Refractory major aphthous stomatitis managed withsystemic immunosuppressants: A case reportMojgan Sarmadi, DDS, MDVJonathan A. Ship.

This articie presents an unusual case ot major recurrent aphthcus stomatitis that was refractory to multiplelopical and systemic immunosuppressive therapies. Ultimately, thaiidomide was seiected despite its weli-recognized adverse potentiai, and was successfui in producing remission of ulcers. Strict ciinicai protocoiswere followed for this therapy in collaboralion with numerous medical providers. This case illustrates theahility of multiple orai health and medical providers to coilaborate in the diagnosis, management, and fol-low-up of a patient with an orai vesiculoerosive disease. (Quintessence Int2004:35:39-48)

Key words: immunosuppressant, major recurrent aphthous stomatitis, steroids, thaiidomide

Recurrent aphthous stomatitis (RAS) is one of themost prevalent oral mucosai diseases and has re-

ceived much attention in the clinical and research lit-erature.'-'^ Despite numerous research attempts, a de-finitive etiology has not yet been elucidated, there arcno definitive preventative strategies, and few treat-ments are effective. Currently, the most widely ac-cepted etiology is a localized immunologie disorder,and the usual therapy is topical administration of glu-cocorticosteroids or just palliative treatment.'^

Typical aphthous lesions begin after the age of 5years/'and their occurrence continues throughout apatient's life with a peak age of onset between 10 and

'Former Fellow, Department of Oral Medicine, Pathology, Oncology,University of Michigan Schooi of Dentistry Ann Arbor, Micliigan.

'Professor, Departmenl of Oral Medicine: Director, Bluestcne Center lorCiinicai Researoh, Mew York University Coiiege of Dentistry, New Vork,New Yoili,

Reprint requests: Dr Jonathan A. Ship, New York University Coliege ofDentistry, 345 East 24th Street, New York, NY 10010-40S6. E-mail:iorathan.ship®nyu.edu

19 years.** The most common presentation is minorRAS, which is characterized by recurrent, round,clearly defined, small, painful ulcers with shallownecrotic centers and raised margins with erythematousborders. A less common variation of aphthous stom-atitis is major RAS. This variety manifests as single ormultiple ulcers larger than 0.5 cm in diameter thatpersist for 10 to 20 days. Major RAS may heal withscarring. A third presentation of RAS is herpetiformRAS, characterized by multiple small clusters of pin-point uicers, which occur throughout the oral cavity.They last 7 to 30 days with potential to scar. Althoughthese lesions are herpeslike or herpetiform in nature,herpes simplex virus is not the etiologic factor.

In a small subset of cases, major RAS presents asnumerous ulcers affecting a large area, or several giantlesions that can persist for months. These unusual le-sions, referred to as "giant aphthous ulcers,"" "relaps-ing RAS,"'* or "refractory RAS,"" cause severe painand compromise a patient's general well-being. Theyare typically seen in immunocompromised conditions(eg, HIV infection'*) and in immune-mediated dis-eases such as cyclic neutropenia,'' Behcet's dis-ease, *'- ^ Crohn's disease, '' "* and celiac sprue.^'

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Fig 1 Large (> 2.0 cm) craterilcrm major recurrent aphthousstomatitis ulcer alfecting the right dorsoiaterai border ot thetcngue. Pretreatment condition

Occasionally, patients without any known systemiccondition develop these giant lesions.'^ Such casescreate a clinical challenge for health care professionalsbecause the presentation of disease is unusual, there isno identifiable cause, no effective prevention protocolhas been established, and no commonly acceptedtreatment is available. This case report describes a pa-tient witb refractory giant apbtbous stomatitis of un-known etiology managed with several systemic im-munosuppressants during a 6-year follow-up.

CASE REPORT

A 21-year-old Caucasian woman was referred to theOral Dermatology Clinic at the University of MichiganMedical Center for diagnosis and management ofmajor recurrent aphthous stomatitis (MaRAS), Thedisease history indicated onset at age 12. At the timeof referral, her oral lesions had become refractory toconventional tberapy, persisting for 1 year prior to berpresentation to tbe clinic.

