Download Unit 3 Autoimmune Diseases That Affect the Oral Cavity 1. Sjogren`s

Unit 3
Autoimmune Diseases That Affect the Oral Cavity
1.
Sjogren’s Syndrome (aka Sicca Syndrome, Gougerat-Sjogren
Syndrome) Siccus = Dry
The specific etiology is unknown. An autoimmune process in which the patient’s own
salivary gland and tear-producing (lacrimal) tissue becomes antigenic (capable of causing
antibody production).
Two types:
a.
b.
Primary: (Sicca Complex) involves eyes and mouth: keratoconjunctivitis sicca
(dry eyes-xerophtalmia), and xerostomia (dry mouth).
Secondary: Seen with connective tissue disease such as rheumatoid arthritis,
lupus or polymyositis.
Chief oral complaint is xerostomia. Recurrent and symmetric parotid gland
enlargement is seen in about half of patients. No cure; it is a chronic syndrome requiring
long-term symptomatic management by dentist, ophthalmologist, and rheumatologist. A
significant consequence is the malignant transformation to lymphoma in about 6-7 % of
cases.
2.
Lupus Erythematosus: (Langlais) An autoimmune process that may be
influenced by genetic or viral factors. 20-40% of patients with LE have oral lesions.
Discoid (chronic), which involves only the skin; systemic lupus erythematosus (SLE),
in which multiple organ systems are involved; and subacute cutaneous with mild
systemic symptoms. The cause is unknown. More common in women, with peak age of
30 for SLE, 40 for DLE.
Discoid type is least aggressive form and manifests skin lesions only (predilection for the
face). Classic feature of discoid type is facial butterfly pattern of erythema over the nasal
bridge.
Systemic type may have oral lesions that are white and plaque-like, resembling erosive
lichen planus but less symmetrically distributed and more subtle striae. Patients often
complain of fever, fatigue, and joint pain. Sunburn can trigger acute reactions. Patients
may be taking high doses of systemic steroids so be aware of delayed wound healing and
risk of infections. Antibiotic prophylaxis required due to risk of subacute bacterial
endocardiditis.
3.
Pemphigus: (Langlais) Immunopathologic dermatologic disease that is potentially
fatal. Histologically, confused antibodies are produced that react with the cementing
materials linking adjacent squamous cells of the skin and oral mucosa. These antibodies
are readily detected in the blood of patients with pemphigus. They bind to cementing
materials (desmosomes) and lead to the destruction of cell-to-cell linkages. With the loss
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in intercellular linkages the surface epithelium becomes weakened and the cells separate,
leading to blister formation and epithelial desquamation.
Rapid development of multiple bullae that tend to rupture and leave erosions of the skin
and oral mucous membranes. Extremely painful. When there is systemic involvement,
severe debilitation may result in death. Disease may be fatal due to septicemia and
dehydration. Mortality rate has decreased with introduction of systemic steroids but
patient may die from long-term steroid therapy. Four types: vulgaris, vegetans,
foliaceous, and erythematosus.
4.
Pemphigus Vulgaris: Oral lesions are always present at some time and in about
60% are the first signs of the disease--cutaneous lesions may follow up to 1 year
later.Bullae rupture, are painful. Application of mild lateral pressure on clinically normal
mucosa in patients with pemphigus often produces blistering and sloughing of the
mucosa, leaving a raw, painful surface = Nikolsky Sign.
The Tzanck test is the examination microscopically of intact vesicles for the presence of
damaged, separated epithelial cells. Direct immunofluorescence is a sophisticated test to
detect the presence of abnormal epithelial antibody in the patient’s tissues. Indirect
immunofluorescence detects the Ab in the patient’s serum.
5.
Cicatricial Pemphigoid (aka Benign Mucous Membrane
Pemphigoid-BMMP, ocular pemphigus, mucosal pemphigoid,
pemphigus conjunctivae): cicatrix = a scar left by a healed wound.
Relatively rare, chronic, self-limiting, mucocutaneous disease. Resembles bullous
pemphigoid but bullae are usually on mucous membranes and in the eyes and also
conjunctival, pharyngeal, anal, and vaginal. Female 2x. Skin lesions precede oral
lesions. Oral lesions are always present, gingiva is most common site. Gingival lesions
range from patchy erythema with mild discomfort to intense generalized erythema and
ulceration extending beyond attached gingiva. Patients with cicatricial pemphigoid
typically demonstrate Nikolsky’s sign.
