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Home , Aphthous stomatitis, Contact stomatitis, Shingles

The scope of orai medicine practice and practitioner competencies is evolutionary in nature This section of riiCTi Medicine Quintessence International is committed to presenting evidenced-based clinical practice guidelines in collabo- Clinical Practice Guidelines ration witti oral and noncral health care providers.

Recurrent aphthous Jonathan A. Ship, DMDVEIisa M. Chavez, DDS^/Patricia A. Doerr, BS, MPH^/ Bradley S. Henson, BS^/Mojgan Sarmadi,

Etiology and Epidemiology: The Greek term apíifíia/was initially used in relation to disorders ot the and is credited to Hippocrates (460-370 BC). Today, reourrent aphthous ulcération, or recurrent (RAS), is recognized as the most common oral mucosal known to human he- ings.'' Considerable research attention has been devoted to elucidating the causes of RAS; local and sys- temic conditions, and genetic, immunologie, and infectious mierobial factors all tiave been idenfiüed as po- tential etiopathogenic agents (Table 1).^-"' However, to date, no principal etiology has been discovered. Epidemiologie studiGS indicate that the prevalence ot RAS is between 2% and 50% in the general popula- tion; most estimates lall between 5% and 25%,^"'™''-^° In selected groups, such as medical and dental students, it has been observed with a frequency as high as 50% to 60%. The peak age ot onset for RAS is between 10 and 19 years.^^'ä' Atter childhood and , it may continue throughout the entire human lifespan without geographic or age-, sex-, or race-related preference. (Quintessence Int 2000;31:95-112)

CLINICAL MANIFESTATIONS ring. The most common loeation is on nonkeratinized oral mueosa [the labial and buccal mucosa and floor Minor RAS of the mouth). Lesions appear as single or multiple ul- cers hut can be distinguished from other mueocuta- he most common presentation of RAS is minor neous based on their history, location, TRAS. Minor RAS manifests as recurrent, round, healthy appearance of adjacent tissues, and the lack of clearly defined, small, painful uleers with shallow distinguishing systemic features.*^" necrotic centers, raised margins, and erythematous halos (Fig 1). They are generally smaller than 10 mm fi/lajor RAS in diameter and have a gray-white pseudomembrane. These lesions heal within 10 to 14 days without scar- Major RAS is occasionally referred to as Sutton's dis- ease or periadeuitis mueosa necrolica recurrens and is less common (approximately 10% to 15"^ of all RAS) 'Protessor and Vice Chair, Department of , Paltiology, yet more severe than minor RAS,*= Major RAS lesions Oncology, University of tulichigan. School ol Dentistry, Ann Arbo^ are similar in appearance to those of minor RAS; how- Michigan. ever, they are larger than 10 mm in diarneter, are 'Fellow, Geriatiic Dentistry Program, Deparlment of Oral Medicine, deeper, often scar, and can last for weeks to months Pathology, Oncology, Universily of Michigan. School ot Denlislrv. Ann (Fig 2), These lesions have a predilection for , Artjor, Michigan. , soft , and the palatal and cause sig- 'Dental Student, University of tJlichigan, Sctiool ot Dentistry, Ann Arbor, Michigan. nificant and dysphagia. They are frequently found Reprint requests: Dr Jonathan A. Ship, Professor and Vice Chair, Depart- in patients infected with human ment of Oral tuledicine, Pathoiogy, Oncology, University of tulicfiigan. (HIV)'"'^^"''^ perhaps because of the amplification School of Dentistry. Ann Arbor, tulichigan 48109-1078. E-mail: of local immune imbalance secondary to [email protected]

95 • Ship et al •

TABLE 1 Possible causes of recurrent aphthous stomatitis

Local and oral factors to SQdium lauryl sulfate in Trauma Salivary gland dysfunction

Microbiai causes Bacterial: streptococci Viral: human herpes 6, heipes simplex, , Epstein-Barr, varicella zoster Systemic conditions and laclors Behcet's disease Crohn's disease Cyclic and autoimmune neutropenia Human immunodeficiency virus / acquired immunodeficiency syndrome Fig 1 Minor recurrent aphthous stomatitis on the inner left aspect Mouth and genital with inflamed cartilage (MAGIC] of the lower . syndrome Periodic , aphthosis, , adenitis (PFAPA) syndrome Reiter's syndrome DIAGNOSIS Systemic erythematosus Nulntionai and aliergic conditions Toothpaste Food allergies The diagnosis of RAS is typically established from the Folie acid, iron, selenium, and zinc deficiencies history and clinical presentation. However, it is im- Gluten-sensitive enteropaihy Vitamin B,, Sj, Bj, and B,¡ deficiencies portant to differentiate aphthous ulcers from other Stomatologie mucocutaneous diseases that have - Genetic ¡actors ative manifestations (Table 2). Usually these condi- immunologie oondltions tions ean be differentiated from RAS by the location Localized T-cell dysfuncticn of the lesion and/or the presence of an additional -dependent cellular cytotoxicity symptom. virus may have similar-appearing lesions; however, primary HSV in- fections present witb a diffuse gingival and fever preceding oral mucosal vesicles and ulcers. Also, recurrent HSV lesions are found primarily on attached keratinized mucosa, such as the or gingiva,^' Ulcers of RAS are not preceded by fever or vesicles, and they occur almost exclusively on mov- able , such as the huccal and labial mu- cosa, tongue, and ,'^ Herpetiform RAS Recurrent aphthous lesions can he differentiated from varieclia zoster virus (VZV) infections () The least common form of KAS is herpetiform aph- based on clinical presentation (VZV lesions have a thous ulcers, which afflict 5% to 10"/b of patients with unilateral extraoral and intraora! distribution pattern RAS.*- Multiple small clusters of pinpoint ulcers char- following the ) and symptoms (VZV acterize this rare form of RAS, and they occur through- infections have a of pain and hurning prior out the oral cavity (Fig 3). They tend to he small (2 to 3 to lesion eruption). Less common oral viral infections, mm) and numerous (ranging from 10 to 100 ulcers) such as and band-foot-and-mouth disease, but can hecome confluent to produce larger, plaque- should also be included in the differential diagnosis of form, irregular lesions. Lesions last 7 to 30 days and RAS when initial symptoms occur."'' However cox- have the potential to scar. Although these lesions are saekie virus-related oral ulcers present with other herpeslike or herpetiform in nature, herpes simplex symptoms, such as a low-grade fever or , and virus (HSV) cannot be cultured from these lesions.'" will resolve within 1 to 2 weeks.

96 i¿Jumber2, 2000 • Ship et al

Fig 2 Major recurrent aphthous stomatitis on the right dorsolat- Fig 3 Herpetiform recurrent aphthous stomatitis on the inner as- eral border of the tongue. pect of the upper lip.