At presentation, review of systems was unremark-able. The patient denied any other medical problemswitb the exception of facial acne, Sbe denied a historyof abdominal and gastrointestinal symptoms, anemia,amenorrbea, skin lesions, or allergies. Sbe was nottaking any prescription medications. Sbe did notsmoke or consume any alcoholic beverages, and herfamily history was negative for significant medicalproblems. Symptoms of RAS were not reported in berfamily. Tbe extraoral exam was significant for facialacne with no otber clinical abnormalities observed.Intraorally, there were multiple deep and large (> 1.0cm) crateriform ulcers affecting the dorsum and dor-soiaterai borders of the tongue, lips, and buccal mu-cosa (Figs 1 and 2). Several ulcers bad a leukoplakicpseudomembrane consistent witb a superimposedcandidal infection.

Fig 2 Large (> 2.0 cm) crateriforrn major recurrent aphthousstomatitis ulcer affecting the inner aspect of the right labial mu-cosa Pretreatment condition.

Evaluation and diagnosis

At initial presentation, tbe patient's bistory was impor-tant for a comprehensive evaluation. Her symptomswere absent in early years but began later in child-bood. Intraoral ulcers would form on all movable mu-cosal surfaces and were not accompanied by blistersor drainage. Tbe surgical patbology report availablefrom a past upper lip lesion biopsy reported reactivebyperplasia of mucosa witb submucosal inflammatioti(possible candidal granuloma). Fungal infections mayfail to grow in culture, and a simple way to detecttbem is Periodic Acid Scbiff (PAS) stain.'^ Tberefore,PAS staining was used to verify candidal infection insmears of several orai lesions, and the results werepositive. A preliminary diagnosis of MaRAS witb can-didal superinfection was suggested after this initialvisit. However, treatment for candidiasis witb topicalantihingal tberapy was not helpful in resolving her un-derlying lesions.

Tbere is no specialized test for RAS at tbe presenttime. Clinical diagnosis is based primarily on presenta-tion and bistory. Results from sérologie and bisto-pathologic tests (Table 1) can assist tbe clinician inruling out otber suspected conditions (Table 2) and inestablisbing a diagnosis by tbe process of elimination.For persistent erythemic mucosai lesions, bistopatbol-ogy is required to rule out dysplasia and neoplasm aswell as mucocutaneous/vesiculobullous diseases. It ispossible that a longstanding lesion may convert to an-other form over years, and therefore, repeated biopsymay be needed in certain cases to reconfirm a patbo-logic diagnosis.

At tbe second visit, tbe RAS lesions were not re-solved following antifungal tberapy. A 14-day trial oftopical corticosteroids (see below) was initiated. Thepatient returned witb essentially uncbanged oral lesions.

At tbe third visit, a buccal mucosal ulcer was biop-sicd under local anesthesia, and histopathologic results

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TABLE 1 Differential diagnosis of recurrent aphthous stomatitis

Differential diagnosis Oral signs Other signs and symptoms

Recurrent aphthous Single or muitiple ulcers on unattached muccsastomatitisHerpes simplex virus Single or muitiple uloers on attacfied mucosa; diffuse

gingival erythemaVaricella Zoster virus Unilaterai distribution; extraorai and intraorai ulcers

Herpangina Multiple ulcers in hard and soft palate and oropharynxHand-foot-m out h disease Ulcers preceded by vesiciesErythema multiforme Lesions on attached and unattactieö mucosa; lip

crusting; may be preceded by herpes infectionOrai iichen planus Erosive and reticular lesions on buccal mucosa, gingiva,

palate, tongue; white striae (Whickham's]Cicatricial pemphigoid Vesiculobuilous lesions on attached and unattached

mucosa; positive Nikolski's signPemphigus vulgans Vesicuiobullous iesions on attached and unattached

mucosa; positive Nit<olskrs sign

May be associated with oropharyngealor gast re intestina i ulcersPreceding fever and muoosal vesicles