Antibodies are directed against the constituents found in the basement membrane zone
between epithelium and connective tissue. These autoantibodies lead to the destruction
of the linkage between these tissues. The lesions are from cleavage of the epithelium
from the underlying connective tissue. The gingival lesions have been called
desquamative gingivitis (a descriptive term...see lichen planus and pemphigus vulgaris).
Treated with systemic steroids.
6.
Bullous Pemphigoid: Similar to cicatricial pemphigoid but no sex predilection,
oral lesions in only about 1/3, otherwise, only the skin is affected.
7.
Behcet’s Syndrome (aka oculo-oral-genital syndrome): (Langlais p.
96) Unknown etiology but may be similar to aphthous ulcers. May also be a genetic
predisposition. See antibodies to human mucosa = evidence for autoimmune
pathogenesis. Lesions affect oral cavity, eye, and genitalia, a triple-symptom complex..
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Oral manifestations appear identical to ulcers of aphthous (minor type). Usually treated
with systemic steroids.
Infectious Diseases
Bacterial Infections:
1.
Tuberculosis: Infectious granulomatous disease caused by Mycobacterium
tuberculosis. TB is found worldwide but is much less prevalent than it was before
antibiotics. Case rate varies regionally and depends on factors that favor spread of
communicable diseases (poor living conditions, compromised immunity from debilitating
or immunosuppressed conditions).
Mantoux test and Tine test are skin tests using a tubercular bacillus antigen (PPD =
purified protein derivative) to see if person is hypersensitive to antigen challenge.
Clinical signs and symptoms of TB are often remarkably inconspicuous. Malaise
(discomfort, uneasiness) and fatigue are often chief early features. May be gradual
weight loss with persistent cough. TB is highly infectious through transmission of airborne droplets that carry the organism to pulmonary air spaces; the portal of entry is the
respiratory tract. Caseous necrosis (looks like cottage cheese) is unique to tuberculosis.
Microscopically langerhans giant cells are present.
Oral lesions occur, but they are rare. They may be on any mucosal surface…tongue and
palate most likely. Lesions occur as superficial or deep, chronic, non-healing ulcers that
are usually painful. Infectious hazard to HCW if barriers not used.
2.
Miliary tuberculosis: includes widespread involvement of many organs due to
blood stream dissemination of microorganisms.
3.
Tuberculous Lymphadenitis or Scrofula: Tuberculous infection of the
submandibular and cervical lymph nodes that may progress to the formation of an actual
abscess, or it may remain as a typical granulomatous lesion. Swelling of the nodes is
obvious clinically. They are tender or painful and often show inflammation of the
overlying skin. When an actual abscess exists, it typically perforates and discharges pus.
There has been a dramatic increase in number of cases, possibly related to HIV.
Treatment continues for many months, up to 2 years. Patients become noninfectious after
treatment begins. Consult physician to be sure treatment is ongoing and that the patient is
no longer infectious.
4.
Actinomycosis: Caused by Actinomyces israelii, an anaerobic, gram-positive
bacterium found in a majority of healthy individuals. Follows tooth extraction or trauma.
Noncontagious. Lumpy jaw from formation of granulation tissue and abscesses in
submandibular region. Lesion may become indurated and eventually form one or more
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draining sinuses, leading from the medullary spaces of the mandible to the skin of the
neck. The pus may contain small yellow granules, known as sulfur granules, that are
aggregates of A. israelii organisms. Treated with antibiotics.
5.
Syphilis: A venereal disease that has been traced as far back as the time of Christopher
Columbus.
Caused by spirochete, Treponema pallidum. Acquired by: 1) sexual contact with a
partner with active lesions, 2) transfusion of infected blood, or 3) transplacental
inoculation from an infected mother.
Three stages:
a.
b.
c.
d.
6.
7.
Primary syphilis results in a painless, indurated ulcer (chancre) with rolled
margins. It forms at the site of inoculation and heals in 3-12 weeks. The lesion
heals spontaneously and enters a latent period. The chancre is highly infectious.
Lymphadenopathy also develops.