TABLE 2 Differential diagnosis of recurrent aphthous stomatitis

Difterential diagnosis Oral signs Other Recurrent aphthous Single or multiple ulcers May be associated with stomatitis on unattached mucosa cropharyngeal or gastrointestinal ulcers Single or multiple ulcers Preceding fever and mucosal on attached mucosa vesicles Diffuse gingival erythema Vancella zoster virus Extraoral and intraorat ulcers Prodrome of pain and burning Unilateral distribution May cause scarring and Herpangina i^ultiple ulcers in hard palate, Fever and malaise soft palate, and cropharynx Hand-toot-and-mcuth Ulcers preceded by vesicles Skin lesions, low-grade tever, disease and malaise Lesions on attached and Sudden onsei ct skin macules unattached mucosa; and lip crusting Target lesions en skin May be preceded by herpes infection Oral Erosive and reticular lesions May be asymptomatic on buccal mucosa, gingiva. Lesions may occur on skin palate, and tongue White (Wickham s) stnae Cicatricial Vesiculobuiious lesions on Can atfect eyes and genitalia attached and unattached Lesions may scar mucosa Positive Nikolsky's sign vulgaris Vesiculobuiious lesions on Lesions can cccur on skin attached and unattached mucosa Positive Nikolsky's sign

97 Quinte s se • Ship et al —

Erythema multiforme presents with painful oral ul- Histopathologic findings cers, but, unlike RAS, erythema multiforme lesions occur on both attached and movable mucosa and usu- A histopatbologic specimen is rarely required for the ally involve crusting of the lips with skin macules and diagnosis of RAS, because of the nonspecific nature of papules.'" Approximately two thii'ds of patients with the ulcer. However, if another oral nuicocutaneous oral lichen planus show ulcerative lesions, which pri- condition is suspected (see the discussion on dilferen- marily occur on tbe buccal mucosa.^' However, sec- tial diagnosis), tben a may be necessary. In the ondary sites on tbe gingiva and hard palate will distin- preulcerative phase there is a mild infiltrate of T4 guish oral lichen planus frotii RAS. In addition, oral helper-inducer lymphocytes, which becomes an infil- lichen planus is not always painful, whereas pain is trate of T8 cytotoxic-suppressor cells in the ulcerative usually the cbief complaint in RAS. Vesiculobullous phase.'"' Extravasation of erythrocytes occurs at and oral lesions that tend to rupture within hours of occur- around the centers of the ulcer. At the ulcer's margins rence, resulting in painful erosions or ulcérations, are there is an accumulation of neutrophilic , characteristic of cicatricial pemphigoid^^^^ and pem- and there is formation of an exúdate undermining the phigus vuigaris.'^ These lesions may occur on both at- oral with numerous phagolysosome-rich tached and unattached oral mucosa, and a biopsy will .'"- Polymorphonuciear are reveal a characteristic histomorphometric pattern. the predominant cell type in tbe established lesion."" Qtjite often, systemic disorders will present with oral ulcers that are similar to tbose of RAS. These in- Immunofiuorescence findings clude systemic ,'*-'^^ ulcerative col- itis,'' Crohn's disease,^^"-'^ Behcet's disease,^" Reiter's Direct and indirect immunoñuorescence studies are not syndrome,-'^ and acquired immunodeficiency syn- sensitive or specific diagnostic tests for RAS, and there- drome (AIDS) or HIV Ínfection.^''^5-sj A detaiied med- fore sbould not be utilized except to rule out other oral ical history and thorough clinical examination are re- mucosal diseases (eg, pemphigus and pemphigoid). quired to establish an accurate diagnosis. Direct immunofluorescence tests have demonstrated Hypersensitivity reactions in the oral cavity can be that circulating immune complexes may play a role in induced by a variety of (eg, foods, , tissue damage in RAS,'""*'''^"' yet findings are usually mints, dental materials, metals, and ) but nonspecific."*^ Once tissue destruction and degeneration are often difficult to diagnose. !n allergic contact occur, it is not unusual to find nonspecific deposition of stomatitis, common manifestations are burning sensa- immunoglobulin and complement components along tions, erythetTia, and edema"*; aphthouslike ulcers do the basement membrane zone or in vessel walls."^ not usually occur. If an allergy is suspected, a more de- tailed patient history will be required, and allergy test- Consultations ing should be considered. Several systemic disorders are associated with RAS, Seroiogic, chemicai, and hématologie findings and they can be undiagnosed or misdiagnosed,'" lead- ing to a delay in effective therapy. Therefore, in the Full hématologie screening of patients with RAS has patient with recrudescent RAS lesions, or persistent been proposed to reveal deficiency states of serum minor or major RAS, consideration must be given to ferritin, iron, , and vitamin B^.^^'^' Deficient an underlying . Consultations with 1 levels of serum ferritin or iron are tbe most common or tnore medical specialists are recommended, de- findings occurring in 11% to 36''/b of patients with pending on the signs and syrnptotns of the disease. j^S.=s.s'-9s levels and red blood cell in- . The patient with chronic minor or dexes are generally within normal range in patients rnajor RAS or lesions resistant to primary or sec- with RAS"^^'' and are similar to levels in control ondary therapy may need long-term ¡mmunosup- patients." However, underlying anetnic states are pressant medications. These patients require regular sometimes discovered on screening^"''^* and replace- supervision to monitor hématologie, renal, hepatic, ment therapy may be attempted to resolve tbe ulcers. neurologic, and oral health, which may become im- Hématologie screening of children with RAS is also paired secondary to medications. Medical specialists recommended, because it has been reported that 21% in dermatology as well as internal medicine, rheuma- of patients have sume type of hématologie abnonnality, tology, and endocrinology can assist oral health pro- most notably latent iron deficiency witbout .'™ fessionals in tbe follow-up of these patients. Otorhinolaryngology (, nose, and throat). The differential diagnosis of RAS includes infectious (eg, herpangina), vesiculobullous (eg, pemphigus), ulcera-

