1. THE PATIENT WITH RECURRING ORAL ULCERS
▼Recurring oral ulcers are among the most common problems
seen by clinicians who manage diseases of the oral mucosa.
There are several diseases that should be included in the differential
diagnosis of a patient who presents with a history of
recurring ulcers of the mouth, including recurrent aphthous
stomatitis (RAS), Behçet’s syndrome, recurrent HSV infection,
recurrent erythema multiforme, and cyclic neutropenia.

2. Recurrent Aphthous Stomatitis
RAS is a disorder characterized by recurring ulcers confined to the oral mucosa in patients with no other signs of disease.

3. RAS affects approximately 20% of the general population,
but when specific ethnic or socioeconomic groups are studied,
the incidence ranges from 5 to 50%. RAS is classified according
to clinical characteristics: minor ulcers, major ulcers
(Sutton’s disease, periadenitis mucosa necrotica recurrens),
and herpetiform ulcers. Minor ulcers, which comprise over
80% of RAS cases, are less than 1 cm in diameter and heal
without scars. Major ulcers, are over 1 cm in diameter and
take longer to heal and often scar.Herpetiform ulcers are considered
a distinct clinical entity that manifests as recurrent
small ulcers throughout the oral mucosa.

4. ETIOLOGY It was once assumed that RAS was a form of recurrent HSV
infection, and there are still clinicians who mistakenly call RAS
“herpes.” Many studies done during the past 40 years have
confirmed that RAS is not caused by HSV. This distinction
is particularly important at a time when there is specific effective
antiviral therapy available for HSV that is useless for RAS.
“Herpes” is an anxiety-producing word, suggesting a sexually
transmitted disease among many laypersons, and its use
should be avoided when it does not apply..

5. The current concept is that RAS is a clinical syndrome with several possible causes. The major factors identified include heredity, hematologic deficiencies, and immunologic abnormalities.
The best documented factor is heredity. Miller
and colleagues studied 1,303 children from 530 families and demonstrated an increased susceptibility to RAS among children
of RAS-positive parents

6. A study by Ship and associates
showed that patients with RAS-positive parents had a 90%
chance of developing RAS, whereas patients with no RAS-positive
parents had a 20% chance of developing the lesions.85
Hematologic deficiency, particularly of serum iron, folate,
or vitamin B12, appears to be an etiologic factor in a subset of
patients with RAS. The size of the subset is controversial, but
most estimates range from 5 to 15%. A study by Rogers and
Hutton reported clinical improvement in 75% of patients with
RAS when a specific hematologic deficiency was detected and
corrected with specific replacement therapy. Some cases of
nutritional deficiency, such as celiac disease, are reported to be
secondary to malabsorption syndrome

7. Most of the research into the etiology of RAS centers on
immunologic abnormalities. Early work suggested either an autoimmune disorder or hypersensitivity to oral organisms such as Streptococcus sanguis. Investigations using more sophisticated
immune assays have not supported the early work and
suggest a role of lymphocytotoxicity,
. Thomas and colleagues showed that lymphocytes from patients with RAS had increased cytotoxicity to oral epithelial.cells

8. Work by Pedersen and colleagues and
other studies demonstrated an alteration in CD4:CD8 lymphocyte ratio, or a dysfunction of the mucocutaneous cytokine network.
Further work is needed to determine if these are specific
or nonspecific responses.
Other factors that have been suggested as being etiologic in
RAS include trauma, psychological stress, anxiety, and allergy
to foods. It is well documented that cessation of smoking
increases the frequency and severity of RAS. In cases of
refractory disease, Hay and Reade reported the benefit of an
elimination diet in some patients with suspected or proven
allergy to foods such as milk, cheese, wheat, and flour.
A detergent present in toothpaste, sodium lauryl sulfate
(SLS), was suspected as an etiologic factor in RAS development,
but a recent double-blind crossover study showed
that use of an SLS-free toothpaste had no significant effect on
ulcer development

9. CLINICAL MANIFESTATIONS
The first episodes of RAS most frequently begin during the second
decade of life and may be precipitated by minor trauma,
menstruation, upper respiratory infections, or contact with
certain foods. The lesions are confined to the oral mucosa and
begin with prodromal burning any time from 2 to 48 hours
before an ulcer appears. During this initial period, a localized
area of erythema develops.Within hours, a small white papule
forms, ulcerates, and gradually enlarges over the next 48 to 72
hours. The individual lesions are round, symmetric, and shallow
(similar to viral ulcers), but no tissue tags are present from
ruptured vesicles (this helps to distinguish RAS from disease
with irregular ulcers such as EM, pemphigus, and pemphigoid). .

