytes and lymphocytes. The relative scarcity of
inflammatory cell infiltration in the vesicle & underlying CT is indicative of pemphigus.
Once secondary infection occurs, this feature is masked.
Diagnosis
Direct immunofluorescence
Antibodies (IgG or IgM) and complement components (C3) can be demonstrated in the
intercellular spaces between the epithelial cells. This test is carried out by incubating a
biopsy specimen (either frozen section or one specially fixed in Michel solution) with a
fluorescein-conjugated antiglobulin
Indirect immunofluorescence - positive in 80% to 90% cases. This is accomplished
basically by incubating normal animal or human mucosa with serum from the patient
suspected of having the disease and adding the fluorescein-conjugated human
antiglobulin
ELISA – can distinguish between anti-DSG1 antibodies from anti-DSG3 in serum
samples of patients.
Differential Diagnosis
 Paraneoplastic pemphigus – neoplasm, dyskeratosis
 Mucous membrane pemphigoid – clinically thick walled, histology, DIF, scarring
 Bullous pemphigoid – histology, DIF
 Erythema multiforme – acute onset
 Aphthous ulcer – R/C episodes, round to ovoid symmetric ulcers, not erosions,
faster healing
 Bullous Lichen planus – clinically B/L symmetrical lesions, histology, DIF
 Epidermolysis bullosa -

Treatment and prognosis

Systemic corticosteroids often in combination with other immunosuppressive drugs.
Pemphigus may undergo complete remission . Although remission & exacerbation are
common .
Before the development of corticosteroid therapy as many as 60-90% of these patents
died, primarily as a result of infections & electrolyte imbalance.
Death occurs in most patients due to septicaemia caused by Staph aureus.
Pemphigus vegetans
 Uncommon variant of PV
 Occurs in 1-2% PV patients
 Age : 40-50yrs
 2 clinical subtypes – Neumann and Hallopeau
Neumann – more common, similar to PV, large bullae and denuded areas. These areas
attempt healing by developing vegetations of hyperplastic granulation tissue
Hallopeau – less aggressive, pustules are the initial lesion (not bullae). These are followed
by hyperkeratotic vegetations
Histology – suprabasilar acantholysis ; older lesions – hyperkeratosis,
pseudoepitheliomatous hyperplasia becomes more prominent
Immunofluorescence – similar to Pemphigus Vulgaris
Pemphigus foliaceus
 Superficial pemphigus, fogo selvage
 benign variety of pemphigus
It is an autoimmune skin disorder characterized by the loss of intercellular adhesion of
keratinocytes in the upper parts of the epidermis (acantholysis), resulting in the formation
of superficial blisters.
It is typified by clinical involvement of healthy-appearing skin that blisters when rubbed
(the Nikolsky sign).
Pemphigus foliaceus is characterized by a chronic course, with little or no involvement of
the mucous membranes.
 It includes the following six subtypes:
1. pemphigus erythematosus (PE),
2. pemphigus herpetiformis (PH),
3. endemic pemphigus foliaceus,
4. immunoglobulin A (IgA) pemphigus foliaceus,
5. paraneoplastic pemphigus foliaceus (PNPF), and
6. drug-induced pemphigus foliaceus
Etiology
Immunoglobulin G (IgG) (mainly IgG4 subclass) autoantibodies directed against a cell
adhesion molecule, desmoglein 1, expressed mainly in the granular layer of the epidermis.
Precipitating factors include medications and ultraviolet light radiation. It was recently
suggested that both factors enhanced autoantibody epidermal binding and preferential
neutrophil adhesion to UV-irradiated epidermis which contribute to acantholysis in photo-
induced PF
Clinical features
Early bullous lesions which rapidly rupture and dry to leave masses of flakes or scales
suggestive of an exfoliative dermatitis or eczema
The disease may originate in this form or may develop from one of the other types of
pemphigus.
It is a relatively mild form of pemphigus, which is most common in older adults but may
occur in young children as well.

Brazilian pemphigus (fogo selvagem or Brazilian wildfire) is a mild endemic form of