98 JJumber 2. 200D Ship et al tive (eg, Crohn's), and autoimmune {erythema multi- PATIENT MANAGEMENT AND TREATMENT forme) diseases, whicfi may also involve the oral , larynx, and , The patient with Goals of treatment symptoms of pain or partial obstruction in the throat, dysphagia, or any other laryngeal or esophageal Treatment of RAS has 4 major goals; (Ij ulcer man- problems should be referred to an otorhinolaryngolo- agement (to promote healing and reduce duration), gist for direct laryngoscopy. (2) pain management (to reduce morbidity and en- Gastroenterology. Aphthous lesions may be as- hance function), (3) nutritional management (to en- sociated with inflammatory bowel disease, such as sure adequate food and fluid intake), and (4j disease «^ and Crohn's disease."^^''5 control (to prevent recurrence or reduce frequency). Aphthouslike ulcerative lesions often precede or co- The relative importance and priority of each goal de- exist with intestinal symptoms.'"' Therefore, gas- pends on the severity of the condition." For example, trointestinal endoscopie examination may be re- minor and infrequent RAS may only require brief quired for a definitive diagnosis. pain management. Alternatively, major RAS, frequent Ophthalmology. A basic ophthalmologic exami- minor RAS. and herpetiform RAS are all associated nation should be conducted if Behçefs disease^*'-"'"*" with greater discomfort, severity, and duration of or Reiter's syndrome^" is suspected. Behcet's disease symptoms that require intervention and nutritional is associated with oral and genital aphthae and ocu- management.'•^'•"° Furthermore, because several sys- temic conditions are associated with RAS, possible lar ( or iritis); however, the diag- underlying causes must be ruled otit before a treat- nosis of Behçefs disease is rare without the presence ment strategy' is selected.'"^ of oral ulcers.*^ The diagnosis of Behçefs disease should not be made premattirely, because the prog- nosis may be grave and the treatment may be toxic.'^ Evidence to support drug therapy Oral lesions, often with ulcération, occur in lOP'o of cases of Reiter's syndrome in which arthritis, con- Evidence to support drug therapy for RAS has im- junctivitis, and urethritis are classic symptoms.-"" Iritis proved recently, in part, because of the greater preva- and uveitis may also occur in patients with inflam- lence of immunocompromised patients with major matory bowel disease.**- RAS.^^^^'"' In addition to drugs, several treatment Infectious disease. Oral RAS lesions are com- modalities for nutritional deficiencies and systemic mon in HIV-positive and AIDS patients,-"''^-^= and disorders have been evaluated for tbeir effect on RAS a number of different concurrent intraoral lesions and have been reported to have variable success among HIV-infectcd persons are associated with se- (these are discussed later). The best therapeutic choice vere and AIDS.^^ Infectious should target the primary treatment goal, based on the diseases that result in oral aphthae (HIV or AIDS) severity of disease; must be supported by scientific evi- and other viral infections (HSV, VZV, coxsackie dence; and should have a high therapeutic index with few or tolerable side effects. virus) that are included in the differential diagnosis of RAS may require concomitant therapy provided by specialists in infectious disease. Initiation of drug therapy Allergy. Oral hypersensitivity reactions [eg, foods, gums, mints, dental materials, metals, and medica- Many patients with RAS experience several episodes a tions) can cause oral mucosal changes,"'^ and aller- year in which lesions heal within 5 to 10 days. These gic reactions such as gluten entcropathy may pro- patients may only require palliative therapy for pain. duce oral aphthae.^' If an allergic or hypersensitive However, the patient who experiences multiple reaction is suspected, the patient should be referred episodes each month, and/or presents with symptoms to an allergist. of severe pain and difficulty in eating, drinking, chew- Hematology/internal medicine. The complete ing, and swallowing, should be considered for more blood count of the RAS patient with signs and extensive drug therapy. symptoms of or nutritional deficien- cies should be monitored; serum ferritin, folate, and Choice of drugs vitamin B,, levels should also be evaluated for defi- ciencies.^ä"" Specialists in hematology and internal Primary line of treatment. Topical gels, creams, medicine can assist in the diagnosis and/or treat- and ointments. The primary treatment of RAS le- ment of these patients. sions utilises topical anti-inflammatory agents. The problem with topical gels, creams, and ointments, however, is establishing effective drug delivery, be-

OuintessiTice l 99 • Ship et al —

TABLE 3 Topical therapy for recurrent aphthous stomatitis

Medicafion Concentration Dosage Mechanism of action Geis, creams, and ointments' Fiuocinonide 0,5% 0,5 cm/0.25 inch Corticosferoid—anti-intiammatory Triamoinoione 0.025% 0.5 cm/0.25 inch —anti-intiammatory 0.5% 0.5 cm/0.25 inch Corticosteroid—anti-intiammatory 5% 0.5 cm/0 25 inch Anfi-inflammatory and antialiergic Doxymycline-cyanoacrylate 0.5 om/0.25 inch Mucosal adherent Rinses* Sucralfafe 1 g/10 mL 5-mL rinse qid Protective effect—binds proteins at the tjicer surface Tefracyoline 2 2 mg/mL 5-mL rinse qid Antimicrobiai—reducescoliagenase activity 2% VISCOUS 5-mL rinse qid hydro chloride Diphenhydramine 12.5 mg/5 mL 5-mL rinse qid Analgesic Dyclcnine 1% soiution 5-mL rinse qid Analgesic hydrochioride 0.5 mg/5 mL 5-mL nnse qid Corticosieroid—anti-inflammatory "FIjocinonide. tnamc nolone, or clobetascl can be combined with Orábase to improve mucosal adher- en ce, nethasone maybe combined in a 1:1 mix ', lidocaine, diphenliydramire, dydonine, or dexa witli sucrairate, Kaopeclate (aiiapulgite) (Upjohn), or Maalox (aiuminurr hydranide, magnesium hydroxide) (Rhcne-Poulerc) tot palliative relief. Other combinations of more ttian one oí these, or similar agenls, can be reviewed with a pharmacist.

cause substances applied to mucosal surfaces are ties is 5% amlexanox (see Drug Monograph, page 110), inevitably rubbed or rinsed away."' This problem is which has demonstrated clinical safety and efficacy in addressed by using strong topical several vehicle-controlled multicenter clinical stud- which, when compounded with mucosal adherents ies,'-'-'-'' Application of paste directly to ulcers, 4 times (eg, Orábase, Bristol-Myers Squihb; isobutyl cyano- daily, resulted in enhanced resolution of pain and heal- acrylate or Iso-Dent, Ellman International) are ef- ing of ulcers with minimal adverse experiences. fective despite limited contact time.^' "= Several other topical medicaments have been used The efficacy of topical agents can he increased with encouraging research results, although additional markedly if they are administered during the early investigations are required to establish reliable safety phase of ulcération (ie, when lymphocyte activity and efficacy data. Topical prostaglandin E; may have is at its maximum"^). Clinicians should be cognizant useful prophylactic activity,'^^ and oral human inter- of the potential of topical to cause feron-a may assist in ulcer remission.'^^ A single topi- aeute pseudomemhranous .'"'" However, cal treatment with doxymycine-cyanoacrjflate was re- the use of topical glucocorticoids will diminish the ported to relieve the intensity of pain for 6 days after a risk of suppressing the hypothalamic-pituitary-adrenal 1-day latency period.'^' Hydroxypropylcellulose film, axis system, a frequent of systemic gluco- or Zilactin [Zila Pharmaceuticais), is a topical medica- eorticoids,"''-"^ tion with mucosal properties; it has been The topical glucocorticoids that have demonstrated demonstrated to adhere to rnucosa significantly longer efficacy for RAS are ,"''"'"" triam- than Orábase and may protect the existing ulcer and cinolone,'"'^" and elobetasol.**^'"^"' ace- provide pain relief.'-*-'^" tonide with Orábase (a mucosal adherent), however, Topical rinses. Topical rinses can also effectively pro- may not he as effective as stronger glucocorticoids, vide symptomatic relief for minor aphthous ulcers such as fluocinonide and clobetasol. Therefore, fluoci- (Table 3), These rinses may be used alone or in combi- nonide (see Drug Monograph, page 109} or clobetasol, nation with other topical drugs, A decrease in the used alone or mixed with Orábase, may be preferable severity or number of ulcers may he observed during for the treatment of recurrent RAS.'" Another topical treatment with these rinses; however, none provides paste with anti-inflammatory and antiallergic proper- prevention or a cure, , which acts by locally