Prodrome of pain and burning; may cause scarringand neuralgiaFever and malaiseSkrn lesions, lew grade tever, malaise

Skin macules and papules; target lesions on skin

May be asymptomatic, lesions may occur on skin

Can affect eyes and genitalia; lesions may scar

Lesions can occur on skin

TABLE 2 Helpful tests in evaluation of oral ulcers of unknown etiology

Condition to be evaiuated Test

BiastcmycesCandidiasisCioatrioial pemphigoid, pemphigus vulgaris,lichen pianusCrohn's and Behcet's, ulcerative colitisCoeliac disease (dermatitis herpetiformis,gluten sensitive enteropathy)Erythema multiformeSystemic lupus erythematosus

Viral infectionsCytomegaiovirus (CfviV)Epstein Barr Virus (EBV)Coxsackie virusHerpes simplex virus (HSV)

Microimmunodiffusion test; Blastomyces A-antigen enzyme immunoassayPeriodic Acid Schiff (PAS) test, fungal culfureHistopaihology; direct and indirect immunofluorescence

Endoscopy, direct laryngoscopy, small bowel series, colonoscopy, sigmoidoscopyAnti-giiadin antibody; anti-reticulin antibody, anti-endomysial antibody; h isto pat he logyand immunohistochemistry; direct immunofluorescence (tor stippled IgA in cfermal papillae)Serum autoantibodies tc desmoplakin I and IIAntinuclear antibody; anti-phospholipids antibody (cardioiipin IgG, Igful); iupus band test;histopathology; direct and indirect immunofluorescence

pp65 Cfi/V antigenemia test, CfwiV culture and antibody testsReccmbinant EBV antigen immunoblot assay, EBV antibody testsVirus-neutralization testHSV cuiture and antibody tests

demonstrated nonspecific infiammation. For furtherevaluation, a series of sérologie tests was performedwith negative findings. Antigliadin antibodies type im-munoglobuiin IgA and IgG for gluten-sensitive en-teropathy and latent coeliac disease ^ ^ were evaluated,and results were negative. A Blastomyces^' antibodytest also was performed to rule out occult fungal infec-tion, and the results were negative. Serum antinuclearantibody {HEP-2),5'' extractable nuclear anti-RNP,anti-SM, anti-RO, anti-LA, ds-antiDNA^' anti-reticulinantibody,^='* and anti-cardiolipin antibody (IgG andIgM phospholipids)'^ tests were performed for hirtherinvestigation of a possible underlying autoimmune dis-ease. All test results were negative. Direct and indirectimmunofluorescence tests to rule out other autoim-mune vesiculobuilous diseases were performed (Table2), and tbe results were negative. Other tests includeddirect immunofluorescence of the patient's oral ulcermucosal biopsy using FITC-conjugated anti-human

IgG, IgA, IgM, C3, and fibrin; serum endomysial anti-body (IgA) for dermatitis berpetiformJs ' and/or coeliacsprue^^^ and bullous pemphigoid antibody differentia-tion test (indirect immunofiuorescence of patient'sserum with normal skin split in the lamina lucida). ''Results of all tests were negative or inconclusive. Nosystemic etiology related to her symptoms could beidentified.

At this time, a diagnosis of MaRAS of unknown eti-ology was established. In addifion to the comprehen-sive evaluation for autoimmune diseases, a completeblood count with differential was evaluated to rule outany possible infectious or hématologie cause of ulcers,such as anemia. A complete blood chemistry, renal,and hepatic profile was performed. All tests revealedno significant findings.