Secondary syphilis (6 weeks after primary) manifests smooth-surfaced mucous
patches and possibly split papules at commissure and maculopapular rash…all
highly infectious. It develops in most of the untreated cases. (Miller). Fever, flulike symptoms, mucocutaneous lesions. Resolves spontaneously.
Tertiary (late-stage) syphilis lesions are seen in about 1/3 of those not treated;
appears years after initial infection. CNS and cardiovascular involved with
noninfectious gumma commonly on palate and tongue, but can be on any organ.
Generalized glossitis (syphilitic glossitis) may develop that may develop
squamous cell carcinoma.
Congenital syphilis occurs when the T. pallidum organism crosses the placenta
from the infected mother. Hutchinson’s triad may be seen as: 1) interstitial
keratitis (inflammatory reaction in cornea), 2) eighth nerve deafness, and 3)
mulberry molars and notched or screw-driver-shaped incisors.
Acute Necrotizing Ulcerative Gingivitis (ANUG):
Painful,
erythematous gingivitis with necrosis of the interdental papilla. Results in cratering of
interdental papilla. Most frequently occurs in young adults. Predisposing factors include
poor nutrition to the point of malnutrition, poor oral hygiene and plaque control,
psychological stress, and immune suppression.
Acute Osteomyelitis: Acute inflammation of bone and bone marrow of mandible
and maxilla most often from extension of a periapical abscess. It also can be caused from
physical injury (fracture or surgery), or from bacteremia.
Infectious. Painful. Not apparent radiographically unless present for more than 1 week.
Treated with antibiotics and drainage.
8.
Chronic Osteomyelitis: Bone inflammation. May follow acute osteomyelitis or
may have never gone through acute phase. Infectious. Irradiated bone is especially
susceptible to infection (osteoradionecrosis). Bacteria (staph, strep, actinomyces) are
believed to be responsible for the great majority of cases.
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Mandible more than maxilla. Jaw swelling is seen often, with loose teeth and sinus tracts
occurring sometimes. Diffuse radiolucency can become opaque, and then it is called
chronic sclerosing osteomyelitis. This condition is treated with debridement and
antibiotics.
Fungal Infections
1.
Candidiasis (aka moniliasis, thrush): The most common oral mycotic
infection. Caused by C. albicans, a unicellular yeast organism living in the oral cavity of
most healthy persons. This condition is complex and has many clinical presentations
along with interrelationships with local and systemic factors.
This disease occurs in four groups: 1) the very young; 2) the very old; 3) those with
reduced resistance and 4) those on long term antibiotic therapy or immunosuppression.
Oral lesions are white, soft plaques that leave an erythematous, tender surface when
wiped away. Favored sites include buccal mucosa, oropharynx, and lateral tongue
borders. Chronic oral candidiasis is a common finding in AIDS.
Pseudomembranous lesions show surface ulceration. In superficial infections, fungi are
limited to surface layers of epithelium, in more severe examples hyphae--filaments of
mold--will extend deeper into the epithelium.
Nystatin (an antifungal mouthwash) or clotrimazole troche to treat. Discontinue
oxygenating agents (hydrogen peroxide).
Types Of Candidasis (Classification Systems Vary)
a.
b.
c.
d.
Pseudomembranous Candidiasis (thrush): This is seen in up to 5% of
neonates, 5% of cancer patients, and 10% of institutionalized, debilitated elderly
patients. Moreover, it is present in 50% of leukemia patients being treated with
radiation or chemotherapy and 70% of patients being treated for solid tumors. It
presents as a white curd-like material on the mucosal surface. Underlying mucosa
is erythematous. Wiping away will leave an erythematous, eroded, or ulcerated
surface that is often tender.
Chronic Mucocutaneous Candidiasis Localized form is characterized by longstanding, persistent candidiasis of oral mucosa, nails, skin, and vaginal mucosa.
Often resistant to treatment.
Acute Atrophic Candidiasis (aka erythematous candidiasis): This presents if
pseudomembranous persists. Can result from broad-spectrum antibiotics.
Chronic Atrophic Candidiasis (aka denture stomatitis): = most common type
of Candidiasis. Present in up to 65% of geriatric individuals who wear complete
maxillary dentures. Women more than men, palate more than mandibular arch.
Poor fitting denture and wearing an appliance at night contribute to development.
It is usually asymptomatic.
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e.
f.
g.
h.