100 i 2, 2000 • Ship et al hinding to proteins at the base of an ulcer, providing a adverse reactions should use that do not protective covering.'"*' may be useful for the relief of contain SLS (eg, Biotene antibacterial dry-mouth pain resulting from minor RAS.'^- Dexamethasone toothpaste, Laclede lne; Rembrandt whitening tooth- elixir (0.5 mg/5 mL), used as a or gargle, paste for canker sore prevention, Den-Mat). can he helpfitl for multiple minor, major, or herpetiform Elimination of possible allergens (eg, glutens, nuts, ulcers that are difficult to treat with topical gels."^'''' strawberries, and tomatoes) may have no benefit un- Tetracycline ean reduce ulcer duration, size, and pain less the restricted item has been demonstrated to because of its ability to reduce collagenase activity.'^-' '" cause hypersensitivity or allergic reactions. Available Patients should be instructed to swish for up to 5 min- data on the role of food allergies and sensitivifies in utes and spit several times a day. Other orai rinses, such RAS are inconsistent. Several studies have reported a as gluconate,"*'^*-'^'' hy- relationship,^'== while others have not established drochloride,'^'^'^* Listerine (Warner-Lambert),"^ tri- food allergies in the etiopathogenesis of RAS.'-''''-'^ closan (Earnest |ohn Group),'-"' aqueous hydrocorti- Alternatively, elimination diets, not diet diaries, have sone."' and triameinolone aqueous suspension,'-" have been used successfully in identification of particular been reported to provide some relief. However, further offending foods in a small subgroup of RAS patients,'*' clinical research studies are needed to establish defini- Eliminafion diets require motivation and strict compli- tive results for all of these topical rinses. ance, and the offending agents found vary from pa- tient to patient. Treatment ot nutritional and hématologie deficiencies. Several deficiencies have been reported at higher rates Other approaches to therapy. Another approach to among patients with RAS compared to non-RAS and treatment is to convert the ulcer into a wound'" by healthy controls, providing a rationale for the evalua- using chemical cautery,'-" electrocautery, or lasers,'•'^'^'' tion of nutritional and hématologie deficiencies,"''*' Ultrasound has been suggested to provide a beneficial Vitamin B deficiencies have been reported to be asso- effect on RAS.''' Stress management, relaxation, and ciated with RAS and may. occasionally, be the primary imagery training are additional therapeutic approaches cause of RAS: deficiencies in vitamin B (tbiamine defi- that have demonstrated some clinical benefits.''^ ciency"-58), vitamin B, (riboflavin deficiency^*), B^ Conversely, no associafions have heen established be- (pyridoxine deficiency^*), and vitamin B^^ (pernicious tween RAS and the premenstrual period, pregnancy, atiemia''''^-"'). Deficiencies in zinc," folie acid,='-^' or menopause, and there are no consistent data to sug- iron,^'-'^' and selenium-* bave also been associated gest that ovarian can be used as an effective witb RAS-like ulcers. These deficiency states may all therapeutic modality.''' have an adverse influence on the , Treatment of underlying systemic disease. Several which may explain, in part, tbeir possible connection systemic disorders have been associated with RAS (as to RAS, Regardless of etiology', replacement therapy is already discussed), and identification and treatment of justified when a deficiency is identified,*''••- these conditions is an important step in the treatment Avoidance of allergy-causing foods. Food sensitivity of RAS. Oral aphthous ulcers may be the first clinical and allergies to other suhstances should be considered sign of a systemic disorder, making clinical judgment as an etiologic factor in hematologically normal pa- difficult. Treatment of numerous systemic conditions tients with recurrent oral ulcération.'-*" For example, (including Crohn's disease"-"; Behcet's disease^^"^"; gluten enteropathy may be a causative factor in RAS, ^-'"'^; a syndrome of periodic fever that resembles human cyclic neutropenia'"; autoim- and withdrawal of gluten from the diet has been re- mune neutropenia'*; pernicious anemia-*'; systemic ported to help eliminate aphthous ulcers in some stud- lupus erythematosus-'ä; HIV infection^*-"; periodic ies53.109.145 but not in others,'-" One potential etiologic fever, aphthosis, pharyngitis, and adenitis [PFAPA] tnechanism of RAS is delayed-type hiTiersensitivity, or syndrome-'-'; and mouth and genital ulcers with in- cell-mediated response to an antigenic stimulus.^" flamed cartilage [MAGIC] syndrome-'^''') has been as- Therefore, any material (food, beverage, , sociated with improved RAS lesions. Because resolu- toothpaste, chewing gum. mint, etc) that comes in con- tion of oral symptoms commonly follows effective tact with the oral mucosa must be considered and systemic therapy, multidisciplinary care is recom- evaluated as a potential causative agent. mended for patients with oral manifestafions of these Sodium lauryl sulfate (SLS), a detergent commonly systemic conditions. used in toothpastes, has been reported to increase the recurrence rate of RAS in several studies.^"-'^ This effect Secondary line of treatment. For the patient whose may be related to destahilizafion of cell membranes by symptoms are not relieved by the primary line of treat- SLS and its denaturing capacity, which increases oral ment or whose signs and symptoms warrant a more mucosal permeability and may cause epithelial desqua- aggressive treatment modahty, should be mation of oral soft tissues.'^= Patients with SLS-related considered for both HIV-negative3o.>»->3>"ä4-iie and

101 siWTcy tfitiifnationar • Ship et al

HIV-positive patients,"''''''i58 Prednisone, an anti-in- factor-K, has been sbown to be an effective treatment flammatory and an immunosuppressive agent, can be for severe RAS, despite the potential for significant used in combination with topical geis and rinses. side effects.-'"'"-''' Use of tbaiidomide in children has Systemic prednisone therapy should be started at 1,0 been documented with some success, but iotig-term ef- mg/kg a day as a single dose in patients with severe fects have not been established.'" therapy RAS and should be tapered after 1 to 2 weeks (see has been more tboroughly researched in HIV-positive Drug Monograph, page HI), Prednisone use has po- patients,-*"'""^ One study I'eported that HIV-infected tentiaily serious side effects, including insomnia, ner- patients with RAS experienced significant improve- vousness, increased appetite, indigestion, diabetes mel- ment, diminished pain, and an increased ability to eat litus, hirsutism, joint pain, and glaucoma. Importantly, after a 4-week course of 200 mg of thalidomide daily however, several studies have found the side effects to when compared to a placebo.''" However, tbe dose was be minimal, especially when prednisone is combined reduced or completely terminated in approximately with and not used for extended periods 2O0/0 of patients because of toxicity (eg, , somno- of time in the treatment of RAS,"-'"'''^*''^ Most ad- lence, or peripherai sensory neuropathy). verse drug effects are related to treatment that persists Initial treatment in either HIV-positive or HlV-neg- for more than 2 weeiis and can be minimized by re- ative patients should be 100 to 200 mg of thalidomide ducing drug dosages,'" When appropriate, alternate- daily, depending on the severity of iesions and the pa- day therapy and prednisone intake as a single dose in tient's tolerance. Once remission has been accom- the morning will help reduce drug-related complica- plished, tberapy may be stopped until ulcers recur. If tions,"^'^^^ Alternate-day dosing allows cell-mediated there is recurrence, the initial regimen should be re- immunity, white blood cell subset levels, and potas- peated until remission, and then a maintenance sium excretion to become normalized on the off-day, dosage of 50 to 100 mg daily or 50 mg every other day and the anti-inflammatory benefits of prednisone will should be attempted. The maintenance dosage should persist ionger than the hypothalamic-pituitary-adrenal be tapered as much as possible to minimize side ef- axis suppression."^ fects. Because of the established teratogenic capacity Prednisone can be combined with another immuno- of thalidomide, strict precautions must be talien in suppressive agent, azathioprine, to reduce the dosage women of child-bearing ages (see Drug Monograph), of prednisone required to provide effective treat- [150 mg daily), an immunotherapeutic jjjgfjj 45.i53,iso Ti^g potentially serious side effects of aza- drug, may also be an effective treatment for RAS. A re- thioprine include thrombocytopenia, leukopenia, sec- cent open iabel study'" and several randomized, dou- ondary infections, anemia, nausea, vomiting, anorexia, bie-blind studies'"""'"" reported significant reduction in , and lymphoreticular and other malignancies pain, number, and duration of aphthae and frequency after long-term therapy,""''^^ Immunosupprcssive of episodes after a course of levamisole. However, at drugs (eg, azathioprine) have been associated with the least 3 similar studies did not report any signiflcant development of such as non-Hodgldns's lym- differences in symptoms between treatment and phoma.'^^ Short- to medium-term therapy probably re- placebo groups,'^'-'"^ sults in a slightly increased risk of malignancy, whereas Several other immunomodulating and anti-inflam- continuous therapy for more than 2 years is poorly matory drugs, including ,'*•'-'** cyclo- documented, and should be used cautiously,'^- sporine,'*"^'** pentoxyfylhne,''^"''*' azelastine,'^- and Drug-related safety and efficacy have heen demon- ,"-''"'' have shown some effectiveness for treat- strated when azathioprine is given as an initial dose of ment of RAS in case studies and open trials. Lysine, 50,0 mg per day for 1 week and then increased to no an amino acid required for protein synthesis, was re- more than 2,5 mg/kg daily with careful monitoring of ported to have effective prophylactic and bealing char- the complete blood count and platelet count,'^"^-'"'^ acteristics."' '''' Most of these drugs require further Azathioprine, used alone in topical form'"* or taken research to demonstrate safe and effective use in pa- systemically with topical dexamethasone,'" has also tients with RAS, been reported to help resolve RAS lesions. Use of prednisone and azathioprine requires careful patient Adjunctive therapy monitoring to identify potential side effects as early as possible as well as to evaluate the effectiveness of the Supportive therapy for persistent and painful RAS le- treatment. Consultation with other medical specialists sions includes topical , fluids, and protein, is recommended for patients who are prescribed long- vitamin, and minerai supplements. For many individu- term immunosuppressive therapy. áis, painful aphthous lesions impair mastication and Tertiary line of treatment. Tbaiidomide {see Drug deglutition, and therefore patients should he encour- Monograph, page 112), an inhibitor of tumor aged to maintain fluid and nutritional intake. Dietary