Serologie monitoring of patients with oral vesiculo-builous diseases is important. These tests may be help-ful in the diagnosis of systemic diseases that present

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with oral signs and symptoms." They are also impor-tatit for patient supervision during immunosupprcssanttherapy (eg, anemia could result as a side eftcct due tobone marrow suppression). Bone marrow function istypically monitored by regular blood counts.'* Certaindrugs used for the treatment of oral ulcers also requirespecial considerations. For example, dapsone, an im-munosuppressant, should be prescribed after a G6PDtest has confirmed the pafient's ability to metabolizethe medication." Cytotoxic therapy requires seroiogicevaluations at periodic visits to monitor any possihiehématologie, renal, or liver abnormalities.'** Alanincaminotransferase (ALT), aspartate aminotransferase(AST), Venereal Disease Research Laboratory (VDRL),and fluorescent treponemal antibody (FTA), primarilyused in other clinical situations, can also he employedto evaluate liver function.^'-"

In summary, a comprehensive series of seroiogictests was used to screen the patient for contraindica-tion to certain medicafions and to monitor her duringpharmacotherapeufic treatment. Overall, she experi-enced marginal to mild changes in her blood countsstibsequent to systemic immunosuppressant therapy,but these changes were mild and remained stable.Toward the end of the reported treatment period, shebecame cushingoid despite a gradual taper of herprednisone therapy and was treated accordingly.

Treatment

Alternative treatment options were chosen based onthe patient's diagnosis, severity of symptoms, and re-sponse to past treatments. Upon initial presentation,nystatin mouthrinse (100,000 units per mL) and clotri-mazole (10 mg) troches were prescribed for the sec-ondary candidal infection. A 14-day course of topicalcorticosteroids''^''" (clobetasol proprionate 0.05% gelqid, and dexamethasone elixir 0.5 mg/5mL rinse andexpectorate tid) was completed without any resolutionof symptoms. Chlorhexidine 0.12% rinse was addedperiodically since the patient experienced difficultiesperforming daily oral hygiene. Multivitamins also weregiven to supplement nutrition and eliminate tbe possi-bility of a subclinical deficiency."-''^ None of thesetherapies produced any significant improvement insymptoms.

ITie next step in treatment was to commence sys-temic steroid therapy. Initially, a tapering dose ofprednisone was prescribed''^'" {60 mg daiiy for 2 daysdiminishing by 10 mg each day) in conjuncfion withdexamethasone mouthrinse.'^ The pafient reported anapproximate 50% reducfion in lesions. However, afterdiscontinuation of prednisone, lesions recurred. Threetapering dose trials of prednisone were subsequentlyattempted; each trial contained a longer period of

steroid maintenance before dose decline (eg, 60 mg for7 days, 50 mg for 7 days, etc), yet the patient neverwent into remission.

Long-term use of corticosteroids is associated withsignificant side effects,'' '» and therefore steroid-spar-ing and immunosuppressant agents are typically con-sidered for patients requiring long-term therapy.Accordingly, azathioprine, a steroid-sparing purineanalog, was added to the prednisone regimen, and theprednisone was gradually discontinued.""^ Therapywith azathioprine and other immunosuppressants (eg,dapsone) may result in nephrotoxicity, liver toxicity, oranemia. Follow-up of complete blood counts heforeand during azathioprine treatment is recommended. *In this case, azathioprine dosage was escalated to 150mg daily with moderate improvement in lesions andwithout any significant changes in her hematopoieticprofile. For approximately 1 year, her condition re-mained relatively stable with new lesions still develop-ing but resolving in 3 to 4 weeks (Fig 3).

After 1 year of azathioprine therapy (150 mg/day),lesions began forming more rapidly and eventually ex-tended to all aspects of her labial and buccal mucosa.Severe involvement of bilateral labial commissuresproduced limited mouth opening, pain, and impairednutritional intake. Therefore, she was gradually takenoff azathioprine, and a new regimen of dapsone** (75mg qd) was initiated after it was determined that thepatient was not deficient in glucose-6-phosphatase de-hydrogenase (G6PD). As with azathioprine, dapsonerequires follow-up with complete blood cotints tomonitor bone marrow function. For approximately 2years, the patient's oral lesions stabilized with new le-sions developing and lasting 3 to 4 weeks but eventu-ally resolving. Additional scar fissue developed in thelip commissure and buccal mucosal regions.

