Presentation on theme: "THE PATIENT WITH RECURRING ORAL ULCERS"— Presentation transcript:
1THE PATIENT WITH RECURRING ORAL ULCERS ▼Recurring oral ulcers are among the most common problemsseen by clinicians who manage diseases of the oral mucosa.There are several diseases that should be included in the differentialdiagnosis of a patient who presents with a history ofrecurring ulcers of the mouth, including recurrent aphthousstomatitis (RAS), Behçet’s syndrome, recurrent HSV infection,recurrent erythema multiforme, and cyclic neutropenia.
2Recurrent Aphthous Stomatitis RAS is a disorder characterized by recurring ulcers confined to the oral mucosa in patients with no other signs of disease.
3RAS 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 accordingto clinical characteristics: minor ulcers, major ulcers(Sutton’s disease, periadenitis mucosa necrotica recurrens),and herpetiform ulcers. Minor ulcers, which comprise over80% of RAS cases, are less than 1 cm in diameter and healwithout scars. Major ulcers, are over 1 cm in diameter andtake longer to heal and often scar.Herpetiform ulcers are considereda distinct clinical entity that manifests as recurrentsmall ulcers throughout the oral mucosa.
4ETIOLOGY 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 haveconfirmed that RAS is not caused by HSV. This distinctionis particularly important at a time when there is specific effectiveantiviral therapy available for HSV that is useless for RAS.“Herpes” is an anxiety-producing word, suggesting a sexuallytransmitted disease among many laypersons, and its useshould be avoided when it does not apply..
5The 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. Millerand colleagues studied 1,303 children from 530 families and demonstrated an increased susceptibility to RAS among childrenof RAS-positive parents
6A study by Ship and associates showed that patients with RAS-positive parents had a 90%chance of developing RAS, whereas patients with no RAS-positiveparents had a 20% chance of developing the lesions.85Hematologic deficiency, particularly of serum iron, folate,or vitamin B12, appears to be an etiologic factor in a subset ofpatients with RAS. The size of the subset is controversial, butmost estimates range from 5 to 15%. A study by Rogers andHutton reported clinical improvement in 75% of patients withRAS when a specific hematologic deficiency was detected andcorrected with specific replacement therapy. Some cases ofnutritional deficiency, such as celiac disease, are reported to besecondary to malabsorption syndrome
7Most 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 sophisticatedimmune assays have not supported the early work andsuggest a role of lymphocytotoxicity,. Thomas and colleagues showed that lymphocytes from patients with RAS had increased cytotoxicity to oral epithelial.cells
8Work 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 specificor nonspecific responses.Other factors that have been suggested as being etiologic inRAS include trauma, psychological stress, anxiety, and allergyto foods. It is well documented that cessation of smokingincreases the frequency and severity of RAS. In cases ofrefractory disease, Hay and Reade reported the benefit of anelimination diet in some patients with suspected or provenallergy 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 showedthat use of an SLS-free toothpaste had no significant effect onulcer development
9CLINICAL MANIFESTATIONS The first episodes of RAS most frequently begin during the seconddecade of life and may be precipitated by minor trauma,menstruation, upper respiratory infections, or contact withcertain foods. The lesions are confined to the oral mucosa andbegin with prodromal burning any time from 2 to 48 hoursbefore an ulcer appears. During this initial period, a localizedarea of erythema develops.Within hours, a small white papuleforms, ulcerates, and gradually enlarges over the next 48 to 72hours. The individual lesions are round, symmetric, and shallow(similar to viral ulcers), but no tissue tags are present fromruptured vesicles (this helps to distinguish RAS from diseasewith irregular ulcers such as EM, pemphigus, and pemphigoid)..
10Multiple lesions are often present, but the number, size, and frequency of them vary considerablyThe 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 cmand begin healing within a week. Healing without scarring is usually complete in 10 to 14 days
11Most patients with RAS have between two and six lesions at each episode and experience several episodes a year.The diseaseis 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. Patientswith major ulcers develop deep lesions that are larger than 1 cmin diameter and may reach 5 cm Largeportions of the oral mucosa may be covered with large deepulcers that can become confluent.
12The lesions are extremely painful and interfere with speech and eating. Many of thesepatients continually go from one clinician to another, lookingfor a “cure.”The lesions may last for months and sometimes bemisdiagnosed as squamous cell carcinoma, chronic granulomatousdisease, or pemphigoid. The lesions heal slowly andleave scars that may result in decreased mobility of the uvulaand tongue and destruction of portions of the oral mucosa. Theleast common variant of RAS is the herpetiform type, whichtends to occur in adults. The patient presents with small punctateulcers scattered over large portions of the oral mucosa.