102 Volume 3-] Niimha. 2, 2000 Ship et al •

supplements, such as Ensure (Abbott Laboratories) or 5. Richards DW, MacPhail LA, Dekker N, Greenspan D, Sustacal (Mead Johnson Nutritionals), may be indi- Greenspan |S, Lozada-Nur F, Regezi )A. Expression cated for severe cases. Foods and beverages that exac- of laminin 5, fibronectin, and epithelium-associated inte- grins in recurrent aphthous ulcers. J Dent Res 1996:75: erbate pain sbouid be avoided: acidic foods; crusty, 1512-1517. hard, and difticult to chew foods; spicy or salty foods; 6. Wu-Wang CY. Patel M, Feng ], Milles M, Wang SL. citrus fruits and liquids; and alcoholic beverages. Decreased levels of salivary and epider- Patients should be encouraged to maintain daily mal growth factor in recurrent aphthous stomatitis. Arch . If dentifrices or precipitate Oral Biol 1995;40:1093-1098. or exacerbate RAS lesions, patients should use less ir- 7. Bennet KR, Reade PC. Salivary immunoglobulin A levels ritating agents and those that do not contain sodium in normal subiects, tobacco smokers, and patients with minor aphthous ulcération. Oral Surg Oral Med Oral lauryl sulfate (eg, Biotene antihacterial dry-mouth Pathol 1982:53:461-465. toothpaste or Rembrandt whitening toothpaste for B. Ben-Aryeh H. Malberger E. Gutman D, Szargel R, Anavi canker sore prevention). Topical are Y. Salivarj' IgA and scrum IgG and IgA in recurrent aph widely used to treat the painful symptoms of RAS. thuus stomatitis. Oral Surg Oral Med Oral Palhoi 1976;42: Oral discomfort may be relieved witb topical anesthet- 746-752. ics, such as 2'^k viscous lidocaine hydrochloride (Xylo- 9. Pedersen A, Ryder LP Gamma delta T-cell fraction of pe- caine, Astra), diphenhydramine elixir (Benadryl, ripheral blood is increased in recurrent aphthous ulcéra- Parke-Davis), dyclonine hydrochloride (Dyclone, tion. Clin Immunol lmmunüpathgl 1994:72 98-104. Astra), and sucralfate (Carafate, Hoechst Marion 10. Pedersen A. Recurrent aphthous ulcération: Virological and immunological aspects. APMIS. Suppl. 1993;101(37): Roussel) (see Table 5). 1-37 11. Natah SS. Hayrinen-Inimonen R, Hietanen |, Malmstrom SUMMARY M, Kcinttinen "\T. Quantitative assessment of mast cells in recurrent aphthous ulcers (RAU]. J Oral Pathol Med 1998; 27:124-129. RAS is the most common oral mucosal disorder found 12. Hasan A. Childerstone A, Pervin K, Shinnick T, Mizushima in men and women of all ages, races, and geographic Y, Vanderzee R. et al. Recognition of a unique peptide epi- regions. The 3 classic forms of lesion are minor, major, tope of the mycobacterial and human and herpetiform. Considerable research attention has 65-60 by T cells of patients with recun^ent oral ul- been devoted to elucidating the causes of RAS; local cers. Clin E\p Immunol 1995 ;99:392-397 and systemic conditions, genetic, immunologie, and 13. Pedersen A, Pedersen BK. Natural killer cell function and infectious microbial factors all bave been identified as number of peripheral blood are nut altered in recurrent aphthous ulcération. Oral Surg Oral Med Oral Pathol potential etiopathogenic agents. However, to date, no 1993;76:616-619. principal etiology has been discovered. 14. Hayrinen-lmmonen R. Immune-activation in recurrent The goals of current treatments are to quickly pro- oral ulcers (ROU). Scand ) Dent Res 1992:100:222-227. mote ulcer healing, to reduce ulcer duration and pain, 15. Pedersen A. Hougen HP. Kenrad B. T-IjTriphocjie subsets to allow the patient to maintain nutritional intake, and in oral mucosa of patients with recurrent aphtbous ulcéra- to prevent recurrence or to diminish frequency of oc- tion. I Oral Pathol Med 1992:21:176-180. currence. Therapies range from topical anti-inflamma- 16. Hayrinen-lmmonen R, Nordstrom D, Malmstrom M, tory and analgesic preparations to systemic glucocorti- Hietanen |. Konttinen YT. 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Silverman SJ, Lozada-Nur P, Migliorati C Clinical efficacy 189-191 of prednisone in the treatment of patients with oral in- Meiller TF, Kutcher MJ, Overholser CD, Niehaus C, flammatory ulcerative diseases: A study of fifty-five pa- DePaola LG. Siegel MA. Effect of an antimicrobial tients. Oral Surg Oral Med Oral Pathol 1985:59: niouthrinse or recurrent aphthous ulcérations. Oral Surg 360-365. Oral Med Oral Pathol lÖ91;72:425-429, 157 Reyes-Teran G, Ramirez-Amador V, De la Rosa E, 140, Skaare AB, Herlofson BB, Barkvoll P. Mouthrinses Gonzalez-Guevara M, Ponce de Leon S Major recurrent containing reduce the incidenc:e of recurrent oral ulcers in AIDS: Report of three cases. J Oral Pathol aphthous ulcers (RAU). ] Clin Periodontol 1996:25: Med 1992 ;21:409-411, 778-781, 158, de ASÍS ML, Bernstein LJ, Schliozberg J, Treatment of re- sistant oral aphthous ulcers in children with acquired im- 141, Holbrook -WP, Kristmundsdottir T. Loftsson T. Aqueous hydrocortisone mouthwash soiutioii: Clinical evaluation. munodeficiency syndrome, J Pediatr 1995:127:663-665. Acta Odontol Scand 1998;56157-160. 159, Lozada E Prednisone and azathioprine in the treatment of Porter S. Flint S, Scully C, Keith O, Recurrent aphthous patient with vesiculoerosive oral diseases. Oral Surg Oral stomatitis: The efficacy of replacement therapy in patients Med Oral Pathol 1981:52(3]:257-265. witb underlying deficiencies, Ann Dent 1992: 160, Frey PJ, Lozada F, Guentert T, Frey BM, A single dose of 51:14-16, azathioprine dues not affeet the pharmacokinetics of pred- Wray D, Gluten-sensitive recurrent aphthous stomatitis. nisolone following oral prednisone. Eur J Clin Pharm 1981;19:209--212. Dig Dis Sei 1981;26:737-740, 161, Connell WR, Kamm MA. Dickson M. Balkwill AM, Hunter IP, Ferguson MM, Scully C, Galloway AR, Main Ritchie JK. Lennard-Jones JE, Long-term neoplasia risk AN, Russell Rl. Effects of dietary gluten elimination in pa- after azathioprine treatment in inflammatory bowel dis- tients with recurrent minor aphthous stomatitis and no de- ease. Lancet 1994;343(8908):1249-1252. tectable gluten etiteropathy. Oral Surg Oral Med Oral Pathol 1993;75:595-598, 162, Forbes A, Reading NG, Review article: The risks of malig- nancy from either i m munosup pression or diagnostic radia- 145, Herlofson BB, Brodln P. Aars H, Increased human gingi- val blood flow induced by sodium lauryl sulfate, J Clin tion in inflammatory bowel disease. Aliment Pharm Periodontol 1996:25:1004-1007, Therap 1995;9:465-470, 163 Kinlen L. Immunosuppressive therapy and acquired im- Eversole LR, Shopper TP, Chambers DW, Effects of sus- 146, munological disorders. Res 1992:52(19 suppi): pected foodstuff challenging agents in the etiology of re- 5474S-5476S, current aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1982:54:33-38. 164. Ploren CH, Ahren B, Bengtsson M, Bartosik ], Obrant K. Bone mineral density in patients with Crohn's disease dur- Hay KD, Reade PC, The use of an elimination diet in the 147. ing long-term treatment with azathioprine, J Intern Med treatment of recurrent aphthous ulcération of the oral cav- 1998;243:125-126, ity Oral Surg Oral Med Oral Pathol 1984;57:504-507,