10. Multiple lesions are often present, but the number,
size, and frequency of them vary considerably
The buccal and labial mucosae are most commonly involved.
Lesions are less common on the heavily keratinized palate or gingiva. In mild RAS, the lesions reach a size of 0.3 to 1.0 cm
and begin healing within a week. Healing without scarring is usually complete in 10 to 14 days

11. Most patients with RAS have between two and six lesions at
each episode and experience several episodes a year.The disease
is an annoyance for the majority of patients with mild RAS, but it can be disabling for patients with severe frequent lesions,
especially those classified as major aphthous ulcers. Patients
with major ulcers develop deep lesions that are larger than 1 cm
in diameter and may reach 5 cm Large
portions of the oral mucosa may be covered with large deep
ulcers that can become confluent.

12. The lesions are extremely
painful and interfere with speech and eating. Many of these
patients continually go from one clinician to another, looking
for a “cure.”The lesions may last for months and sometimes be
misdiagnosed as squamous cell carcinoma, chronic granulomatous
disease, or pemphigoid. The lesions heal slowly and
leave scars that may result in decreased mobility of the uvula
and tongue and destruction of portions of the oral mucosa. The
least common variant of RAS is the herpetiform type, which
tends to occur in adults. The patient presents with small punctate
ulcers scattered over large portions of the oral mucosa.

13. DIAGNOSIS RAS is the most common cause of recurring oral ulcers and is
essentially diagnosed by exclusion of other diseases. A detailed
history and examination by a knowledgeable clinician should distinguish RAS from primary acute lesions such as viral stomatitis
or from chronic multiple lesions such as pemphigoid, as well
as from other possible causes of recurring ulcers, such as connective tissue disease, drug reactions, and dermatologic disorders.
The history should emphasize symptoms of blood dyscrasias, systemic complaints, and associated skin, eye, genital, or rectal
lesions.

14. Laboratory investigation should be used when ulcers
worsen or begin past the age of 25 years. Biopsies are only indicated
when it is necessary to exclude other diseases, particularly
granulomatous diseases such as Crohn’s disease or sarcoidosis.
Patients with severe minor aphthae or major aphthous
ulcers should have known associated factors investigated,
including connective-tissue diseases and abnormal levels of
serum iron, folate, vitamin B12, and ferritin
Patients with abnormalities in these values should be referred
to an internist to rule out malabsorption syndromes and to initiate
proper replacement therapy. The clinician may also
choose to have food allergy or gluten sensitivity investigated in
severe cases resistant to other forms of treatment. HIV infected
patients, particularly those with CD4 counts below
100/mm3, may develop major aphthous ulcers

15. TREATMENT
Medication prescribed should relate to the severity of the disease.
In mild cases with two or three small lesions, use of a protective
emollient such as Orabase (Bristol-Myers Squibb,
Princeton, NJ) or Zilactin (Zila Pharmaceutions, Phoenix,AZ)
is all that is necessary. Pain relief of minor lesions can be
obtained with use of a topical anesthetic agent or topical
diclofenac, an NSAID frequently used topically after eye
surgery. In more severe cases, the use of a high-potency topical
steroid preparation, such as fluocinonide, betamethasone
or clobetasol, placed directly on the lesion shortens healing
time and reduces the size of the ulcers. The effectiveness of the
topical steroid is partially based upon good instruction and patient compliance regarding proper use.