Chronic Hyperplastic Candidiasis (aka candida leukoplakia, hypertrophic
candidiasis): Some say is premalignant. The white lesion does not wipe off-important diagnostic feature is its response to antifungal medication.
Angular Cheilitis: is seen in those with chronic atrophic candidiasis. Often
there are deep folds at commissures due to overclosure. Saliva gathers there and
is colonized by yeast. Also seen in those who lick their lips habitually.
Median Rhomboid Glossitis: (see Ch. 1) Candida organisms identified in some,
but not all lesions. Therefore, though often associated with Candida, cause is not
yet clear.
Chronic Mucocutaneous Candidiasis: Localized form is characterized by longstanding, persistent candidiasis of oral mucosa, nails, skin, and vaginal mucosa.
Often resistant to treatment.
2.
Deep Fungal Infections (ex. histoplasmosis, coccidiodo-mycosis,
blastomycosis, cryptococcosis): Primarily involve the lungs. Infections are
distributed regionally. Oral lesions can look like squamous cell carcinoma because they
are chronic, non-healing ulcers. Therefore, must biopsy. Treat with antifungal meds
such as amphotericin B or ketoconazole. However, lesions may be resistant to treatment
and may reappear if the individual’s immune system becomes deficient.
3.
Mucormycosis (aka phycomycosis): Rare. Palate perforated from infection
by a phycomycete. Seen in a patient with a debilitating illness (diabetic, chemotherapy
patient, immunosuppressed transplant patients). Organisms of this family of fungi
normally found in bread mold or decaying fruit and vegetable, infect humans when
systemic health is compromised. Route of infection is GI tract or respiratory. Lesions in
head and neck most likely in nasal cavity, paranasal sinuses, possibly oropharynx. Death
is a relatively frequent consequence of this infection, especially if lung is infected.
Viral Infections
Viruses are composed of an inner nucleic acid core (genome) of either DNA or RNA that
represents their genetic code. The genome is surrounded by a protein coat known as a capsid.
With some types of viruses, a lipid envelope further encases the capsid. The complete virus
particle is known as the virion.
Viruses are infective agents that lack the necessary structures for self-replication. They require
living cells for maintenance and multiplication. Therefore, viruses are intracellular parasites.
The infecting virus attaches to the preferred cell type and penetrates the plasma membrane.
Once entry into the cell is accomplished, the capsid (and envelope) are lost, leaving the viral
genome to encode the cell for the manufacture of capsid proteins, viral nucleic acid, and
enzymes necessary for assembly. The infecting virus also directs intracellular assembly of new
particles. Eventually, newly replicated (and enveloped) virus is released, with subsequent
infection of other cells. This usually occurs at the expense of the originally infected cell.
In certain types of viral infection, cell death may not occur, allowing the virus to infect dividing
host cells in a chronic pattern. Viral latency, in which the infectious agent lies dormant within
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the host cell, is another non-cytocidal infection. This is common to the herpes viruses, papilloma
viruses, and retroviruses. In this latter form of viral infection, overt clinical signs and symptoms
of viral replication and infection may follow certain triggering events, such as stress or
alterations in the immune state.
Another non-cytotoxic type of viral infection is related to tumor-associated viruses that have the
ability to become incorporated in the host cell DNA. This newly incorporated viral genetic
information results in “ transformation” of the host cell into a neoplastic cell.
Because viruses are integrally associated with host cell biologic function and metabolic pathways
and because they utilize similar enzymatic pathways, development of a chemotherapeutic agent
that kills the virus and spares the cell has been especially difficult. Antiviral chemotherapy,
therefore, has been directed toward certain enzymes that are virus specific and unique to viral
replication.
Papillomavirus Infection
(Human Papillomavirus--HPV, Papovavirus)
1.
Verruca Vulgaris (aka wart): Generally asymptomatic skin neoplasm caused by
a papilloma virus. Patients may have verrucae on hands or fingers and oral lesions
appear to arise through autoinoculation by finger sucking or fingernail biting. White,
papillary, exophytic lesions that look like a papilloma. Treated by excision.
2.
Condyloma Acuminatum: Characteristically in anogenital region but may also
involve oral mucosa. Caused by HPV. Increasingly seen in AIDS patients. Benign,
papillary lesion. Pink, more diffuse than papilloma or verruca vulgaris, and not as well
keratinized.