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165. Candy S, Wright J, Gerber M, Adams G, Gerig M, 180. Zissis NP, Hatzioti AJ, Antoniadis D, Niniku A, Hatziotis Goodman R. A eontrolled double blind study of azathio- [C. Therapeutic evaluation of levamisole in recurrent apht- prine in the management of Crohn's disease. Gut 1995: hous stomatitis. Double-bhnd comparison of two dosage 37:674-678. schedules of levamisoie and placebo. J Oral Med 1983; 166. Eggleston DJ, Naliy FF Treatment üf aphthous ulcération 38:161-163. with topical azathioprine. A double blind trial. Br J Oral 181. Olson JA, Silverman S Jr. Double-blind study of levamisole Surg 1972;9:233-236. therapy in recurrent aphthous stomatitis. J Oral Pathol 167 Greenspan D. Significant response of oral aphthosis to 1978:7:393-399. thalidomide treatment. J Am Acad Dermatol 1985;12(1 Pt 182. Miller MF, Silvert ME, Laster LL, Green P, Ship II. Effect l):85-90. of levamisole on the incidence and prevalence of recurrent 168. Greenspan D. Blanco GF, Agüero S. Treatment of aphthae apbthotis stomatitis. A double-blind clinical trial. J Oral with thalidomide. ] Am Acad Devmatol 1989:20(6): Palhoi I978;7:387-392. 1060-1063 183. Drinnan AJ, Fischman SL. Randomized, double-blind 169. Revuz J, Guillaume |C, Janier M. Hans P, Marchand C, study of levamisole in recurrent aphthous stomatitis. J Souteyrand P. et al. Crossover study of thalidomide vs Oral Palhoi 1978:7:414-417. placebo in severe recurrent aphthous stomatitis. Arcb 184. Mangeisdorf HC, Wbite WL, Jorizzo )L. Behcet's disease. Dermatol 1990:126|7¡:923-927 Report of twenty-five patients from the United States with 170. Gard ner-Med win |M, Smith NJ, Fowell R|. Clinical expe- prominent mucocutaneous involvement. J Am Acad Denn rience with thalidomide in the management of severe oral 1996:34(5 Pt l):745-750. and gcnitai ulcération in conditions such as Behcet's dis- 185. Katz J, Langevitz P, Shemer J, Barak S, Livneh A. Pre- ease: Use of neurophysiological studies to detect thalido- vention of recurrent aphthous stomatitis with colchicine: mide neuropathy. Ann Rheum Dis 1994:53:828-832. An open trial J Am Acad Derm 1994:31(3 Pt 1):459-461. 171. Bonnetblane |iVl, Royer C, Bédane C. Thalidomide and re- 186. Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, current aphthous stomatitis: A follow-up study. Derma- lnaba G. Double-masked trial of cyclosporin versus tology 1996:193:321-323. colchicine and iong-term open study of cyclosporin in 172. Menni S, Imondi D. Brancaleone W, Croci S. Recurrent Behcet's disease. Lancet 1989:1(8647]:1O93-IO96. giant aphthous ulcers in a child: Protracted treatment with 187. Ruah CB, Stram JR, Chasin WD. Treatment of severe re- thalidomide. Pediatr Derm 1993;10:283-285. current aphthous stomatitis with colchicine. Areh 173. Weidle PJ. Thalidomide for aphthous ulcers in patients in- Otolaryngol Head Neck Surg 1988:114:671-675. fected with the human immunodeficiency virus. Am ] 188. Gatot A, Tovi P. Colchicine therapy in recurrent oral ul- Health Sys Pharm 1996:53:371-372. cers. Arch Dermatol 1984^120:994. 174. Paterson DL, Georghiou PR, Allworth AM, Kemp RJ. 189. Diaz-Llopis M, Cervera M, Menezo JL. Cyclospüdn A Thalidûmide as treatment of refractory aphthous ulcéra- treatment of Behcet's disease: A long-term study. Curr Eye tion related to human immunodeficiency vims infection. Res 1990:9:17-23. Ciin Infect Dis 1995;20:250-254. 190. Pizarrg A, Herranz P. Navarro A, Casado M. Recurrent 175. Sun A. Chiang CP, Chiou PS, Wang JT, Liu BY, Wu YC. apbthous stomatitis: Treatment with . Acta Immunomodulation by levamisole in patients with recur- Derm Venereol 1996:76:79-80. rent aphthous ulcers or oral lichen planus. J Oral Pathol 191. Wahba Yahav AV. Pentoxifylline in intractable recurrent Med 1994:23:172-177. aphthous stomatitis. J Am Acad Derm 1995:33:680-682. 176. Lehner T, Wilton JM, Ivanyi L. Double blind crossover 192. Ueta E, Osaki T, Yoneda K, Yamamoto T, Kato I. A clinical triai of levamisole in recurrent aphthous ulcération. trial of Azelastine in recurrent aphthous ulcération, with Lancet 1976:2{7992):926-929. an analysis of its actions on leukocytes. J Oral Pathol Med 177 Van de Heyning J. Levamisole in the treatment of recur- 1994:23:123-129. rent aphthous stomatitis. Laryngoscope 1978;88:522-527 193. Wright EF. Clinical effectiveness of lysine in treating recur- 178. Meyer JD, Degraeve M, Clarysse J, De Loose F, Feremans rent aphthgus ulcers and herpes labialis. Gen Dent W. Levamisole in aphthous stomatitis: Evaluation of three 1994:42:40-42. regimens. Br Med J1977 ; 1 (6062) :671-674. 194. Papanayotou PH. Treatment of recurrent aphthous ulcers 179 Kaplan B. Cardarelli C, Finnell SR. Double-blind study of with anabolic drugs. Preliminary report. J Oral Med levamisole in aphthous stomatitis, j Oral Patho! 1978;7: 1972;27:n3-114, 400-404.