16. The gel can be carefully applied directly to the lesion after meals and at bedtime
two to three times a day, or mixed with an adhesive such as
Orabase prior to application. Larger lesions can be treated by
placing a gauze sponge containing the topical steroid on the
ulcer and leaving it in place for 15 to 30 minutes to allow for
longer contact of the medication. Other topical preparations
that have been shown to decrease the healing time of RAS
lesions include amlexanox paste and topical tetracycline, which
can be used either as a mouth rinse or applied on gauze
sponges.

17. Intralesional steroids can be used to treat large indolent
major RAS lesions. It should be emphasized that no available
topical therapy decreases the onset of new lesions. In
patients with major aphthae or severe cases of multiple minor
aphthae not responsive to topical therapy, use of systemic therapy
should be considered. Drugs that have been reported to
reduce the number of ulcers in selected cases of major aphthae
include colchicine, pentoxifylline, dapsone, short bursts of systemic
steroids, and thalidomide Each of these drugs has
the potential for side effects, and the clinician must weigh the potential benefits versus the risks

18. . Thalidomide has been shown
to reduce both the incidence and severity of major RAS in both
HIV-positive and HIV-negative patients, but this drug must be
used with extreme caution in women during childbearing years
owing to the potential for severe life-threatening and deforming
birth defects. All clinicians prescribing thalidomide in the
United States must be registered in the STEPS (System for
Thalidomide Education and Prescribing Safety) program, and
patients receiving the drug must be thoroughly counseled
regarding effective birth control methods that must be used
whenever thalidomide is prescribed. For example, two methods
of birth control must be used, and the patient must have a
pregnancy test monthly. Other side effects of thalidomide
include peripheral neuropathy, gastrointestinal complaints, and
drowsiness.

21. A 42-year-old woman with a recent increase in severity
of recurrent aphthous ulcers. An iron deficiency was detected, and the
ulcers resolved when this deficiency was corrected.

22. Major aphthous ulcer in an HIV-infected patient.

23. Behçet’s Syndrome
Behçet’s syndrome, described by the Turkish dermatologist
Hulûsi Behçet, was classically described as a triad of symptoms
including recurring oral ulcers, recurring genital ulcers, and eye lesions. The concept of the disease has changed from a
triad of signs and symptoms to a multisystem disorder. The
highest incidence of Behçet’s syndrome has been reported in
eastern Asia, where 1 in 10,000 is affected, and the eastern
Mediterranean, where it is a leading cause of blindness in
young men; however, cases have been reported worldwide,
including in North America, where it is estimated that 1 in
500,000 persons is affected. The highest incidence of Behçet’s
syndrome is in young adults, but cases of Behçet’s syndrome
in children are being reported with increasing frequency.

24. ETIOLOGY Behçet’s syndrome is caused by immunocomplexes that lead to
vasculitis of small and medium-sized blood vessels and inflammation
of epithelium caused by immunocompetent T lymphocytes
and plasma cells. Increased neutrophil activity
has also been noted. There is a genetic component to the
disease,with a strong association with HLA-B51. Studies of the
immune abnormalities associated with Behçet’s syndrome
have included findings described above for patients with RAS.
This has led some investigators to believe that Behçet’s syndrome
and RAS are both manifestations of a similar disorder
of the immune response.

25. CLINICAL MANIFESTATIONS
The most common single site of involvement of Behçet’s syndrome
is the oral mucosa.Recurring oral ulcers appear in over
90% of patients; these lesions cannot be distinguished from
RAS . Some patients experience mild recurring
oral lesions; others have the deep large scarring lesions characteristic
of major RAS. These lesions may appear anywhere on
the oral or pharyngeal mucosa. The genital area is the second
most common site of involvement and involves ulcers of the
scrotum and penis in males and ulcers of the labia in females.
The eye lesions consist of uveitis, retinal infiltrates, edema and
vascular occlusion, optic atrophy, conjunctivitis, and keratitis.
Generalized involvement occurs in over half of patients
with Behçet’s syndrome. Skin lesions are common and usually
manifest as large pustular lesions.

26. These lesions may be precipitated
by trauma, and it is common for patients with Behçet’s
syndrome to have a cutaneous hyper-reactivity to intracutaneous injection or a needlestick (pathergy). Positive pathergy
is defined as an inflammatory reaction forming within 24 hours
of a needle puncture, scratch, or saline injection.
Arthritis occurs in greater than 50% of patients and most
frequently affects the knees and ankles. The affected joint
may be red and swollen as in rheumatoid arthritis, but
involvement of small joints of the hand does not occur, and
permanent disability does not result.