pemphigus foliaceus found in tropical regions, particularly in Brazil, that often occurs
in children and frequently in family groups.
Histologic Findings
Acantholysis of the upper epidermis
More established lesions may have acanthosis and mild-to-moderate papillomatosis.
Hyperkeratosis and parakeratosis may also be evident, with dyskeratotic cells within the
granular layer.
A mild dermal lymphocytic infiltrate occurs, often with the presence of eosinophils
Treatment
 Therapy for PF is usually less aggressive than that for pemphigus vulgaris because of
their lower morbidity and mortality rates.
 Few results indicate that nonsteroidal treatment of pemphigus is possible.
Paraneoplastic Pemphigus
 Anhalt et al, first described paraneoplastic pemphigus in 1990.
 Paraneoplastic pemphigus is often fatal. Mortality rates approach 90%.
Causes of death include sepsis, with resultant multiorgan failure and respiratory failure due to
the direct effects of the disease on the respiratory epithelium.
The susceptibility to infection caused by the loss of skin integrity is exacerbated by the
potent immunosuppressive medications used to treat the condition.
A summary of criteria for the diagnosis of paraneoplastic pemphigus includes the following:
 • Painful mucosal erosions, sometimes with a skin eruption that eventually results in
blisters and erosions, in the setting of confirmed or occult malignancy.
• Histopathologic changes of acantholysis, keratinocyte necrosis, and interface dermatitis.
• Direct immunofluorescence (DIF) typically reveals IgG and complement (C3) within
the epidermal intercellular spaces as well as at the epidermal basement membrane.
• Indirect immunofluorescence (IDIF) observation of circulating antibodies specific for
stratified squamous or transitional epithelia (transitional epithelium) is found.
• Immunoprecipitation of a complex of proteins with typical molecular weights.
Etiology
Tumor antigens are hypothesized to evoke an immune response that leads to the development
of an autoimmune response to intercellular adhesins (plakins).
This autoantibody response leads to blistering in mucosa and other epithelia.
Clinical features
 mean age - 60 years ( 7 to 76 years )
 Males = females
With the exception of a few patients, all patients with paraneoplastic pemphigus have had
tumors, most of which have been malignant. The most common malignancy associated with
paraneoplastic pemphigus is non-Hodgkin lymphoma. Other associated malignancies
include chronic lymphocytic leukemia, Castleman tumor, giant cell lymphoma (reticulum
cell sarcoma), Waldenström macroglobulinemia, thymoma, poorly differentiated sarcoma,
bronchogenic squamous cell carcinoma, and follicular dendritic cell sarcoma.
Oral Manifestations
Painful oral erosions , often accompanied by a generalized cutaneous eruption.
The eruption can assume a wide variety of morphologies, including morbilliform, urticarial,
bullous, papulosquamous, or erythema multiformelike lesions.
Some patients complain of pruritus or pain.
The erosions can occur anywhere in the mouth, including the buccal, the labial, the gingival,
and the lingual mucosa.
Erosions and subsequent crusting on the vermilion of the lips are typical and similar to that
seen in Stevens-Johnson syndrome.
 The nose, the pharynx, and the tonsils can be affected, as can the genital mucosal surfaces.
Nasal ulcers may cause epistaxis
Histologic Findings
Vesicular lesions express the most characteristic histopathologic features.
Oral and cutaneous lesions show variable epidermal necrosis, suprabasal acantholysis,
dyskeratotic keratinocytes, vacuolar interface dermatitis, and lymphocytic infiltration.
Oral mucosal lesions show the greatest acantholysis, while some skin lesions may not have
any acantholysis at all.
A distinctive feature of paraneoplastic pemphigus is dyskeratosis. Dyskeratosis is a constant
feature, but the number of dyskeratotic keratinocytes is variable. Dyskeratotic keratinocytes
are found at all levels in the epidermis, especially within the zones of acantholysis, and they
can be found in cutaneous adnexa.
The presence of dyskeratosis in a suprabasal acantholytic bullous disorder is a clue to the
presence of paraneoplastic pemphigus.
Treatment
 Initial care is aimed at treating superinfection, if present. Warm compresses, nonadherent
wound dressings, and topical antibiotic ointments are helpful.
 Potent immunosuppressive agents are required to decrease blistering, but they are often
ineffective.
 In general, skin lesions are more responsive to therapy than mucosal lesions.
 Other therapeutic options include plasmapheresis and immunopheresis.
 For solid neoplasms, curative resection should be attempted when appropriate.
 The prognosis of paraneoplastic pemphigus is poor.
CICATRICIAL PEMPHIGOID
• Cicatrix = scar
• Mucous membrane pemphigoid (-oid – similar to pemphigus)
Cicatricial pemphigoid (CP) is an autoimmune blistering disease that predominately affects
the mucous membranes, including the mouth and the oropharynx, the conjunctiva, the nares,
and the genitalia
Patients with cutaneous involvement present with tense blisters and erosions, often on the
head and the neck or at sites of trauma. Blisters heal with scarring and pigmentation.
Sequelae of mucosal involvement include decreased vision, blindness, and supraglottic
stenosis with hoarseness or airway obstruction
Etiology
The two major antigens associated with CP are bullous pemphigoid antigen 2(BPAG2) and
epiligrin (laminin-5).
Autoantibodies of the IgG subclass, particularly IgG4, are associated with CP; however, IgA
antibodies have also been detected
Clinical features
• 40 and 50 years
• Female : male = 2:1
Oral mucous membranes and conjunctiva. Lesions also occur on the skin, particularly around
the genitalia and near the body orifices in about 25% of cases. Typically, these lesions heal by
scar formation, particularly on the conjunctiva.
Other mucous membrane surfaces may be involved such as the nose, larynx, pharynx,
esophagus, vulva, vagina, penis and anus.
Most significant complication : ocular involvement
Earliest change : subconjunctival fibrosis
Following the initial conjunctivitis, adhesions called symblepharon develop between the
palpebral and bulbar conjunctivae resulting in obliteration of the palpebral fissure, with
opacity of the cornea frequently leading to complete blindness
Scarring causes eyelid to turn inward (entropion)
Eyelashes rub against cornea & globe : trichiasis
Scarring closes opening of lacrimal glands - loss of tears
 Eyes become dry
Cornea produces keratin as protective mechanism
Laryngeal lesions - airway obstruction by the bullae
Oral Manifestation
Gingiva – desquamative gingivitis
Vesiculobullous - thick-walled lesion
May persist for 24–48 hours before rupturing and desquamating.
Eventually their rupture does occur leaving a raw, eroded, bleeding surface.
The gingivae frequently manifest a persistent erythema for weeks or even months after the
original erosions have healed. These oral lesions rarely scar. In the past, this disease has often
been diagnosed as chronic desquamative gingivitis
Histopathologic features
Subepidermal split
no evidence of acantholysis
The basement membrane structure appears to detach with the epithelium from the underlying
connective tissue
nonspecific chronic inflammatory infiltrate in the connective tissue, chiefly lymphocytes,
plasma cells and eosinophils
Direct immunofluorescence: continuous linear band of immunoreactants (IgG, C3, IgA &
IgM) at the basement membrane zone in nearly 90% of affected patients
Indirect immunofluorescence: positive in only 5% of these patients
Treatment and prognosis
• Topical and systemic corticosteroid with/without immunosuppressant are used for
therapy.
• Surgical correction of symblepharon may be attempted once the condition is under
control or else it may lead to acute flare up of ocular lesion
Rare conditions can mimic pemphigoid histopathologically.
• linear IgA disease
• angina bullosa hemorrhagica, and
• epidermolysis bullosa acquisita.
Linear IgA disease
• Characterized by the linear deposition of only IgA along the basement membrane zone
and thus can be distinguished.
• Autoantibodies against BP180 (collagen XVII)
Angina bullosa hemorrhagica
Rare, poorly characterized oral mucosa disorder
Exhibits variably painful blood-filled vesicles or bullae
Usually affect soft palate
Middle aged or older adults.
Blisters rupture spontaneously and heal without scarring.
A subepithelial cleft is noted microscopically.
No hematologic or immunopathologic abnormalities
h/o trauma or corticosteroid inhaler use
Epidermolysis bullosa acquisita
Autoantibodies directed against type VII collagen,
Principal component of the anchoring fibrils.
formation of bullous lesions of the skin and mucosa with minimal trauma.
Immunoflurescent evaluation shows deposition of IgG autoantibodies on the floor of the
bulla.
Special technique to distinguish:
1. perilesional skin is incubated in concentrated salt solution
2. causes the epithelium to separate from the connective tissue
3. forming an artificially induced bulla
BULLOUS PEMPHIGOID
• Parapemphigus
• Most common of the autoimmune blistering conditions.
Bullous pemphigoid (BP) is a chronic, autoimmune, subepidermal, blistering skin disease
that rarely involves mucous membranes. Immunoglobulin G (IgG) autoantibodies specific for
the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2).
IgG autoantibodies bind to the skin basement membrane and activate complement and
inflammatory mediators. These inflammatory cells in turn are postulated to release proteases,
which degrade hemidesmosomal proteins and lead to blister formation.
Eosinophils are characteristically present, although not an absolute diagnostic criteria
Clinical features
• Older people, 60 - 80 years of age
Pruritis - early symptom followed by the development of multiple, tense bullae on either
normal or erythematous skin. Vesicles and bullae are relatively thick-walled and may remain
intact for some days. These lesions eventually rupture after several days, causing a
superficial crust to form. Eventually, healing without scarring.
The oral lesions also begin as bullae but tend to rupture sooner.
Large, shallow ulcerations with smooth, distinct margins are present after the bullae rupture.
Histopathologic features
subepithelial separation.
Presence of eosinophils within the bulla itself- characteristic.
Direct immunofluorescence
• studies show a continuous linear band of immunoreactants
• IgG and C3, localized to the basement membrane zone in 90% to 100% of affected
patients.
• Bullous pemphigoid antigens (BP 180 and BP 230).
Indirect immunofluorescence pattern is identical to that of the direct immunofluorescence.
Treatment and prognosis
• Mild/localized form : topical corticosteroid preparation
• Moderate/severe : systemic immunosuppressive therapy
 • Prognosis is generally good
DERMATITIS HERPETIFORMIS
• Duhring-Brocq disease
Rare ,benign, chronic, recurrent, immune-mediated blistering dermatologic disease with an
associated, most often asymptomatic, gluten-sensitive enteropathy (GSE).
Characteristic skin lesions found in patients with dermatitis herpetiformis are extremely itchy
grouped vesicles most frequently located on extensor surfaces.
The pathogenesis of DH is associated with the presence of GSE; an increased expression of
human leukocyte antigen1 (HLA-A1), human leukocyte antigen B8 (HLA-B8), human
leukocyte antigen DR3 (HLA-DR3), and human leukocyte antigen DQ2 (HLA-DQ2) haplo
types; and granular deposition of IgA at the dermal-epidermal junction of the skin.
Clinical Features
• 20 and 55 years of age, although children are occasionally involved.
• slight male predilection
The first manifestations of the disease are usually pruritus and severe burning, followed by
the development of erythematous papules, vesicles, bullae or pustules.
These occur most frequently on the extremities, trunk and buttocks as well as on the face,
scalp and sometimes oral cavity. The vesicle is the most common and characteristic lesion,
usually occurring symmetrically and in groups.
Pigmentation of involved areas of skin ultimately develops in most cases.
Patients frequently show increased severity of the disease in summer months.
Oral Manifestations
Vesicles and bullae which rupture rapidly to leave areas of superficial ulceration at any
intraoral site are the characteristic finding.
Histologic Features
The lesions begin by accumulation of neutrophils and eosinophils in the dermal papillae
producing a microabscess.
The connective tissue becomes necrotic and the overlying epithelium separates, usually
forming a subepithelial vesicle with destruction of basement membrane.
 The presence of eosinophils is generally prominent and characteristic, aiding in the
differential diagnosis by excluding epidermolysis bullosa, erythema multiforme and
pemphigus.
Direct immunofluorescent staining of uninvolved paralesional skin has been shown by Katz
to be positive at the epidermal dermal junction. Almost invariably, IgA alone or in
combination with the immunoglobulins IgG or IgM will be found in the upper dermis. When
IgA deposits occur at the dermal-epidermal junction in a linear pattern (about 14% of cases)
rather than as granules, the variant has been termed linear IgA disease. This has been
discussed by Wiesenfeld and his colleagues, who also described the oral manifestations as
being similar to those in the usual form of dermatitis herpetiformis.
Laboratory Findings
Some patients develop a blood eosinophilia of over 10%.
Interestingly, these patients also show a sensitivity to the halogens (chlorine, bromine, iodine
and fluorine) both by patch test and after ingestion.
Treatment
• Skin lesions of dermatitis herpetiformis can be treated with dapsone, with relief of
symptoms within 24–48 hours of the start of therapy.
• Alternatively, many patients can control the skin disease with a gluten-free diet, often
without medication.
• Prognosis is good for patients who can tolerate dapsone and for the few who maintain a
gluten-free diet.