108 r 2. 2000 •Ship el al

RECURRENT APHTHOUS STOMATITIS: R^ FLUOCINONIDE

Fluocinonide. a high-polency topical corlicosteroid. has anii-intlammalory and vasoconslnctive ac- tions. The mechanism of action is not weii defined; however. ¡I is believed to result trom a combina- tion of 3 properties: anti-inflammatory, immunosuppressive, and antiproiiferative- Drug upfate is by absorption following topical application. The extent ot absorption is dependent on the amount ap- plied, the vehicle, the mucosai integrity, and the use of occlusive dressings. Foiiowing absorption, the drug is protein bound, metaboiized in the , and then removed by the kidneys. Pregnancy risk factor C.

1. Indications Drug ot choice for Ihe management of minor aphthous ulcers and as an adjunct to prednisone and other systemic immunosuppressive therapy tor major recurrent aphthous stomatitis.

2. Contraindications History of adverse reaction to lluocinonide. Infections (virai, fungai, or bacleriai): In the presence of infecfion, appropriate adjunctive treat- ment should be insfituted. Low doses should be used in patients witn glaucoma, osteoporosis, diabetes meiiifus. or psy- choses.

3. Drug interactions • None is known.

4. Administration • 0.5 cm (V; inch) of gei is appiied topically to the affected area, up to 5 times daily, immediateiy (route and dosage) following meais and orai hygiene and at bedtime. • Dosage form: 0.05% gei in 15-, 30-, 60-, and 120-g tubes. • Apply as soon as symptoms of ulcer are noticed.

5. Monitored efficacy • Monitor the patient for reiief of symptoms, remission, or resoiution of lesions. and tovicity • Extended use may increase the risk of developing oral fungai infections. • In some patients, topicai corticosteroids have been absorbed in amounts adequate to produce reversible hypothalamic-pituitary-adrenai axis suppression, manifestations of Cushing's syn- drome, and hyperglycemia as a function of dosage, duration ot treatment, and the surface area covered An attempt should be made to reduce the frequency of applicalicn, to substitute less potent topicai corticosteroids, or to withdraw the drug. Chiidren may absorb larger amounts of topicai corticosteroids and are therefore more susceptibie to systemic toxicity.

6. Length of • Continue Ireatment untii there is significant improvement, and then begin to laper the number of treatment applications. • If significant reduction in pain and healing have not occurred in 10 days, consider additicnai pri- mary and/or secondary lines of treatment.

7. Cessation of • Taper siowiy and watch for exacerbation of disease. treatment

8. Instructions to • As soon as symptoms of ulcers are noticed, apply 0.5 cm {'A inch) of gel direcfly to Ihe uicers, the patient up to 5 times daily, immediately following meais and oral hygiene and at bedtime. • Avoid contact wifh eyes. If contact occurs and irritation ensues, immediately tiush with a large volume of water. • Report any signs of iocal adverse reaction. • Inform aii your health care providers that you are using fiuocinonide. For additional information, please review the manufacturer's recommendations.

109 Qu iitessadce international • Ship et ai —

RECURRENT APHTHOUS STOMATITIS: R^ AMLEXANOX

Amlexanox is a toploai anti-inflammatory and antialiergic drug. It inhibits chemical mediatory release of the slow-reacting substance of anaphyiaxis and may have antagonist effects on in- terleukin-3: however, the mechanism by which amlexanox accelerates the healing of aphthous ulcers is unknown. Most systemic absorption probabiy occurs in the gastrointestinal tract after swallowing the 5% amlexanox paste rather than directly through the ulcer. Amlexanox is me- tabolized to a hydroxylated and conjugated product, and 17% is excreted unchanged. Pregnancy risk factor B.

1. Indications • Drug of ohoice for the management ot minor aphthous ulcers and as an adjunot to prednisone and other systemic immunosuppressive therapy for major recurrent aphthous stomatitis.

2. Contraindications • History of adverse reaotion to amlexanox. • Infections (viral, fungal, or bacterial). In the presence ot infection, appropriate adjunctive treat- ment shouid be instituled.

3. Drug interactions • None is known.

4. Administration • 0.5 cm (% inch) of paste is appiied topically to the aflected area. 4 times daily, immediateiy fol- (route and dosage) lowing meals and orai hygiene and at bedtime. • Dosage form: 5% paste in 5-g tube. • Appiy as soon as symptoms of ulcer are noticed.

5. Monitored efficacy • Monitor the patient for relief of symptoms, remission, or resolution ot lesions. and toxicity • Ingestion overdose may cause gastrointestinal upset (diarrhea and vomiting).

6. Length of • Continue treatment until there is significant improvement, and then begin to taper the number ot treatment appiications. • If significant reduction in pain and heaiing have not occurred in 10 days, consider additional pri- mary and/or secondary lines ct treatment.

7. Cessation of •Taper slowly and watch tor exacerbation of disease. treatment

8. Instructions to • As soon as symptoms of ulcers are noticed, apply 0.5 cm {'A inch) of paste directly to the ulcer, the patient 4 times daily, immediateiy foilowing meals and oral hygiene and at bedtime. • Avoid contact with eyes, it contact occurs and irritation ensues, immediately flush with a iarge volume of water. • Report any signs of locai adverse reaction. - Inform ali your health care providers that you are using amlexanox.

For additional information, please review the manufacturer's recommendations.

110 r 2, 3000 • ShiD et al •

RECURRENT APHTHOUS STOMATITIS: R^ PREDNISONE

Prednisane. a glucocorticosteroid. decreases inflammation by suppressing ciiemotaxis ol polymor- phonuelear neutrophil leukocytes and reducing capillary permeability. It is an immunosuppressant that reduces lymphocytic activity and suppresses adrenal function. It is tiigt¡iy protein bound after absorption into the vascular compartment. Prednisone is rapidly metabolized in the iiver (pred- nisoione is the active metabolite) and eliminatod in the kidneys (tiaif-tife: 18 to 36 hours). Pregnancy risk factor B.

1. Indications • When the lirst line of treatment has been ineffective, or when signs and symptoms are more se- vere and prolonged (eg, major aphthous ulcers or herpetiform aphthae).