13DIAGNOSIS RAS is the most common cause of recurring oral ulcers and is essentially diagnosed by exclusion of other diseases. A detailedhistory and examination by a knowledgeable clinician should distinguish RAS from primary acute lesions such as viral stomatitisor from chronic multiple lesions such as pemphigoid, as wellas 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 rectallesions.
14Laboratory investigation should be used when ulcers worsen or begin past the age of 25 years. Biopsies are only indicatedwhen it is necessary to exclude other diseases, particularlygranulomatous diseases such as Crohn’s disease or sarcoidosis.Patients with severe minor aphthae or major aphthousulcers should have known associated factors investigated,including connective-tissue diseases and abnormal levels ofserum iron, folate, vitamin B12, and ferritinPatients with abnormalities in these values should be referredto an internist to rule out malabsorption syndromes and to initiateproper replacement therapy. The clinician may alsochoose to have food allergy or gluten sensitivity investigated insevere cases resistant to other forms of treatment. HIV infectedpatients, particularly those with CD4 counts below100/mm3, may develop major aphthous ulcers
15TREATMENTMedication prescribed should relate to the severity of the disease.In mild cases with two or three small lesions, use of a protectiveemollient 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 beobtained with use of a topical anesthetic agent or topicaldiclofenac, an NSAID frequently used topically after eyesurgery. In more severe cases, the use of a high-potency topicalsteroid preparation, such as fluocinonide, betamethasoneor clobetasol, placed directly on the lesion shortens healingtime and reduces the size of the ulcers. The effectiveness of thetopical steroid is partially based upon good instruction and patient compliance regarding proper use.
16The 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 asOrabase prior to application. Larger lesions can be treated byplacing a gauze sponge containing the topical steroid on theulcer and leaving it in place for 15 to 30 minutes to allow forlonger contact of the medication. Other topical preparationsthat have been shown to decrease the healing time of RASlesions include amlexanox paste and topical tetracycline, whichcan be used either as a mouth rinse or applied on gauzesponges.
17Intralesional steroids can be used to treat large indolent major RAS lesions. It should be emphasized that no availabletopical therapy decreases the onset of new lesions. Inpatients with major aphthae or severe cases of multiple minoraphthae not responsive to topical therapy, use of systemic therapyshould be considered. Drugs that have been reported toreduce the number of ulcers in selected cases of major aphthaeinclude colchicine, pentoxifylline, dapsone, short bursts of systemicsteroids, and thalidomide Each of these drugs hasthe 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 bothHIV-positive and HIV-negative patients, but this drug must beused with extreme caution in women during childbearing yearsowing to the potential for severe life-threatening and deformingbirth defects. All clinicians prescribing thalidomide in theUnited States must be registered in the STEPS (System forThalidomide Education and Prescribing Safety) program, andpatients receiving the drug must be thoroughly counseledregarding effective birth control methods that must be usedwhenever thalidomide is prescribed. For example, two methodsof birth control must be used, and the patient must have apregnancy test monthly. Other side effects of thalidomideinclude peripheral neuropathy, gastrointestinal complaints, anddrowsiness.
21A 42-year-old woman with a recent increase in severity of recurrent aphthous ulcers. An iron deficiency was detected, and theulcers resolved when this deficiency was corrected.
22Major aphthous ulcer in an HIV-infected patient.
23Behçet’s SyndromeBehçet’s syndrome, described by the Turkish dermatologistHulûsi Behçet, was classically described as a triad of symptomsincluding recurring oral ulcers, recurring genital ulcers, and eye lesions. The concept of the disease has changed from atriad of signs and symptoms to a multisystem disorder. Thehighest incidence of Behçet’s syndrome has been reported ineastern Asia, where 1 in 10,000 is affected, and the easternMediterranean, where it is a leading cause of blindness inyoung men; however, cases have been reported worldwide,including in North America, where it is estimated that 1 in500,000 persons is affected. The highest incidence of Behçet’ssyndrome is in young adults, but cases of Behçet’s syndromein children are being reported with increasing frequency.