APHTHOUS ULCERS
• It is one of the most common oral mucosal pathoses.
Etiology and pathogenesis
Cause appears “ different things in different people”
The mucosal destruction appears to represent a T cell mediated immunologic reaction
allergies, genetic predisposition, nutritional deficiencies, hematologic abnormalities,
hormonal influences, infectious agents, trauma and stress.
Various causations can be clustered into
1. Primary immunodysregulation
 2. Decrease of the mucosal barrier
3. Increase in antigenic exposure
Clinical features
1. Minor apthous ulcerations
2. Major apthous ulcerations (PMNR)
3. Herpetiform ulcers
Prodromal symptoms of burning, itching or tingling
Minor aphthous ulceration(Miculiz disease)
Fewest recurrences, shortest duration. Development of erythematous macule.
Macule develops an ulceration that is covered by a yellowish white, removable
fibrinopurulant membrane encircled by an erythematous halo1-5 lesions, measure about 3 to
10 mm ,heal without scaring in 7 to 14 days
Major type (Sutton’s disease)
Larger and more painful ulcers and persist for longer period.The ulcerations are deeper than
minor variant.1 to 3 cm in diameter.2 to 6 weeks to heal and heal with scar formation.
Number of lesion varies from 1 to 10Any oral surface area may be affected.
Herpetiform ulcers
Demonstrate the greatest number of lesions and the most frequent recurrences
1 to 3 mm and as many as 100 may be present in a single recurrence.
It resemble a primary herpes simplex infection and heal within 7 to 10 days
Histopathology
Characteristic but not pathognomonic.
The early ulcerative lesion demonstrate a central zone of ulceration covered by a
fibrinopurulant membrane.
Deep to this, the connective tissue exhibits an increased vascularity and a mixed
inflammatory cellular infiltrate that consist of lymphocytes, histiocytes and neutrophils.
The epithelium at the margin demonstrate spongiosis and numerous mononuclear cells in the
basilar one third.
A band of lymphocytes intermixed with histiocytes is present in the superficial connective
tissue and surrounding deeper blood vessels.
Differential Diagnosis
• Secondary (recurrent) herpes
• Traumatic ulcer
• Pemphigus vulgaris
• MMP
Treatment
For mild cases topical corticosteroids can be given.
• patients medical history should be reviewed for any systemic disorder.
• acyclovir, chemical cauterizing agents, sucralfate etc.
• The success of these therapies are highly variable.
BEHCET’S SYNDROME
commonly known as silk road disease named after the Turkish dermatologist, Hulusi Behçet
Behçet's disease is particularly common in the Far East and the Mediterranean basin, and is
frequently noted between the 30th and 45th degree latitudes in Asian and European
populations,corresponding to the Old Silk Road, an ancient trading route stretching between the
Mediterranean, the Middle East and the Far East. In contrast, this disorder is uncommon in the
American continents, Oceania and sub‐Saharan Africa
Consist of chronic ocular inflammation and orogenital ulcerations
Evidence shows immunologic basis because of strong association with certain HLA types
An immunodysregulation that may be primary or secondary to one or more triggers
Clinical features
Young adults
Oral involvement is an important component
Lesions similar to aphthous ulcerations and demonstrate same duration and frequency
Commonly involves the soft palate and oropharynx
Genital lesions are similar to the oral forms.
Cutaneous lesions - erythematous papules, pustules, pyoderma, folliculitis etc.
Skin manifestations - presence of positive “Pathergy”
 Ocular involvement is more frequent and severe in males
Posterior uveitis , conjunctivitis, corneal ulcerations, papilloedema and arteritis
Blindness is rare.
Arthritis
Histologic features
• features similar to aphthous stomatitis.
• pattern most commonly seen is leukocytoclastic vasculitis.
Treatment
• topical or intralesional corticosteroids in combination with oral colchicine or dapsone.
• Severe ocular and systemic diseases require systemic immunosuppressive agents.
REITER’S SYNDROME
Triad of nonspecific urethritis, conjunctivitis and arthritis that follows bacterial dysentery or
exposure to sexually transmissible disease
Pathogenesis:
• Abnormal response to bacterial antigens
• Male with HLA-B27 – 20% risk of syndrome after an episode of Shigella dysentery
Clinical features
Acute onset
Simultaneous appearance of urethritis, conjunctivitis and oligoarthritis affecting large and
small joints of lower limb
1-3 weeks after sexual episode or dysentery
Bilateral conjunctivitis, acute iritis – 10% cases
Arthritis – self limiting, remission in 2-3 months
Fever, weight loss, vosomotor abnormalities in the feet
Skin – faint macules, vesicles, pustules on hands & feet
Oral lesions :
Relatively painless aphthous type ulcers – any site
Tongue lesion – geographic tongue
Diagnosis
Recognition of various signs and symptoms
HLA-B27 genotype – 70%
Elevated ESR
Treatment
• NSAIDs
• Antibiotics
• Corticosteroids – rarely required.

ERYTHEMA MULTIFORME(EM)
Blistering, ulcerative mucocutaneous condition
EM minor - localized eruption of the skin with mild or no mucosal involvement.
EM major and Stevens-Johnson syndrome (SJS) are more severe mucosal and skin diseases
and are potentially life-threatening disorders
EM and SJS could be separated as two distinct clinical disorders with similar mucosal
reactions but different patterns of cutaneous lesions
Erythema multiforme major - mucosal erosions of raised atypical target lesions, usually on
the extremities and/or on the face.
SJS - mucosal erosions plus widespread distribution of flat atypical targets or purpuric
macules. The lesions may be present on the trunk, the face, and on the extremities.
Etiology
Immunologically mediated process
EM minor - triggered by HSV in nearly 100% of cases
Idiopathic EM minor may be precipitated by subclinical HSV infection
EM major - herpetic etiology (55% of cases)
Mycoplasma infection appears to be a common cause
SJS and EM major - Drugs (esp. Sulfa drugs)
These agents may trigger the immunologic derangement that produces the disease.
Clinical features
An acute onset and may display a wide spectrum of clinical disease.
Young adults – 20s or 30s
Men > Female
Prodromal symptoms - fever, malaise, headache, cough and sore throat.
Self-limiting
20% - recurrent episodes.
Asymptomatic, vividly erythematous discrete macules, papules or occasionally vesicles and
bullae distributed in a rather symmetrical pattern most commonly over the hands and arms,
feet and legs, face and neck
Erythematous skin lesions develop - 50% of cases
Early lesions appear on the extremities - flat, round and dusky red
become slightly elevated and evolve into bullae with necrotic centers
target or iris lesion - concentric erythematous rings.
Oral Lesions
begin as erythematous patches that undergo epithelial necrosis
large, shallow erosions and ulcerations with irregular borders.
Hemorrhagic crusting of the vermillion zone of the lips is common
Inability to ingest liquid as a result of mouth pain
tongue, palate, buccal mucosa & gingiva - most common sites.
oral involvement without dermal lesions has been questioned
oral lesions only (reported by Lozada and Silverman in 12 of 50 patients)
Erythema multiforme major
Diagnosis is made if 2 or more mucosal sites are affected in conjunction with widespred skin
lesions.
In most cases the oral mucosa is involved in addition to either ocular or genital mucosa
With severe ocular involvement scarring (symblepharon formation) may occur
Histopathologic features
Subepithelial or intraepithelial vesiculation with necrotic basal keratinocytes.
A mixed inflammatory infiltrate is present, Sometimes arranged in a perivascular orientation.
the immunopathologic features are also non specific,
diagnosis is often based on the clinical presentation and exclusion of other vesiculo-bullous
disorders.
Treatment & prognosis
• Self limiting – lasting for 2 – 6 wks
• Recurrence in 20% patients – esp in spring & autumn
• If triggered byu HSV – oral acyclovir / valacyclovir to prevent recurrence