2. Contraindications • History of adverse reaction to prednisone. • Infections (viral, fungal, or bacterial): In the presence of infection, appropriate adjunctive treat- ment should be instituted. • Concurrent administration witn a . • Use witfi caution in patients witfi gastrointestinai uicerations, diabetes, glaucoma, psychoses, renal disease, osteoporosis, seizures, congesti^ie heart failure, and hypertension,

3. Drug interactions • Decreases effects of anticoagulants. • Increases metabolism ot isoniazid and salioyiates, • Causes hyperglyoemia, resulting in a need to adjust doses of insulin or otfier hypoglycémie agents, • Increases risi< of gastrointestinal irritation with concomitant use of uicerogenic agents, suoh as nonsteroidal anti-intlammatory drugs,

4. Administration • Oraily, taken with food or milk. (route and dosage) • Dosage forms: 1.0-, 2.5-, 5.0-, 10.0-, 20.0-, 25.0-, and 50,0-mg tablets: 5-mg/5-mL syrup. • Dose is individually titrated in accordance with the patient s response. • initially, give 1.0 to 1.5 mg/kg a day for 1-2 weeks, monitor the patient's response. • If there is no response, the dosage should be increased in 0,25-mg/kg increments a day until the lesions respond, compiications anse, or a dosage of 2.0 to 2.5 mg/i

5. Monitored efficacy • Monitor the patient for relief of symptoms, remission, or resolution of lesions. and toxicity Early signs and symptoms of toxicity • Fluid and eiectroiyte disturbances: hypertension. • Hyperglycemia, poiydypsia, poiyphagia, orpolyurea. • Increased susceptibility to infection—Treat infections aggressively, • psychosis—Particularly in patients with psychoiogic disorders receiving more than 40,0 mg of prednisone daily. • Peptic ulcer disease—Especially in patients taking nonsteroidal anti-inflammatory drugs, con- sider an Hj blocking agent for prophyiaxis. Late signs and symptoms of toxicity: • Gushing's syndrome: moon tacies, buffalo hump, hirsutism, obesity. • Hypothalamic, pituitary, and adrenal axis suppression—Usuaily occurs after 3 weeks of treat- ment: taper dosage as soon as possibie. -,. , ^ • Osteoporosis and osteo nee ros is—Patients should be instructed to supplement diet with 1.0 q/day of elemental caicium and to report any joint pain or discomfort. • Cataracts—It a 15,0-mg dosage of prednisone is maintained for more than 1 year, instruct the patient to schedule annual ophthalmoiogic examinations.

6. Length of • Continue treatment untii there is significant improvement, and then begin to taper dosage. treatment

7. Cessation of • Aiways taper dosage. . , _, ^ , „ treatment • Siow taper aiiows for close monitoring for evidence ot exacerbation of disease and symptoms . llpe^byTo mg per week until 10 mg is reached, then taper by 2.5-mg increments untii discon- tinued or the iowest effective dose is reached. • If withdrawal occurs, raise the dosage again and taper by 1 mg weekly.

e. Instructions to the • Do not stop taking prednisone all at once. patient • Keep a good supply readiiy available. • If a dose is forgotten, resume taking the medication as soon as possible. . Report any adverse etfects, such as joint pain, excessive thirst or urination, black, tarry stoois, vision changes, etc. , . ^ . ,. . j • intorm all your health care providers that you are taking prednisone and at what dosage.

For additional information, please review the manufacturer's recommendations. • Ship et ai —

RECURRENT APHTHOUS STOMATITIS: Rv THALIDOMIDE

Thalidomide. a derivative oí glutamic acid, was first prescribed in ¡he 1950s as a sedative and lo prevent morning sickness in pregnancy, but was withdrawn from the world market in 1961 beoause of severe teratcgenic effects. Recently, it iias been demonstrated that thalidomids is an immune- modulator and is effective for the symptomatic treatment of certain cutaneous and mucooutaneous disorders. The mechanism of action of the nonsedative effects is unofear; t^owever. it has been shown to decrease the production of tumor necrosis factor a and inhibit leukocyte chemotaxis. Pregnancy risk factor X.

1. Indications • Treatment ol severe recurrent aphthous stomatitis that is not controlied by topical or oral steroids, • iHuman immunodeiicienoy virus-positive patients with recurrent aphthous stomatitis.

2. Contraindications • Women who are pregnant or who oould beoome pregnant whiie taking the drug. • Women who are nursing a baby. • individuals with preexisting human immunodeficiency virus-reiated or enoephaiopathy.

3. Drug interactions • Enhances the activity c( barbiturates, alcohol, ohiorprcmazine, and reserpine, • May antagonize the action cf histamine, serotonin, acetylcholine, and prostag land ins,

4. Administration • Dosage forms: 50-mg tablets, (route and dosage) • initiai treatment: taken oraiiy, 100 to 200 mg daily, tor 2 months. • Maintenance: tai

5. Monitored efficacy • Monitor the patient tor reiiet of symptoms, remission, or resoiution of lesions, and toxicity - The neurologic status of the patient must be carefuily obsen^ed, - May oause drowsiness, dizziness, si

6. Length of • Continue treatment until signiiioant improvement or remission is observed or the patient cannot treatment tolerate side eifeots, and then toliow maintenance therapy.

7. Cessation oi • May be stopped abruptly, treatment

8. Instructions to the Femaie patients patient ' Even 1 dose ol thalidomide, early in pregnancy, can produce signilicant birth deleots, including stunted growth ot arms and legs and severe defects of vitai organs, • You must have a negative biood or urine pregnancy test to begin treatment and the test shouid he repeated at least every month while you are tailing thalidomide and 4 weeks after your last dose • You must abstain from sexual intercourse or use 2 highly effective and medicaliy approved birth controi metnods beginning 1 month before and continuing 1 month after treatment, • Stop taking thalidomide immediateiy and report to your doctor if any of the foiiowing occurs: you have a late or an irregular menstrual period, you stop practicing sexual abstinence, you stop using birth control methods, you think that you are pregnant, or you become pregnant. Male patients • Abstain from sexuai intercourse cr use a condom during intercourse while, and fcr 1 month after, taking thalidomide, it is not known if thaiidomide is present m semen. For ali patients • Do not give fhalidomide tc anyone fcr use because it can be extremely harmfui if used by others • Thaiidomide often causes drowsiness; avoid drinking alcohol and taking other sedatives, it may affect your ability to drive or operate machinery. • Thaiidomide may cause nerve damage: report to your doctor if you experience burning, numb- ness, or tingiing of your arms, hands, iegs, cr feet. • Check with your doctor before taking any other medications, • If you develop a skin rash with or without a fever, changes in your heart rate, or icw blood pres- sure, stop taking thaiidomide and contact your doctor, • Repcrt any side effects to your doctor. These inciude mood changes, dry mouth, headache, nausea, constipation, increased appetite, puffiness of the face and iimbs, dry skin, itching, irreg- uiar menstrual period, iow white biood celi count, thyroid problems, blood sugar that is too high or too iow, brittie fingernaiis, decreased iibido, dizziness, and red palms.

For additionai information, please review the manufacturer's recommendations or visit the web site of the manufacturer at http://www,celgene.com/thalomid.htm or the web site of the US Food and Drug Administration at http://www.rda.gov/cder/news/thalinfo/default,htm