After this 2-year period of time, an exacerbation oflesions occurred without resolution, and therefore addi-tional prednisone (50 mg qd) was added to the medica-tion regimen. As symptoms improved, prednisone taperswere instituted during the next year but were frequentlyinterrupted by re-exacerbation of lesions. Dapsone wastben discontinued, and a trial of levamisole hydrochlo-ride^" was initiated. Complete blood and platelet countsand liver function profiles were performed weekly dur-ing the first month of therapy and then monthly after-ward to monitor the patient for evidence of agranulocy-tosis and other hématologie abnormalifies. Levamisoletherapy resulted in a 3-month period of lesion quies-cence, widi no additional lesions developing.

After 3 months of levamisole, MaRAS lesions beganto develop and persist. Topical cyclosporine (100mg/mL)5i was added for additional immunosuppres-sant effects. This regimen was maintained for approxi-mately 6 months, but a large lesion progressed in the

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Rg 3 Improved major reoutrent aphttious stomatitis lesions tol-lowing systemic prednisone and azathioprine therapy tor 1 year.

Fig 4 Right labial commissure ma|or recurrent aphthous stomati-t le on t nt tc therapy with cyclosporine (topical], systemicdapsone, levamisole, and oentoïifyHine

Fig 5 One month postsurgery for repair of a chronic granuloma-tous ulcer in the right labial oommissure and for removal of hyper-plastic scar tissue restricting mouth opening.

right labial commissure (Fig 4), and therefore cy-closporine and levamisole were discontinued,

A new trial of pentoxifylline was attempted basedupon recent reports of suppression of RAS, ^ Dosagewas maintained at 400 mg tid with moderate improve-ment in iesions for approximateiy 4 months. Duringthis time the patient reported no new lesions; how-ever, after 4 months, her oral condition rapidly deteri-orated, and prednisone was reinstituted with a taper-ing of the pentoxifylline. Her maximum mouthopening was reduced by approximately 50%, and shebecame cushingoid as a result of steroid dependency.

In summary, the patient's oral condition exacer-bated and remitted over a period of approximately 4years without permanent remission. During this time,ulcers eroded through her right labial commissurecausing significant pain, nutritional impairment, anddifficulty with performing oral hygiene (see Fig 4), Sheunderwent surgery for repair of a chronic granuloma-tous ulcer in this region and for removal of hyperplas-tic scar tissue restricting mouth opening. Followingsurgical healing (Fig 5), she was considered a candi-date for thalidomide (Celgene) therapy, which has

Fig 6 Major recurrent aphthous stomatitis iesions, prior tcthaiidomide use, on the inner aspects of the iabial muoosa andanterior borders of the torigue

been used for the management of HIV-associatedmajor recurrent aphthous stomatitis ukers,^''^''

For appropriate thahdomide therapy according tothe manufacturer and the United States Food and DrugAdministration (FDA) guidelines, a System forThalidomide Education and Prescribing Safety(STEPS) oversight program was initiated, '''** The pa-tient underwent three phases: (1) education, (2) screen-ing, and (3) therapy under close observation, A concur-rent prednisone taper was plarmed for this final phase.Prior to thahdomide use, MaRAS lesions were presenton the inner aspect of the patient's lips, anterior andposteriolateral borders of the tongue, and inner aspectsof the buccal mucosa (Fig 6),

Education of thalidomide. Patient education ex-tended over 4 months and included the patient as wel!as her parents. It consisted of repeated discussions andsupplemental reading material obtained from the FDAand Celgene regarding the significant teratogenic po-tential of the medication and other possible hémato-logie, gastrointestinal, and neurologic side effects. Eachmeeting was followed by question and answer sessions.Finally, a quiz was given to the patient to assess the

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Fig 7 Resolution of tongue major recurrent .-¡pi-thcus ^'L. -".¿II ( slesions alter 1 montii ol Ihalidomide 200 mg/Qay

Fig 8 (right) Resolution of iip major recurrent aphttious stomatitislesions after 1 month of thaiidomide 200 mg/day.

effectiveness of patient education. ' She successfullypassed this phase and subsequently signed an informedconsent for medication use.