Steven Jonson Syndrome & Toxic Epidermal Necrolysis

In the past – both considered as severe form of erythema multiforme
EM is usually triggered by HSV while the above lesions are triggered by drug exposure
Damage to epithelium is due to severe apoptosis of epithelial cells
Flu like prodromal symptoms – fever, malaise, sore throat, headache, loss of apetite
Skin lesions appear on trunk – erythematous macules – within 1-14 days – sloughing of skin
and flaccid bullae develop . All patients will have mucosal involvement
If patient survives, skin lesions heal in 3 – 5 wks ; oral lesions – longer
Residual ocular damage seen in half of the patients
Histopathology
• Subepithelial blister – characterized by degenerating, necrotic basal keratinocytes
• Connective tissue – sparse inflammatory cells
Treatment & prognosis
• Identifing & discontinuing the drug
• Toxic epidermal necrolysis lesions are similar to those of burned patient – hence
management in burn unit of hospital is recommended. Corticosteriod must be avoided
 • Pooled human immunoglobulin i.v – remarkable resolution of lesion
• Mortality in SJS – 1-5% ; Toxic epidermal necrolysis – 25-30%
Stevens-Johnson syndrome
Less than 10% of body surface involved
1-7 / million population / yr
Younger patients
For its Diagnosis - either the ocular or genital mucosa should be affected in conjunction with
the oral and skin lesions . With severe ocular involvement, scarring may occur, similar to that
in cicatricial pemphigoid.Mucosal vesicles or bullae occur which rupture and leave surfaces
covered with a thick white or yellow exudate. Erosions of the pharynx are also common.
The lips may exhibit ulceration with bloody crusting and are painful
• The oral lesions may be the chief complaint of the patient - mistaken for acute
necrotizing ulcerative gingivostomatitis.
• Interestingly organisms of Vincent's infection are scarce in patients with this disease.
• Eye lesions consist of photophobia, a characteristic of the disease referable to the
conjunctivitis, corneal ulceration and panophthalmitis which may occur.
Keratoconjunctivitis sicca also has been described. Blindness may result chiefly from
intercurrent bacterial infection
• Genital lesions are reported to consist of a nonspecific urethritis, balanitis and/or vaginal
ulcers
• Other reported complications are related to respiratory tract involvement such as
tracheobronchial ulceration and pneumonia. The patients usually recover unless they
succumb to a secondary infection
Toxic epidermal necrolysis or Lyell’s disease
Most severe form of erythema multiforme. It is almost always triggered by drug exposure
More than 30% of body surface area . Diffuse sloughing of a significant proportion of the
skin and mucosal surfaces makes it appear as if the patient had been badly scalded.
Tends to occur in older people and a female predilection.
Differential Diagnosis
• Primary HSV
• Aphthous ulcer
• Pemphigus vulgaris
• MMP
• Erosive lichen planus

LUPUS ERYTHEMATOSUS
Classic example of an immunologically mediated condition . It is the most common
‘collagen vascular’ or connective tissue diseases.
It may exhibit any one of the several clinicopathologic forms
1. Systemic lupus erythematosus (SLE)
2. Chronic cutaneous lupus erythematosus (CCLE)
3. Subacute cutaneous lupus erythematosus
SLE
Serious multi-system disease with a variety of cutaneous and oral manifestations. There is
increase in the activity of the B lymphocytes in conjunction with abnormal function of the T
lymphocytes.Genetic factors also play a role. Appears in a nonspecific, vague fashion,
frequently with periods of remission or disease inactivity . it is difficult to diagnose in the
early stages.
Common findings include fever, weight loss, arthritis, fatigue and general malaise
40% to 50% of affected patients, a characteristic rash, having the pattern of a butterfly,
develops over the malar area and nose.
Kidneys may be affected leading to kidney failure and is most significant.
Pericarditis, Warty vegetations affecting the heart valves (Libman-Sacks endocarditis)
Oral lesions of SLE develop in 5% to 25% of patients. Common sites are palate, buccal
mucosa and gingival. May appear as lichenoid areas or look nonspecific or even
granulomatous.
Involvement of vermilion border of lower lip (lupus cheilitis) may also be seen.
 Varying degrees of ulceration, pain, erythema, and hyperkeratosis may be present. Other
manifestations include xerostomia, stomatodynia, candidiasis, periodontal disease.
CCLE
few or no systemic signs or symptoms,
Lesions being limited to skin or mucosal surfaces.
The skin lesions known as discoid lupus erythematosus.
They being as scaly, disc shaped erythematous patches that are frequently distributed on sun
exposed skin.
The lesion heals in one area and appears in another area.
Healing results in cutaneous atrophy with scarring and hypopigmentation or
hyperpigmentation of the resolving lesion.
Oral manifestation
Clinically identical to lichen planus
Oral lesions rarely occur in the absence of skin lesions.
An ulcerated or atrophic, erythematous central zone, surrounded by white, fine, radiating
striae, characterizes the oral lesion of CCLE
Sometimes, the erythematous atrophic central region of a lesion may show a fine stippling of
white dots
SCLE
intermediate clinical manifestations between SLA and CCLE . Skin lesions are the most
prominent feature of this variation. It is characterized by photosensitivity and lesions do not
show the induration and scarring seen with the skin lesions of CCLE and also systemic
abnormalities are not present.
Histopathologic features
The skin lesions of CCLE are characterized by hyperkeratosis with follicular plugging
(keratin packed into openings of hair follicles).
In all forms of LE, degeneration of the basal cell layer is frequently observed and underlying
connective tissue supporters patchy to dense aggregates of chronic inflammatory cells.
In deeper CT, inflammatory infiltrate often surround small blood vessels
Oral lesions demonstrate
• hyperkeratosis,
• alternating atrophy and thickening of the spinous cell layer,
• degeneration of the basal cell layers and
• subepithelial lymphocytic infiltration.
These features are also seen in oral Lichen Planus
• presence of patchy deposits of a PAS positive material in the basement membrane zone,
• subepithelial edema and
• a more diffuse, deep inflammatory infiltrate often in perivascular orientation.
Direct immunofluorescence
Lesional tissue shows deposition of one or more immunoreactants (usually IgM, IgG or C3)
in a shaggy or granular band at the basement membrane zone.
Normal skin of SLE patients - shows a similar deposition of IgG, IgM or complement
component.
This finding is known as positive lupus band test.
Anti nuclear antibodies (ANA) in the serum.
Antibodies directed against single stranded DNA, double stranded DNA, nuclear ribonuclear
protein
• Anti-Ro/SSA and La/SSB antibodies
Diagnosis
According to American College of Rheumatology, 4 out of 11 criteria must be fulfilled for the
diagnosis of SLE.
Arthritis; Renal disease (proteinuria, cellular casts); ANA (positive antinuclear
antibody); Serositis (pleurisy or pericarditis); H aematological disorders (haemolytic anaemia or
leucopenia or lymphopenia or thrombocytopenia); Photosensitivity; Oral ulcers; Immunological
disorder (positive LE cell, anti-DNA, anti-Sm, false positive serological test for
syphilis); N eurological disorders (seizures or psychosis, in the absence of other causes); Malar
rash; Discoid rash
SJOGREN SYNDROME
A chronic, systemic autoimmune disorder
Principally involves the salivary and lacrimal glands, resulting in xerostomia and
xerophthalmia.
keratoconjunctivitis sicca – ocular manifestations
sicca syndrome.
Two forms of the disease are recognized.
1. Primary Sjogren syndrome (sicca syndrome alone)
2. Secondary Sjogren syndrome.
• The cause of Sjogren’s syndrome is unknown.
• not a hereditary disease
• genetic influence and viral etiology have been suggested.
Clinical features
Predominantly middle aged adults . It is more common in females. (10:1)
Secondary Sjogren syndrome is most commonly associated with other auto-immune
disorders like rheumatoid arthritis and less commonly SLE.
Xerostomia - principal oral symptom
Frothy saliva
lack of the usual pooling saliva in the floor of the mouth.
Difficulty in swallowing, altered taste,difficulty in wearing dentures,Fissured tongue and
exhibits atrophy of the papillae. Oral mucosa may be red and tender, usually as a result of
secondary candidiasis. Denture sore mouth and angular cheilitis are common.
The lack of saliva may predispose to cervical caries.
Diffuse , firm enlargement of the major salivary glands during the course of their disease.
Swelling is bilateral, may be non painful or slightly tender may be intermittent or persistent
in nature. There is great risk for retrograde bacterial sialadenitis
Sialographic examination
Sialography reveals punctate sialectasia and lack of normal arborization of the ductal system
typically demonstrating a “fruit-laden, branchless tree” pattern.
 Scintigraphy shows decreased uptake and delayed emptying of the isotope
Keratoconjunctivitis Sicca
Reduced tear production by the lacrimal glands
pathologic effect on the epithelial cells of the ocular surface.
Decrease of the aqueous layer of the tear film.
Scratchy , gritty sensation.
Manifestations are severe in the morning on awakening and become more pronounced as
the day progresses.
Schirmer test - confirm the decreased tear secretion
various other body tissues also affected
Skin - dry, as are the nasal and vaginal mucosae.
Fatigue is fairly common and depression can occur. Lymphadenopathy , primary biliary
cirrhosis, Raynaud’s phenomenon, interstitial nephritis, interstitial lung fibrosis, vasculitis
and peripheral neuropathies.