27. In some patients, central nervous system involvement is the
most distressing component of the disease. This may include
brainstem syndrome, involvement of the cranial nerves, or neurologic degeneration resembling multiple sclerosis that can be
visualized by magnetic resonance imaging of the brain. Other
reported signs of Behçet’s syndrome include thrombophlebitis,
intestinal ulceration, venous thrombosis, and renal and pulmonary
disease. Involvement of large vessels is life threatening
because of the risk of arterial occlusion or aneurysms.

28. Behçet’s syndrome in children, which most frequently
presents between the ages of 9 and 10 years, has similar manifestations
as does the adult form of the disease, but oral
ulcers are a more common presenting sign in children, and
uveitis is less common. Oral lesions are the presenting
symptom in over 95% of children with Behçet’s syndrome.A
variant of Behçet’s syndrome, MAGIC syndrome, has been
described. It is characterized by Mouth And Genital ulcers
with Inflammed Cartilage.

29. DIAGNOSIS Because the signs and symptoms of Behçet’s syndrome overlap
with those of several other diseases, particularly the connective-
tissue diseases, it has been difficult to develop criteria
that meet with universal agreement. Five different sets of diagnostic
criteria have been in use during the past 20 years. In
1990, an international study group reviewed data from 914
patients from seven countries. A new set of diagnostic criteria
was developed that includes recurrent oral ulceration
occurring at least three times in one 12-month period plus two
of the following four manifestations:
1. Recurrent genital ulceration
2. Eye lesions including uveitis or retinal vasculitis
3. Skin lesions including erythema nodosum, pseudofolliculitis,
papulopustular lesions, or acneiform nodules
in postadolescent patients not receiving corticosteroids
4. A positive pathergy test

30. TREATMENT The management of Behçet’s syndrome depends on the severity
and the sites of involvement. Patients with sight-threatening
eye involvement or central nervous system lesions require more
aggressive therapy with drugs with a higher potential for serious
side effects. Azathioprine combined with prednisone has been
shown to reduce ocular disease as well as oral and genital
involvement.120 Pentoxifylline, which has fewer side effects than
do immunosuppressive drugs or systemic steroids, has also been
reported to be effective in decreasing disease activity,particularly eye involvement.

31. Cyclosporine or colchicine in combination
with corticosteroids has also been shown to be useful in severe
disease. Colchicine and thalidomid have been
shown to be useful in mucocutaneous and gastrointestinal manifestations.
Systemic corticosteroids remain a mainstay of treatment
and are particularly useful in rapidly controlling the disease
until immunosuppressive agents begin to work.
Plasmapheresis has also been used successfully in emergencies.
Oral mucosal lesions not adequately controlled by systemic
therapy may be treated with topical or intralesional steroids.

32. Aphthous-like lesion in a patient with Behçet’s syndrome.

33. Recurrent Herpes Simplex Virus Infection
Recurrent herpes infection of the mouth (recurrent herpes
labialis [RHL]; recurrent intraoral herpes simplex infection
[RIH]) occurs in patients who have experienced a previous
herpes simplex infection and who have serum-antibody protection
against another exogenous primary infection. In otherwise
healthy individuals, the recurrent infection is confined
to a localized portion of the skin or mucous membranes.
Recurrent herpes is not a re-infection but a reactivation of virus
that remains latent in nerve tissue between episodes in a nonreplicating state.

34. Herpes simplex has been cultured from
the trigeminal ganglion of human cadavers, and recurrent herpes
lesions commonly appear after surgery involving the ganglion.
Recurrent herpes may also be activated by trauma
to the lips, fever, sunburn, immunosuppression, and menstruation.
The virus travels down the nerve trunk to infect
epithelial cells, spreading from cell to cell to cause a lesion.
The published evidence demonstrating that RAS is not.
RAS and herpes lesions can both exist intraorally and are two
separate and distinct disease processes.