Screening for thaiidomide. Screening involved acomplete physical and neurologic and hématologieevaluations according to recommended guidelines,' ' ^The purpose was to discover any unusual systemic con-ditions (eg, neurologic deficit, unknown pregnancy)that could have placed the patient at an increased riskof developing thalidomide-rclated adverse sequelae.Following medical clearance, the patient was placed onhirth control medication. She indicated that she wasnot sexually active, however, she agreed to use at leasttwo methods of birtb control throughout the therapy.She chose abstinence in addition to the use of birtbcontrol pills. Birth control practices were in effect for atleast 2 months and two human chorionic gonadotropin(HCG) tests were negative prior to initiation of tbe nextphase. The patient and her parents were informed thatblood HCG tests would he performed monthlythroughout thaiidomide therapy, continuing until 1month following the completion of the drug regimen.

Thaiidomide therapy and prednisone taper

Two months after the birth control regimen began, afinal blood HCG test was negative and the first doseof thaiidomide was given. Thaiidomide was increasedfrom 50 mg qd to 200 mg qd over 1 week since titra-tion of dosage has been reported to reduce abdominalside effects." A maximum dose of 200 mg daily wasselected since this dose has been reported to cause re-mission of oral lesions with fewest chances of neuro-logic sequela.' ' "' ' After 2 weeks of therapy, the pa-tient's oral mucosa exhibited signs of improvement bythe absence of new ulcers and healing of existing ul-cers. In 1 month, all oral mucosai surfaces bad com-

pletely healed without any evidence of new lesions[Figs 7 and 8). The patient was referred to endocrinol-ogy for evaluation and management of her ctishingoidfeatures as a resuft of her extensive prednisone ther-apy. A gradual prednisone taper was carried out grad-ually without any side effects over the next 6 months.

After 3 montbs of thaiidomide therapy, a 2-monthtaper of thaiidomide was commenced. During the 5-montb period of thaiidomide therapy (as well as a 1-montb post-thalidomide completion), the patient re-mained in complete remission. iVledical and neurologicre-evaluation found no side effects of the medication.Sbe continued ber birth control regimen as well asserum HCG pregnancy tests every month in the eventthat she might require thaiidomide again in the future.

Two months after discontinuatioti of thaiidomide, thepatient was physically assaulted, and she experiencedsome slight bruises to the abdominal region. Three dayslater, a new ulcer formed in the inner aspeet of thelower lip despite no reported trauma to this region. Theulcer gradually increased in size and pain over a 3-weekperiod of time, and despite topical corticosteroids, mea-sured 1.5 em in diameter witb raised erytbematous mar-gins. The remaining oral, head, neck, and physical ex-amination was unremarkable. There was no evidence ofiymphadenopathy or oral-facial infection, and a diagno-sis of MaRAS was suggested. A new trial of thaiidomidewas instituted at a lower dose (50 mg daily) due to thepresence of only one lesion. Careful monitoring of HCGlevels and use of birth control pills were maintained.After 1 month, tbe lesion completely healed without anyevidence of exacerbation. One additional month ofthaiidomide was recommended, and then thaiidomidewas discontinued with complete remission of oral symp-toms. The patient has been lesion free for over 1 year,has completed her prednisone taper, and continues touse birth control pills.