Laboratory values
The ESR is high and serum immunoglobulin levels, especially IgG, are elevated.
A positive rheumatoid factor (RF) is found in 75% cases regardless of whether patient has
rheumatoid arthritis.
Antinuclear antibodies are also present in most patients. Two particular nuclear
autoantibodies – anti-SS-A (ant0-Ro) and anti-SS-B (anti-La) – are frequently found.
Occasionally, salivary duct autoantibodies can also be demonstrated. Salivary protein
electrophoresis is a potentially useful test for the diagnosis of Sjogren’s syndrome.
Histopathologic features
The basic finding is lymphocytic infiltration of the salivary glands with destruction of the
acinar units.
If the major glands are enlarged microscopic examination usually shows progression to a
lymphoepithelial lesion, with characteristic epimyoepithelial islands in a background
lymphoid stroma.
Epimyoepithelial islands are rarely seen in minor glands.
Biopsy of the minor salivary glands of the lower lip is useful for diagnosis.
 The presence of more than one focus of focal chronic inflammatory cells aggregates adjacent
to normal-appearing acini of 50 or more cells within a 4mm2 area of glandular tissue is
considered supportive of the diagnosis of Sjogren’s syndrome.
Diagnosis
American-European Consensus Criteria for Sjögren’s Syndrome
In order to make a diagnosis of Sjögren’s syndrome, the following criteria must be met:

I. Ocular Symptoms (at least one)

 Symptoms of dry eyes for at least 3 months

 A foreign body sensation in the eyes
 Use of artificial tears 3 or more times per day
II. Oral Symptoms (at least one)

 Symptoms of dry mouth for at least 3 months

 Recurrent or persistently swollen salivary glands
 Need for liquids to swallow dry foods
III. Ocular Signs (at least one)

 Abnormal Schirmer’s test, (without anesthesia; ≤5 mm/5 minutes)

 Positive vital dye staining of the eye surface
IV. Histopathology

 Lip biopsy showing focal lymphocytic sialoadenitis (focus score ≥1 per 4 mm2)
V. Oral Signs (at least one)

 Unstimulated whole salivary flow (≤1.5 mL in 15 minutes)

 Abnormal parotid sialography
 Abnormal salivary scintigraphy
VI. Autoantibodies (at least one)

 Anti-SSA (Ro) or Anti-SSB (La), or both

For a primary Sjögren’s syndrome diagnosis:

 Any 4 of the 6 criteria, must include either item IV (Histopathology) or VI

(Autoantibodies)
 Any 3 of the 4 objective criteria (III, IV, V, VI) 
For a secondary Sjögren’s syndrome diagnosis:
In patients with another well-defined major connective tissue disease, the presence of one
symptom (I or II) plus 2 of the 3 objective criteria (III, IV and V) is indicative of secondary SS.

Exclusion Criteria

 Past head and neck radiation treatment

 Hepatitis C infection
 Acquired immunodeficiency syndrome (AIDS)
 Pre-existing lymphoma
 Sarcoidosis
 Graft versus host disease
 Current use of anticholinergic drugs
American College of Rheumatology/European League Against Rheumatism
classification criteria for primary Sjogren’s syndrome:
The classification of primary Sjogren’s syndrome applies to € any individual who meets
the inclusion criteria,* does not have any of the conditions listed as exclusion criteria,†
and has a score of >=4 when the weights from the 5 criteria items below are summed.
Item Weight/score
 Labial salivary gland with focal lymphocytic sialadenitis 3
and focus score of >=1 foci/4 mm2
 Anti-SSA/Ro positive 3
 Ocular Staining Score >=5 (or van Bijsterveld score >=4) 1
in at least 1 eye
 Schirmer’s test <=5 mm/5 minutes in at least 1 eye 1
 Unstimulated whole saliva flow rate <=0.1 ml/minute 1

These inclusion criteria are applicable to any patient with at least 1 symptom of ocular or
oral dryness, defined as a positive response to at least 1 of the following questions:
1) Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2) Do you have a recurrent sensation of sand or gravel in the eyes?
3) Do you use tear substitutes more than 3 times a day?
4) Have you had a daily feeling of dry mouth for more than 3 months?
 5) Do you frequently drink liquids to aid in swallowing dry food?, or in whom there is
suspicion of Sjogren’s syndrome (SS) from the European € League Against Rheumatism
SS Disease Activity Index questionnaire (at least 1 domain with a positive item).
Treatment and prognosis
• Treatment is mostly supportive therapy. The dry eyes are best managed by periodic use
of artificial tears.
• Artificial salivas are available for xerostomia. Sialogogues are useful if functional
salivary tissue is present. Antifungal therapy is needed to treat secondary candidiasis.
• Patients with SS have an increased risk for lymphoma. They may arise initially within
the salivary glands or within lymphnodes.

RHEUMATOID ARTHRITIS

Is a chronic, presumably auto-immune disorder characterized by nonsuppurative

inflammatory destruction of the joints. It may result from a cross-reaction of antibodies
generated against hemolytic streptococci or other microorganisms, or it may represent an
antibody attack against bacterial cell walls or viral capsule fragments deposited within the
synovium.
Rheumatoid arthritis begins as an attack against the synovial membrane (synovitis). A
reactive macrophage-laden fibroblastic proliferation (pannus) from the synovium creeps onto
the joint surface. This releases collagenases and other proteases, which destroy the cartilage
and underlying bone.

Clinical and radiographic features

 Affects women three times more frequently than men. The onset and course of the
disease are extremely variable. For many patients, only one or two joints become
involved and significant pain or limitation of motion never develops. In others, disease
rapidly progresses to debilitating polyarthralgia.
 Typically, the signs and symptoms become more severe over time and include swelling,
stiffness, pain, joint deformity and disability, with possible fibrous or bony fusion of
 opposing articular surfaces (ankylosis). Periods of remission often are interspersed with
periods of exacerbation. Symmetric involvement of the small joins of the hands and feet
almost always is present. Twenty percent of patients have firm, partially movable, non
tender rheumatoid nodules beneath the skin near the affected joint. These are
pathognomonic for the disease. Joints involved with rheumatoid arthritis have a
characteristic ‘anvil’ shape, with an irregular flattening of the central articular surface and
a splaying of the lateral bone. The TMJ is affected to some degree in more than 40% of
persons with rheumatoid arthritis. When present, TMJ involvement is usually bilateral
and occurs late in the disease. The signs and symptoms are seldom as severe as in other
joints and include stiffness, crepitation, pain or ache, tenderness, or limitation of mouth
opening. Swelling is less obvious than other joints. The pain of TMJ rheumatoid arthritis
is related to pressure on the joint rather than to motion. Clenching of the teeth on one
side produces pain on the contralateral joint. Subluxation or ankylosis is less frequent in
the TMJs than in other joints but gross destruction of the condylar heads may be so
severe that mandibular micrognathia causes a receding chin and malocclusion.
Permanent TMJ subluxation may also occur.
 Radiographically, involved TMJ’s demonstrate a flattened condylar head with irregular
surface features an irregular temporal fossa surface, perhaps with remodeling of the fossa
itself and anterior displacement of the condyle. CT scans, scanning arthrography and
arthroscopy are excellent tools for assessing TMJ damage. MRI’s are sensitive and have,
in recent years, become the diagnostic tool of choice.
 Laboratory values – Approximately 80% of patients exhibit elevated rheumatoid factor
(RF). Also, antinuclear antibody (ANA) can be detected in 50% patients but it is not
diagnostic. Elevated ESR and mild anemia also may be noted.
Histopathologic features
 Needle biopsy is the most popular technique for obtaining diagnostic synovial material.
 Early cases demonstrate hyperplasia of the synovial lining cells with deeper portions of
the membrane showing hyperemia, edema and infiltration by lymphocytes, macrophages
and occasional neutrophils. Neutrophils are the predominant inflammatory cell in the
synovial fluid. Older lesions show continued, often pronounced synovial proliferation
and edema, with cholesterol crystals and fewer inflammatory cells. Typically, the
membrane protrudes into the joint space as villi or finger-like projections. These
projections occasionally undergo necrosis, producing rice bodies, small whitish villi
fragments composed of cellular debris admixed with fibrin and collagen. When the TMJ
is severely involved, the meniscus is typically perforated or replaced completely by
fibrous scar.
 The rheumatic nodule is represented by a moderately well-demarcated area of
amorphous, eosinophilic necrosis surrounded by a thick layer of mononuclear cells. The
 mononuclear cells closest to the amorphous center are typically large and palisaded.
Neutrophils are seen in the centre.
Treatment and prognosis
 No cure exists for RA drug therapy in early and mild cases consists of NSAIDS, and
aided by occasional corticosteroid injection into the joint.
 Systemic corticosteroids, gold injections, pencillamine, cyclophosphamide and
methotrexate are the commonly used second-line medications. Severely damaged joints
may have to be replaced surgically.