35. All patients who experience primary herpes infection do
not experience recurrent herpes. The number of patients with
a history of primary genital infection with HSV2 who subsequently
experience recurrent HSV infections is approximately
15%. The recurrence rate for oral HSV1 infections is estimated
to be between 20 and 40%.
Studies have suggested several mechanisms for reactivation
of latent HSV,
Individuals with T-lymphocyte deficiencies owing to
AIDS or transplant or cancer chemotherapy may develop
large chronic lesions or, rarely, disseminated
HSV infection.

36. CLINICAL MANIFESTATIONS
RHL, the common cold sore or fever blister,may be precipitated
by fever, menstruation, ultraviolet light, and perhaps emotional stress. The lesions are preceded by a prodromal period of tingling
or burning. This is accompanied by edema at the site of the
lesion, followed by formation of a cluster of small vesicles . Each vesicle is 1 to 3 mm in diameter, with the size of the
cluster ranging from 1 to 2 cm.Occasionally, the lesions may be
several centimeters in diameter, causing discomfort and disfigurement.
These larger lesions are more common in immunosuppressed
individuals.

37. The frequency of recurrences varies.
RIH lesions in otherwise normal patients are similar in
appearance to RHL lesions, but the vesicles break rapidly to
form ulcers. The lesions are typically a cluster of small vesicles
or ulcers, 1 to 2 mm in diameter, clustered on a small portion
of the heavily keratinized mucosa of the gingiva, palate, and
alveolar ridges, although RIH lesions can occasionally involve
other mucosal surfaces. In contrast, lesions of
RAS tend to be larger, to spread over a larger area of mucosa,
and to have a predilection for the less heavily keratinized buccal
mucosa, labial mucosa, or floor of the mouth.

38. DIAGNOSIS
If laboratory tests are desired, RIH can be distinguished from
RAS by cytology smears taken from the base of a fresh lesion.
Smears from herpetic lesions show cells with ballooning
degeneration and multinucleated giant cells; those from RAS
lesions do not. For more accurate results, cytology smears may
also be tested for HSV using fluorescein-labeled HSV antigen.
Viral cultures also are used to distinguish herpes simplex from
other viral lesions, particularly varicella-zoster infections.

39. TREATMENT Recurrent herpes infections of the lips and mouth are seldom
more than a temporary annoyance in otherwise normal individuals
and should be treated symptomatically. Patients who experience
frequent, large, painful, or disfiguring lesions may request
professional consultation. The clinician should first attempt to
minimize obvious triggers. Some recurrences can be eliminated
by the wearing of sunblock during intense sun exposure.

40. Crusted lesions of recurrent herpes labialis.

41. Drugs are available that suppress the formation and
shorten the healing time of new recurrent lesions. Acyclovir,
the original antiherpes drug, has been shown to be both safe
and effective. The newer antiviral drugs such as valacyclovir,
a prodrug of acyclovir, and famciclovir, a prodrug of penciclovir,
have greater bioavailability than does acyclovir, but
they do not eliminate established latent HSV.However, in the
mouse model, famciclovir appeared to decrease the rate of
HSV latency. The clinical importance of this finding in
human HSV infection is not known. The effectiveness of
these antiherpes drugs to prevent recurrences of genital HSV
has been studied extensively. Acyclovir 400 mg twice daily,
valacyclovir 250 mg twice daily, and famciclovir 250 mg were
each highly effective in preventing genital recurrences.

42. .
Systemic therapy should not be used to treat occasional or
trivial RHL in otherwise healthy individuals, but episodic
use to prevent lesions in susceptible patients before highrisk
activities such as skiing at high altitudes or before undergoing
procedures such as dermabrasion or surgery involving
the trigeminal nerve is justifiable. Some clinicians advocate
the use of suppressive antiherpes therapy for the small percentage
of RHL patients who experience frequent deforming
episodes of RHL. Acyclovir 400 mg twice daily has been
shown to reduce the frequency and severity of RHL in this
group of patients. Both acyclovir and penciclovir are available
in topical formulations, but use of these preparations
shortens the healing time of RHL by less than 2 days.