24ETIOLOGY Behçet’s syndrome is caused by immunocomplexes that lead to vasculitis of small and medium-sized blood vessels and inflammationof epithelium caused by immunocompetent T lymphocytesand plasma cells. Increased neutrophil activityhas also been noted. There is a genetic component to thedisease,with a strong association with HLA-B51. Studies of theimmune abnormalities associated with Behçet’s syndromehave included findings described above for patients with RAS.This has led some investigators to believe that Behçet’s syndromeand RAS are both manifestations of a similar disorderof the immune response.
25CLINICAL MANIFESTATIONS The most common single site of involvement of Behçet’s syndromeis the oral mucosa.Recurring oral ulcers appear in over90% of patients; these lesions cannot be distinguished fromRAS . Some patients experience mild recurringoral lesions; others have the deep large scarring lesions characteristicof major RAS. These lesions may appear anywhere onthe oral or pharyngeal mucosa. The genital area is the secondmost common site of involvement and involves ulcers of thescrotum and penis in males and ulcers of the labia in females.The eye lesions consist of uveitis, retinal infiltrates, edema andvascular occlusion, optic atrophy, conjunctivitis, and keratitis.Generalized involvement occurs in over half of patientswith Behçet’s syndrome. Skin lesions are common and usuallymanifest as large pustular lesions.
26These lesions may be precipitated by trauma, and it is common for patients with Behçet’ssyndrome to have a cutaneous hyper-reactivity to intracutaneous injection or a needlestick (pathergy). Positive pathergyis defined as an inflammatory reaction forming within 24 hoursof a needle puncture, scratch, or saline injection.Arthritis occurs in greater than 50% of patients and mostfrequently affects the knees and ankles. The affected jointmay be red and swollen as in rheumatoid arthritis, butinvolvement of small joints of the hand does not occur, andpermanent disability does not result.
27In some patients, central nervous system involvement is the most distressing component of the disease. This may includebrainstem syndrome, involvement of the cranial nerves, or neurologic degeneration resembling multiple sclerosis that can bevisualized by magnetic resonance imaging of the brain. Otherreported signs of Behçet’s syndrome include thrombophlebitis,intestinal ulceration, venous thrombosis, and renal and pulmonarydisease. Involvement of large vessels is life threateningbecause of the risk of arterial occlusion or aneurysms.
28Behçet’s syndrome in children, which most frequently presents between the ages of 9 and 10 years, has similar manifestationsas does the adult form of the disease, but oralulcers are a more common presenting sign in children, anduveitis is less common. Oral lesions are the presentingsymptom in over 95% of children with Behçet’s syndrome.Avariant of Behçet’s syndrome, MAGIC syndrome, has beendescribed. It is characterized by Mouth And Genital ulcerswith Inflammed Cartilage.
29DIAGNOSIS 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 criteriathat meet with universal agreement. Five different sets of diagnosticcriteria have been in use during the past 20 years. In1990, an international study group reviewed data from 914patients from seven countries. A new set of diagnostic criteriawas developed that includes recurrent oral ulcerationoccurring at least three times in one 12-month period plus twoof the following four manifestations:1. Recurrent genital ulceration2. Eye lesions including uveitis or retinal vasculitis3. Skin lesions including erythema nodosum, pseudofolliculitis,papulopustular lesions, or acneiform nodulesin postadolescent patients not receiving corticosteroids4. A positive pathergy test
30TREATMENT The management of Behçet’s syndrome depends on the severity and the sites of involvement. Patients with sight-threateningeye involvement or central nervous system lesions require moreaggressive therapy with drugs with a higher potential for seriousside effects. Azathioprine combined with prednisone has beenshown to reduce ocular disease as well as oral and genitalinvolvement.120 Pentoxifylline, which has fewer side effects thando immunosuppressive drugs or systemic steroids, has also beenreported to be effective in decreasing disease activity,particularly eye involvement.
31Cyclosporine or colchicine in combination with corticosteroids has also been shown to be useful in severedisease. Colchicine and thalidomid have beenshown to be useful in mucocutaneous and gastrointestinal manifestations.Systemic corticosteroids remain a mainstay of treatmentand are particularly useful in rapidly controlling the diseaseuntil immunosuppressive agents begin to work.Plasmapheresis has also been used successfully in emergencies.Oral mucosal lesions not adequately controlled by systemictherapy may be treated with topical or intralesional steroids.
32Aphthous-like lesion in a patient with Behçet’s syndrome.