ORAL LICHEN PLANUS

Oral lichen planus (OLP) is a common mucocutaneous disease. It was first described by
Wilson in 1869 and is thought to affect 0.5–1% of the world's population.
The condition can affect either the skin or mucosa or both. It can cause bilateral white
striations, papules, or plaques on the buccal mucosa, tongue, and gingivae.
Erythema, erosions, and blisters may or may not be present. The involvement of the oral
mucous membrane is so frequent and accompanies or precedes the appearance of lesions on
the skin and genital mucous membrane.

Etiology
T-cell-mediated autoimmune disease in which cytotoxic CD8+ T-cells trigger the apoptosis of
oral epithelial cells. However, the precise cause of OLP is unknown.
The CD8+ lesional T-cells may recognize an antigen associated with the major
histocompatibility complex (MHC) class I on keratinocytes. After antigen recognition and
activation, CD8+ cytotoxic T-cells may trigger keratinocyte apoptosis. Activated CD8+ T-
cells (and possibly keratinocytes) may release cytokines that attract additional lymphocytes
into the developing lesion.
The lichen planus antigen is unknown, although it may be a selfpeptide.
The expression or unmasking of the lichen planus antigen may be induced by drugs
(lichenoid drug reaction), contact allergens in dental restorative materials or toothpastes
(contact hypersensitivity reaction), mechanical trauma (Koebner phenomenon), viral
infection, or unidentified agents.
 It is interesting to note that the disease is seldom seen in carefree persons; the nervous, high-
strung person is almost invariably the one in whom the condition develops.
The course of the disease is long, from months to several years, frequently undergoing
periods of remission followed by exacerbations which often correspond to periods of
emotional upset, overwork, anxiety or some form of mental strain. Other causes suggested
include traumatism (since outbreaks often develop along scratch lines), malnutrition and
infection.
An interesting association of lichen planus, diabetes mellitus and vascular hypertension has
been described by Grinspan, the triad being described as Grinspan's syndrome by Grupper.
However, the reported associations between OLP and systemic diseases may be coincidental,
because OLP is relatively common, it occurs predominantly in older adults, and many drugs
used in the treatment of systemic diseases trigger the development of oral lichenoid lesions as
an adverse effect
Clinical Features
female-to-male ratio of 1.4:1
adults older than 40 years, although younger adults and children can be affected
The skin lesions of lichen planus appear as small, angular, flat-topped papules only a few
millimeter in diameter. These may be discrete or gradually coalesce into larger plaques, each
of which is covered by a fine, glistening scale. The papules are sharply demarcated from the
surrounding skin.
Early in the course of the disease the lesions appear red, but they soon take on a reddish,
purple or violaceous hue. Later, a dirty brownish color develops.
The center of the papule may be slightly umbilicated. Its surface is covered by characteristic,
very fine grayish-white lines, called Wickham's striae.
The lesions may occur anywhere on the skin surface, but usually are distributed in a
bilaterally symmetrical pattern, most often on the flexor surfaces of the wrist and forearms,
the inner aspect of the knees and thighs, and the trunk, especially the sacral area. The face
frequently remains uninvolved.
In chronic cases, hypertrophic plaques may develop, especially over the shins. The primary
symptom of lichen planus is a severe pruritus that may be intolerable. In patients with OLP,
scalp involvement (lichen planopilaris) and nail involvement is rare.
Oral Manifestations
The majority of patients with dermal lichen planus have associated oral lesions of the
disease, according to the study of Shklar and McCarthy.
Characterized by lesions consisting of radiating white or gray, velvety, thread-like papules in
a linear, annular or retiform arrangement forming typical lacy, reticular patches, rings and
streaks over the buccal mucosa and to a lesser extent on the lips, tongue and palate.
A tiny white elevated dot is frequently present at the intersection of the white lines, known
here also as the striae of Wickham. When plaque-like lesions occur, radiating striae may
often be seen on their periphery.
Shklar and McCarthy have reported the following distribution of oral lesions: buccal mucosa,
80%; tongue, 65%; lips, 20%; gingiva, floor of mouth and palate, less than 10%
These oral lesions produce no significant symptoms, although occasionally patients will
complain of a burning sensation in the involved areas.
Vesicle and bulla formation has been reported in oral lesions of lichen planus, but this is not a
common finding, and the diagnosis of lichen planus from the clinical appearance of the
lesions is extremely difficult. This bullous form of lichen planus has been discussed by
Shklar and Andreasen.
Still another type, the so-called erosive form of lichen planus, usually begins as such and not
as a progressive process from ‘nonerosive’ lichen planus. Nevertheless the vesicular or
bullous form of the disease may clinically resemble erosive lichen planus when the vesicles
rupture.
Eroded or frankly ulcerated lesions are irregular in size and shape and appear as raw, painful
areas in the same general sites involved by the simple or reticular form of the disease.
Despite the erosion of the mucosa, the characteristic radiating striae may often be noted on
the periphery of the individual lesions.
An atrophic form of lichen planus occurs with some frequency and appears clinically as
smooth, red, poorly defined areas, often but not always with peripheral striae evident.
A hypertrophic form of lichen planus may also occur on the oral mucosa, generally appearing
as a well-circumscribed, elevated white lesion resembling leukoplakia. In such cases biopsy
is usually necessary to establish the diagnosis.
The oral manifestations of lichen planus may occur weeks or months before the appearance
of the skin lesions.
Other mucous membranes may be affected also, such as those of the penis, vagina and
epiglottis. The genitals are involved in as many as 25% of women with OLP, compared with
only 2–4% of men with OLP. Involvement of these locations may occur concomitant with or
independent of oral lesions.
A variety of drugs may cause lesions that appear clinically similar to lichen planus and are
termed as lichenoid lesions. Oral mucosal lichenoid lesions may occur after the
 administration of systemic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs),
sulfonylureas, antimalarials, beta-blockers, and some angiotensin-converting enzyme (ACE)
inhibitors. The period between the commencement of the drug therapy and the clinical
appearance of OLP-like disease varies. In rare cases, oral mucosal lichenoid lesions occur
after a dental restoration is performed or after the patient starts using a denture; the lag period
varies. Patients with an associated allergy to metals or components of the appliance should be
evaluated by means of patch testing. In many patients, a cause for the oral lichenoid lesions
cannot be identified; in these patients, the disease is called idiopathic OLP. Oral lichenoid
reactions are considered to be a part of the spectrum of graft-versus-host disease.
They are present as reticular, erythematous, erosive lesions or ulceration, with whitish streak
similar to that of Wickham's striae of lichen planus. Clinical manifestations of LR are very
much similar to that of lichen planus. An important factor which distinguishes LR from
lichen planus is its atypical location and absence of bilateral occurrence.
There is no specific test to diagnose LR. The widely accepted criterion is based on the
observation of disappearance of the lesions after withdrawal of triggering agent and
recurrence of the lesions when it is reintroduced.
Though histologically LR has superficial resemblance to lichen planus there are notable
differences. The inflammatory infiltrate is diffuse and extends deeper into the lamina propria
unlike the sharp band of infiltrate seen in lichen planus. Inflammatory infiltrate consists of
plasma cells and eosinophils in addition to lymphocytes. Increased numbers of colloid or
Civatte bodies may be present in LR compared to lichen planus. A perivascular chronic
inflammatory cell infiltrate can be seen in drug related lichenoid lesions, which is not
commonly found in lichen planus.
Proliferative verrucous leukoplakia, an unusual form of leukoplakia shares some
demographic and clinical similarities with lichen planus. It occurs most commonly in older
female patients and is not associated with tobacco usage. Microscopically it exhibits
epithelial dysplasia with a band-like inflammatory infiltrate which on low-power can mimic
lichen planus and is known as lichenoid dysplasia.
Identification and elimination of the triggering factors play a major role in the management
of LR. Lichenoid lesions can take many months or longer to resolve. The malignant
transformation rate is reportedly higher in oral lichenoid lesions which do not have all the
typical clinical and histologic features of oral lichen planus.
Histologic Findings
Hyperparakeratosis or hyperorthokeratosis with thickening of the granular layer
Acanthosis with intracellular edema of the spinous cells in some instances and development
of a ‘saw tooth’ appearance of the rete pegs.
 Band-like subepithelial mononuclear infiltrate consisting of T-cells and histiocytes;
Increased numbers of intraepithelial T-cells; and degenerating basal keratinocytes that form
colloid (Civatte, hyaline, cytoid) bodies, which appear as homogenous eosinophilic globules
are consistently seen.
Degeneration of the basal keratinocytes and disruption of the anchoring elements of the
epithelial basement membrane and basal keratinocytes (e.g. hemidesmosomes, filaments,
fibrils) weakens the epithelial-connective tissue interface. As a result, histologic clefts (i.e.
Max-Joseph spaces) may form, and blisters on the oral mucosa (bullous lichen planus) may
be seen at clinical examination.
B cells and plasma cells are uncommon findings
Direct immunofluorescent studies of lichen planus by Daniels and Quadra-White have shown
that nearly all specimens from oral lesions of this disease react with antifibrinogen and
exhibit an intensely positive fluorescence that outlines the basement membrane zone with
numerous irregular extensions into the superficial lamina propria. This particular pattern is
characteristic of both lichen planus and lupus erythematosus. This is not present in
pemphigoid or erythema multiforme, in both of which the fluorescence instead tends to form
a patchy linear pattern, nor is it seen in pemphigus, in which the fluorescence has a granular
pattern.
In OLP, electron microscopy is used principally as a research tool. The ultrastructure of the
colloid bodies suggests that they are apoptotic keratinocytes, and recent studies of the
endlabeling method revealed DNA fragmentation in these cells. Electron microscopy shows
breaks, branches, and duplications of the basement membrane in OLP.