3.
Focal Epithelial Hyperplasia (aka Heck’s disease): Definitive etiology
unknown but HPV is increasingly suspected. Asymptomatic. Multiple whitish to pale
pink nodules distributed throughout the oral mucosa. No treatment indicated--resolve
spontaneously in a few weeks.
Herpesvirus
Two distinct serotypes: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2)
exist. However, these viruses are nearly indistinguishable except for a variable DNA segment.
HSV-1 occurs primarily above the waist in the oral-facial area and HSV-2 below the waist in the
anal-genital area. Clinically the lesions appear identical, and HSV-1 can occur genitally and
HSV-2 orally.
Herpes Simplex Infection (HSV-1) Type 1
(Oral Manifestations)
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1.
Primary Herpetic Gingivostomatitis: Usually seen in children between ages
of 1 and 10. Typical route of viral exposure is physical contact with an infected
individual. With initial inoculation, clinical manifestations may or may not result. Most
individuals develop a subclinical infection.
Characterized by painful, erythematous, and swollen gingiva and multiple tiny vesicles
on the perioral skin, vermilion border of the lips, and the oral mucosa. They progress to
form ulcers. Fever, malaise, and cervical lymphadenopathy generally occur first,
followed by gingival involvement and mucosal vesicles and ulcers. Intraoral lesions may
appear on any mucosal surface (secondary lesions are confined to hard palate and
gingiva). Infection lasts 1 week to 10 days and lesions heal without scar.
2.
Ocular herpes: is from a primary herpetic eye infection. Usually unilateral.
Keratoconjunctivitis and/or follicular conjunctivitis result.
Following resolution of primary herpetic gingivostomatitis, the virus migrates along the
peri-axon sheath of the trigeminal nerve to the trigeminal ganglion, where it is capable of
remaining in a latent state.
3.
Recurrent Herpes Simplex Infection: A large majority of the population (up
to 90%) have antibodies to HSV, and 1/3 to 1/2 of the U.S. population may develop
secondary herpes. Exact triggering mechanism is unknown. Factors associated with
reactivation of virus include exposure to sunlight (“fever blisters”), exposure to cold
(“cold sores”), trauma, stress, menstruation, and immunosuppression. occur on oral
mucosa that is bound to the periosteum. Attached gingiva and hard palate are most
common locations. However, lesions may occur anywhere in the oral cavity in patients
who are immunocompromised.
4.
Herpes labialis (aka cold sore or fever blister): is the most common
recurrent oral herpetic infection. Usually prodromal symptoms of tingling, burning, or
pain in the site where lesions will appear. Lesions are map-like superficial ulcer(s) that
heal without scarring in 1 to 2 weeks.
Patients should be advised that if hands come into direct contact with a herpetic lesion,
they should be thoroughly washed to prevent cross infections. Some advise against
treating patients with active lesions because it is theorized that treatment procedures may
prolong the course of the disease and make current lesions more severe.
5.
Herpetic Whitlow: Can be primary or recurrent infection. Involves the fingers.
Duration may be as long as 4 to 6 weeks. Swelling, itching and redness followed by
intense pain.
Herpes Simplex Virus (HSV-2)
Type 2 (genital infections)
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1.
Primary
2.
Secondary Latent virus is maintained in the lumbosacral ganglion.
Varicella Zoster Virus (VZV: a herpesvirus)
1.
Chickenpox (primary Varicella-zoster): Primary infection for the disease.
Oral ulcerations on the palate are common with chickenpox. Oral lesions have no
diagnostic significance and present no serious problem. Lesions are on trunk and face
primarily and are very pruritic. “Herald spot” is first and largest lesion to appear.
2.
Zoster (Secondary Varicella-zoster) (aka Shingles Herpes):
Reactivation of latent VZV. Can follow a depressed cellular immune state
(hematopoietic or lymphoid malignancy, drug administration, irradiation or surgery on
spinal cord, local trauma). Usually in those older than 50.
Shingles occurs when VZV is activated from the dorsal ganglion or the trigeminal
ganglion where it was sequestered. The previously hidden virus migrates down the
peripheral nerve and infects the skin and mucous membranes supplied by the nerve.