33Recurrent Herpes Simplex Virus Infection Recurrent herpes infection of the mouth (recurrent herpeslabialis [RHL]; recurrent intraoral herpes simplex infection[RIH]) occurs in patients who have experienced a previousherpes simplex infection and who have serum-antibody protectionagainst another exogenous primary infection. In otherwisehealthy individuals, the recurrent infection is confinedto a localized portion of the skin or mucous membranes.Recurrent herpes is not a re-infection but a reactivation of virusthat remains latent in nerve tissue between episodes in a nonreplicating state.
34Herpes simplex has been cultured from the trigeminal ganglion of human cadavers, and recurrent herpeslesions commonly appear after surgery involving the ganglion.Recurrent herpes may also be activated by traumato the lips, fever, sunburn, immunosuppression, and menstruation.The virus travels down the nerve trunk to infectepithelial 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 twoseparate and distinct disease processes.
35All patients who experience primary herpes infection do not experience recurrent herpes. The number of patients witha history of primary genital infection with HSV2 who subsequentlyexperience recurrent HSV infections is approximately15%. The recurrence rate for oral HSV1 infections is estimatedto be between 20 and 40%.Studies have suggested several mechanisms for reactivationof latent HSV,Individuals with T-lymphocyte deficiencies owing toAIDS or transplant or cancer chemotherapy may developlarge chronic lesions or, rarely, disseminatedHSV infection.
36CLINICAL MANIFESTATIONS RHL, the common cold sore or fever blister,may be precipitatedby fever, menstruation, ultraviolet light, and perhaps emotional stress. The lesions are preceded by a prodromal period of tinglingor burning. This is accompanied by edema at the site of thelesion, followed by formation of a cluster of small vesicles . Each vesicle is 1 to 3 mm in diameter, with the size of thecluster ranging from 1 to 2 cm.Occasionally, the lesions may beseveral centimeters in diameter, causing discomfort and disfigurement.These larger lesions are more common in immunosuppressedindividuals.
37The frequency of recurrences varies. RIH lesions in otherwise normal patients are similar inappearance to RHL lesions, but the vesicles break rapidly toform ulcers. The lesions are typically a cluster of small vesiclesor ulcers, 1 to 2 mm in diameter, clustered on a small portionof the heavily keratinized mucosa of the gingiva, palate, andalveolar ridges, although RIH lesions can occasionally involveother mucosal surfaces. In contrast, lesions ofRAS tend to be larger, to spread over a larger area of mucosa,and to have a predilection for the less heavily keratinized buccalmucosa, labial mucosa, or floor of the mouth.
38DIAGNOSISIf laboratory tests are desired, RIH can be distinguished fromRAS by cytology smears taken from the base of a fresh lesion.Smears from herpetic lesions show cells with ballooningdegeneration and multinucleated giant cells; those from RASlesions do not. For more accurate results, cytology smears mayalso be tested for HSV using fluorescein-labeled HSV antigen.Viral cultures also are used to distinguish herpes simplex fromother viral lesions, particularly varicella-zoster infections.
39TREATMENT Recurrent herpes infections of the lips and mouth are seldom more than a temporary annoyance in otherwise normal individualsand should be treated symptomatically. Patients who experiencefrequent, large, painful, or disfiguring lesions may requestprofessional consultation. The clinician should first attempt tominimize obvious triggers. Some recurrences can be eliminatedby the wearing of sunblock during intense sun exposure.
41Drugs 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 safeand effective. The newer antiviral drugs such as valacyclovir,a prodrug of acyclovir, and famciclovir, a prodrug of penciclovir,have greater bioavailability than does acyclovir, butthey do not eliminate established latent HSV.However, in themouse model, famciclovir appeared to decrease the rate ofHSV latency. The clinical importance of this finding inhuman HSV infection is not known. The effectiveness ofthese antiherpes drugs to prevent recurrences of genital HSVhas been studied extensively. Acyclovir 400 mg twice daily,valacyclovir 250 mg twice daily, and famciclovir 250 mg wereeach highly effective in preventing genital recurrences.
42.Systemic therapy should not be used to treat occasional ortrivial RHL in otherwise healthy individuals, but episodicuse to prevent lesions in susceptible patients before highriskactivities such as skiing at high altitudes or before undergoingprocedures such as dermabrasion or surgery involvingthe trigeminal nerve is justifiable. Some clinicians advocatethe use of suppressive antiherpes therapy for the small percentageof RHL patients who experience frequent deformingepisodes of RHL. Acyclovir 400 mg twice daily has beenshown to reduce the frequency and severity of RHL in thisgroup of patients. Both acyclovir and penciclovir are availablein topical formulations, but use of these preparationsshortens the healing time of RHL by less than 2 days.