Differential Diagnosis
• lichenoid reactions
• leukoplakia
• candidiasis
• pemphigus
• cicatricial pemphigoid
• erythema multiforme
• syphilis
 • recurrent aphthae
• lupus erythematosus
Malignant Transformation
• There seems to be a slightly higher incidence of oral squamous cell carcinoma in patients
with oral lichen planus than in the general population
• Frequency : 0.3 and 3%
• The forms that more commonly undergo malignant transformation are the erosive and
atrophic forms.
Treatment
• At present there is no cure, although various agents have been tried. Due to its minimal
potential for malignant transformation, these patients used to be kept on longterm follow-
up.
• The principal aims of current OLP therapy are the resolution of painful symptoms, the
resolution of oral mucosal lesions, the reduction of the risk of oral cancer, and the
maintenance of good oral hygiene.
• As it is an autoimmune mediated condition, corticosteroids are recommended. In patients
with recurrent painful disease, another goal is the prolongation of their symptom free
intervals.

PSORIASIS
Psoriasis is a noncontagious skin disorder that most commonly appears as inflamed,
edematous skin lesions covered with a silvery white scale.
The most common type of psoriasis is plaque psoriasis and is characterized by patches on the
scalp, trunk, and limbs. The nails may be pitted and/or thickened. In rare instances it has been
reported to manifest oral mucous membrane lesions.
Etiology
The cause of psoriasis is unknown.
 Patients do have a genetic predisposition for the disease; the disease has a strong association
with HLA Cw6 and B57 region. Recent evidence suggests that in addition to these regions
many other gene loci such as 19p13, 17q25, and 1q21 may also increase the susceptibility to
this disease.
The trigger event may be unknown in most cases but is likely to be an immunologic event.
Significant evidence is accumulating that psoriasis is an autoimmune disease.
Lesions of psoriasis are associated with increased activity of T-cells in underlying skin.
Also of significance is that 2.5% of persons with HIV develop psoriasis during the course of
the disease.
Perceived stress can cause exacerbation of psoriasis. Some authors suggest that psoriasis is a
stress-related disease and offer findings of increased concentrations of neurotransmitters in
psoriatic plaques.
The pathogenesis of psoriatic lesions is due to an increase in the turnover rate of dermal cells,
from the normal turnover duration of 23 days to three to five days in affected areas. As would
be expected, there is also a dramatic increase in the mitotic index of psoriatic skin which is
said to even surpass that of epidermoid carcinoma.

Clinical Features
Psoriasis of the skin is characterized by the occurrence of small, sharply delineated, dry
papules, each covered by a delicate silvery scale which has been described as resembling a
thin layer of mica.
If the deep scales are removed, one or more tiny bleeding points are disclosed, a
characteristic feature termed Auspitz's sign. After removal of the scale the surface of the skin
is red and dusky in appearance.
The cutaneous lesions, which are painless and seldom pruritic, may be few in number or
extensive in distribution.
The papules enlarge at the periphery and tend to become slightly infiltrating and elevated,
smaller lesions coalescing to form large plaques of irregular outline.
They are roughly symmetrical and are most frequently grouped on the extensor surfaces of
the extremities, particularly the elbows and knees, the scalp, back and chest, face and
abdomen. Involvement of the hands and feet, with the exception of the fingernail, is
uncommon.
The disease commences with the appearance of a few small papules, which gradually
increase in size. New lesions slowly arise over a period of weeks, months or even years.
 The disease may remain static for a long time, progresses slowly to involve more and more
skin area, or exhibits acute generalized exacerbations.
The disease is more severe in the winter and less severe in the summer as a result of
increased exposure to ultraviolet light; patients who move to a warm sunny climate usually
undergo improvement in their condition.
Mental anxiety or stress almost invariably appears to increase the severity of the disease or
induce acute exacerbations.
Arthritis is a complication in about 12% of persons with psoriasis, according to Allen.
Psoriasis is uncommon in children, and seldom does a primary attack occur after the age of
45 years; it most frequently arises in the second and third decades of life.
The median age at onset is 28 years.
Psoriasis is slightly more common in women.
Oral Manifestations
extremely rare
Oral lesions occurring concomitant with psoriasis of the skin are actually other diseases such
as leukoplakia or lichen planus. In occasional cases oral lesions have exhibited all histologic
features of psoriasis and in some instances have been identical with the coexisting skin
lesions.
Such lesions have been reported on the lips, buccal mucosa, palate, gingiva and floor of the
mouth.
Clinically, they are described as gray or yellowish-white plaques; as silvery white, scaly
lesions with an erythematous base; as multiple papular eruptions which may be ulcerated; or
as small, papillary, elevated lesions with a scaly surface.
Fischman and his coworkers studied an oral lesion in a patient with skin lesions of psoriasis
utilizing light and electron microscopy, as well as immunologic methods, and noted in all
instances that the findings in the oral lesion were similar to those in the skin lesions. They
concluded that true oral lesions do occur in psoriasis.
The general problem of ‘psoriasiform’ lesions of the oral mucosa has been reviewed by
Weathers and his associates. These lesions included psoriasis, Reiter's syndrome, benign
migratory glossitis and 'ectopic geographic tongue', and the authors concluded that their exact
interrelationship, if any, is still unknown
Histologic Features
 Exhibits uniform parakeratosis. There is absence of the stratum granulosum and elongation
and clubbing of the rete pegs.
The epithelium over the connective tissue papillae is thinned, and it is from these points that
bleeding occurs when the scales are peeled off. Tortuous, dilated capillaries extending high in
the papillae are prominent. Intraepithelial microabscesses (Monro's abscesses) are a common
but not invariable finding; they are reported by Pisanty and Ship to be absent in oral
psoriasis.
Mild lymphocytic and histiocytic infiltration of the connective tissue is also typical,
particularly perivascular and periadnexal in location.
Treatment
• The lesions are usually benign but a few cases may be refractory to treatment.
• Treatments for more general or advanced psoriasis include UV-A light, psoralen plus UV-
A light (PUVA), retinoids (e.g., isotretinoin, acitretin), methotrexate (particularly for
arthritis), cyclosporine, and alefacept.

GRAFT-VERSUS-HOST DISEASE (GVHD)

• Occurs mainly in recipients of allogenic bone marrow transplantation. To provide the
patient with an immune system, an HLA-matched donor must be found. Unfortunately,
the HLA match is not always exact and the result is an attack known as GVHD.
Clinical features
• In most patients with oral GVHD, there is a fine, reticular network of white striae that
resembles oral lichen planus. The tongue, the labial mucosa and the buccal mucosa are
the common sites. Skin involvement, which is the most common manifestation, may
resemble LP or even systemic sclerosis.