Lesions begin as prodromal paresthesia or pain, followed shortly by multiple crops of
vesicles and subsequent ulcers and crusts. The total lesion duration is usually less than 1
month. Since the virus cannot migrate far beyond the area of skin or mucous membrane
supplied by the infected nerve, the lesions usually do not cross the midline but conform to
the anatomic pattern of the branches of the affected nerve. Hence, the acutely painful
vesicles follow sensory nerves unilaterally (especially thoracic and abdominal nerves).
May affect any branch of trigeminal. Oral lesions are rare.
Epstein-Barr Virus (EBV: a herpesvirus)
1.
Infectious Mononucleosis: Palatal petechiae, lethargy, malaise, bilateral
lymphadenopathy, sore throat, fever. Most commonly in adolescents and young adults.
Low contagiousness (may be spread by saliva exchange from deep kissing). Oral lesions
often are first sign. Multiple red palatal petechiae turn brown and fade after 7 to 10 days.
Downey cells (atypical lymphocytes) are diagnostic. Palliative treatment. 1-2 months for
recovery.
2.
Hairy Leukoplakia: Most commonly on lateral border of tongue in HIV patients.
This lesion has been associated with subsequent or concomitant development of the
clinical and laboratory features of AIDS in up to 80% of cases. Unilateral or bilateral,
irregular surface contour often folded or corrugated. No symptoms. After hairy
leukoplakia diagnosed, studies show about 10% have AIDS and 18% developed AIDS
within 8 months, 50% at 16 months, 80% at 30 months.
Burkitt’s Lymphoma: Considerable but not totally conclusive evidence that the
Epstein-Barr virus is causally related to Burkitt’s lymphoma.
3.
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There is a considerable amount of evidence linking HSV-II to carcinoma of the cervix.
Coxsackie virus (a picornavirus)
1.
Herpangina: Contagious, painful, light-gray vesicles that rupture to form multiple,
discrete, shallow ulcers. Lesions are only found in oropharynx on soft palate and fauces.
More often in children than adults and common in the summer months. Symptoms
usually last less than a week. Sore throat, fever, malaise, headache, lymphadenitis,
abdominal pain, vomiting.
2.
Hand, Foot, and Mouth Disease (HFM): Contagious, painful vesicles in oral
cavity (tongue, lips and buccal mucosa), on hands and feet (pathognomonic sign).
Usually in children under 5 years old. Pain from oral lesions is usually chief complaint.
Self limiting, resolves spontaneously in 1 to 2 weeks.
Other Viral Infections that May Have Oral Manifestations
Paramyxovirus
1.
Measles (rubeola): Caused by a paramyxovirus. After 7 to 10 days incubation and
prodromal symptoms (fever, malaise, conjunctivitis, photophobia, cough) then will see
Koplik’s spots intraorally 1 to 2 days before skin rash. German measles (rubella) is
caused by an unrelated virus of the togavirus family. Significant because it can cause
congenital defects in developing fetus.
2.
Mumps (aka epidemic parotitis): caused by a paramyxovirus. Considered the
most common of all salivary gland diseases. 2-3 week incubation then fever, malaise,
headache, and chills in addition to preauricular pain. Prevention is now possible using a
live attenuated vaccine that induces a non-communicable, subclinical infection.
Human Immunodeficiency Virus (see chapter 7)
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Comparison of oral herpes and aphthous stomatitis
Oral herpes (caused by herpes simplex type I)
Lesion
Location
Gingivostomatitis
Gingiva, all mucous
membranes
Herpes labialis
Lips—vermilion
Intraoral recurrent
Gingiva, hard palate,
tissue attached to
bone
Clinical
Characteristics
Multiple vesicles,
multiple ulcers, fever;
malaise
Prodrome; multiple
small vesicles;
crust(s)
Prodrome; multiple
small vesicles;
multiple small ulcers
Salivary-bearing
mucous membrands
Singular enlarging
ulcers
Salivary-bearing
mucous membranes
Salivary-bearing
mucous membranes
Singular, very large
ulcers; scarring
Multiple, small,
herpetiform ulcers
Apthous Stomatitis
Recurrent aphthous
ulcers
Major apthous ulcers
Herpetiform ulcers
Course
7-14 days
7-14 days; recurrent;
with predisposing
factors
7-14 days; recurrent;
with predisposing
factors
7-14 days; recurrent;
with predisposing
factors
14-28 days; frequent
7-14 days; frequent
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