Histopathologic feature
• It resembles those of lichen planus to a certain degree with hyper keratinisation, short
pointed reteridges and degeneration of basal layer. But the inflammatory response is not
as intense. With advanced cases an abnormal deposition of collagen is present.
Treatment
• The primary strategy is to prevent its occurrence. The patient can be given prophylactic
therapy with immunomodulatry and immunosuppressive drugs. Other treatment
modalities are thalidomide, topical corticosteroids for oral ulcers, Psoralen and Ultra-
violet A (PUVA). The prognosis depends on the extent to which the condition progresses.
SYSTEMIC SCLEROSIS
• Scleroderma, dermatosclerosis, hidebound disease
Systemic sclerosis (SSc) is a systemic connective tissue disease, characterized by vasomotor
disturbances; fibrosis; subsequent atrophy of the skin, subcutaneous tissue, muscles, and
internal organs (e.g. alimentary tract, lungs, heart, kidney, CNS); with associated
immunologic disturbances.
Etiology
Systemic sclerosis is an autoimmune disease of unclear etiology; however, different factors,
including genetic, environmental, and vascular factors are involved in SSc pathogenesis.
One theory states that antigens from the human leukocyte antigen (HLA) histocompatability
complex, including HLA-B8, HLA-DR5, HLA-DR3, HLA-DR52, and HLA-DQB2, are
involved in SSc.

Some data suggest that apoptosis and the generation of free radicals may be involved in the
pathogenesis of SSc. Increased collagen deposition in tissues is a characteristic feature of
SSc.
Clinical Features
Progressive systemic sclerosis is a disease characterized by the ultimate induration of the
skin and fixation of the epidermis to the deeper subcutaneous tissues.
It may begin in children or young adults, although the greatest incidence is between 30 and
50 years of age
females being affected more frequently then males (3-6:1).
Systemic sclerosis usually begins on the face, hands or trunk. Simultaneously with the
development of the early typical indurated edema of the skin, neuralgia and paresthesia may
occur as well as arthritis or simply vague joint pain.
Erythema usually accompanies this cutaneous change. The disease progresses at a variable
rate, but eventually much, if not all, of the body surface becomes involved.
The skin takes on a yellow, gray or ivory-white waxy appearance. Brown pigmentation of the
skin may also occur, but this is usually a late manifestation of the disease.
Sometimes deposition of calcium in affected areas is also found.
 The skin becomes hardened and atrophic and cannot be wrinkled or picked up because of its
firm fixation to the deep connective tissue. This contracture of the skin gives a mask-like
appearance to the face and a claw-like appearance to the hands
Progressive diffuse systemic sclerosis may ultimately involve many internal organs by
fibrosis, loss of smooth muscle and loss of visceral function. Those organs most frequently
involved are the gastrointestinal tract, lungs cardiovascular-renal system, musculoskeletal
system, and central nervous system.
One variant of systemic sclerosis is the CREST syndrome, an acronym of the five major
findings: calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and
telangiectasia. This form of the disease is sometimes not as severe as the usual systemic type.
Circumscribed scleroderma, commonly termed morphea, is manifested by the appearance of
one or more well-defined, slightly elevated or depressed cutaneous patches, which are white
or yellowish and are surrounded by a violaceous halo. The plaques are varied in both size and
shape. The lesions commonly occur on the sides of the chest and the thighs.
Occasionally the lesions occur as linear bands or ribbons on the face, particularly the
forehead, on the chest and trunk or on an extremity. This has been termed linear scleroderma.
Such a band, made up of a furrow with an elevated ridge on one side, is often termed a coup
de sabre, since it resembles the mark produced by the blow of a saber. The circumscribed
lesions eventually become stiff and hard. It has been reported that facial hemiatrophy is
associated with this form of the disease occurring in children. The lesions are generally
asymptomatic, although prickling, tingling and itching sensations have been described.
The disease may persist for several months to many years, but, in this form, causes no deaths.

Oral Manifestations
The tongue, soft palate and larynx are the intraoral structures usually involved in progressive
systemic sclerosis.
Early mild edema of these structures is gradually followed by atrophy and induration of
mucosal and muscular tissues.
The tongue often becomes stiff and board like, causing the patient difficulty in eating and
speaking. The gingival tissues are pale and unusually firm.
 The lips become thin, rigid and partially fixed, producing microstomia.
Dysphagia, a choking sensation, inability to open and close the mouth and difficulty in
breathing also occur.
The reduced opening of the mouth and fixation of the jaw are a result of involvement of the
peritemporomandibular joint tissues, and make dental care very difficult.
In addition, Alarcon-Segovia and his coworkers, studying 25 patients with progressive
systemic sclerosis, found that all had pathologic changes in the minor salivary glands
characteristic of Sjögren's disease: lymphocyte infiltration, duct cell proliferation and
collagen infiltration.
Radiographic Features
Extreme widening of the periodontal ligament, two to four times normal thickness.
This may be so striking that, once the association is recognized, the occurrence of the
periodontal disturbance as found on routine dental radiographs may be sufficient to establish
a tentative diagnosis of systemic sclerosis.
Bone resorption of the angle of the mandibular ramus, usually bilaterally
One additional radiographic feature reported has been partial or complete resorption of
condyles and/or coronoid processes of the mandible.
Histologic Features
Shows thickening and hyalinization of the collagen fibers in the skin . there is the loss of
dermal appendages, particularly the sweat glands and atrophy of the epithelium with loss of
rete pegs . Increased melanin pigmentation
Increase in PAS-positive, diastase-resistant material present in the areas of the homogeneous
collagen.
Subcutaneous fat disappears, and the walls of the blood vessels become sclerotic. Mucous
membrane changes are similar to those occurring in the skin.
The microscopic changes in the periodontal ligament consist of a widening due to an increase
of collagen and oxytalan fibers as well as an appearance of hyalinization and sclerosis of
collagen with a diminution in the number of connective tissue cells usually found.
Treatment
There is no adequate treatment for progressive diffuse systemic sclerosis, although partial
remissions have been reported following cortisone therapy. Circumscribed scleroderma has an
excellent prognosis, since spontaneous remission usually occurs.
Conclusion:
Autoimmune disorders are developing due to loss of self tolerance. Clinicians should be
aware that oral lesions in Autoimmune diseases ma look similar, and might be the only
manifestation of disease.A quick and proper diagnosis is necessary for adequate treatment which
may take place in a multi-disciplinary setting. Direct immunofluorescence on a biopsy from skin
or mucosa combined with Indirect immunoflourescence and additional serological tests are the
cornerstones for the diagnosis of Autoimmune blistering diseases. By following the described
diagnostic algorithm, clinicians should be able to recognize and accurately diagnose
Autoimmune blistering diseases affecting the oral mucosa.

References:
1. Pathologic basis of Diseases – Robbins and Cotran
2. Oral and Maxillofacial Pathology. 2nd Edition – Neville, Damm, Bouquot, Allan.
3. Sivapathasundharam B. Shafer's Textbook of Oral Pathology-E Book. Elsevier Health
Sciences; 2016 Jul 25.
4. Lever WF. Histopathology of the Skin. Histopathology of the skin.. 1949.
5. Rashid H, Lamberts A, Diercks GF, Pas HH, Meijer JM, Bolling MC, Horváth B. Oral
lesions in autoimmune bullous diseases: an overview of clinical characteristics and
diagnostic algorithm. American journal of clinical dermatology. 2019 Dec;20(6):847-61.
6. Reilly RJ, Johnston W, Culshaw S. Autoimmunity and the oral cavity. Current Oral
Health Reports. 2019 Mar;6(1):1-8.
7. Saccucci M, Di Carlo G, Bossù M, Giovarruscio F, Salucci A, Polimeni A. Autoimmune
diseases and their manifestations on oral cavity: diagnosis and clinical management.
Journal of immunology research. 2018 May 27;2018.
8. Maślińska M, Przygodzka M, Kwiatkowska B, Sikorska-Siudek K. Sjögren’s syndrome:
still not fully understood disease. Rheumatology international. 2015 Feb;35(2):233-41.
9. Parisis D, Chivasso C, Perret J, Soyfoo MS, Delporte C. Current state of knowledge on
primary Sjögren’s syndrome, an autoimmune exocrinopathy. Journal of clinical medicine.
2020 Jul;9(7):2299.
10. Asano Y. The pathogenesis of systemic sclerosis: an understanding based on a common
pathologic cascade across multiple organs and additional organ-specific pathologies.
Journal of Clinical Medicine. 2020 Sep;9(9):2687.