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DISCUSSION

Major recurrent aphthous stomatitis (MaRAS) mani-fests as single or muitipie ulcers larger than 1 cm ingreatest diameter. They affect the movable nonkera-tinized oral mucosa, particularly the labial and buccalmucosa and floor of the mouth. MaRAS lesions typi-cally last 10 to 20 days, however, in rare cases large le-sions can persist for montbs. Tbey cause severe pain,interfere witb nutritional intake, compromise tbe gen-eral well-being of the affected individual, and scarwhen completely healed. The underlying etiopatho-genesis is poorly understood, however it has been re-ported that MaRAS occurs in certain systemic disor-ders, such as HIV.'"' "-^^ RAS ulcers of this nature arereferred to as "giant aphthous ulcers," depending ontheir size and "relapsing or refractory RAS," depend-ing on their duration and frequency.'^-" Occasionallythey are reported in isolated cases without any knownsystemic disorder. The first approach to treatment isan accurate diagnosis,'^

The differential diagnosis for MaRAS includes her-pes simplex, varicella zoster, herpangina, hand-foot-mouth disease, erythema multiforme, oral lichenpianus, cicatricial pemphigoid, pemphigus vulgaris,and neoplasia (see Table 2), There is no specializedtest for RAS at the present time; however, biopsy, mi-crobiologie and sérologie tests can help identify othersimilar disorders (see Table 1). Clinical diagnosis isbased primarily on presentation and history,

Afler a diagnosis of RAS is established, tbe searchfor an effective treatment begins, Tbere are four majorgoals for treatment of RAS: (Ï) ulcer management, (2)pain management, (3) nutritional management, and(4) disease control (prevention).'^ Palliative treatmentis typically sufficient for minor RAS and most typicalMaRAS ulcers, yet it may be insufficient for severe re-fractory RAS or giant major RAS.

RAS may involve a local immune dysregulation oftbe inflammatory response, and T cell-mediated immu-nity.63.«* ¡NF-alpba is suspected to play a role In manycases,'"' ^ Tberefore, corticosteroids are the flrst choiceof treatment. Topical steroids are recommended qid forup to 1 month without serious risk of side ef-fects.5.«''2,66,67 Systemic steroids are indicated for moreextensive lesions that do not respond to topical therapy.Prednisone is a systemic corticosteroid with immuno-suppressive, as well as anti-inflammatory properties. ^""The adrenal gland normally secretes corticosteroids andis regulated by the hypothaiamic-pituitary-adrenai axis(HPA) through feedback loops. Exogenous cortico-steroid administration provides negative feedback tothis axis. Corticosteroids are essential for an individ-ual's ability to cope with physical and emotional stressas well as other metabolic demands. Excessive negative

feedback to tbe HPA axis by the use of long-term ex-ogenous steroids will alter its response to stress.

For long-term systemic corticosteroid treatment,current steroid dose is tbe best indicator of HPA sup-pression. Patients taking less tban 5 mg/day of pred-nisone are likely to bave a normal HPA. Prednisonedosages of > 5 mg/day will probably produce an ab-normal HPA response to stress.''" Tbe severity ofadrenal suppression varies considerably, and its clini-cal significance has been debated. For example, abnor-mal test results do not always demonstrate an adverseclinical outcome.^' When regimens are given for 2weeks or longer and in excess of 30 mg hydrocorti-sone equivalent/day, adrenal insufficiency is sus-pected. After treatment at this dose level, the HPA axismay take up to 2 years to completely recover, al-though the stress response may normalize much ear-lier, even in several weeks.'' ''

For short-term therapy of MaRAS in otherwisehealthy adults, systemic prednisone doses as high as60 to 80 mg/day for 7 to 10 days may be used butsbould be avoided in children, elderly, and pregnant orlactating women,"' •'" Longer treatment regimens in-crease the risk of hyperglycemia, systemic infections,glaucoma, hypertension, osteoporosis, Cushing's syn-drome, and behavioral changes, and therefore requireendocrinologie evaluation and follow-up by medicalproviders, A prednisone taper should be performedgradually and must involve tbe patient's medicaiprovider. Insulin tolerance tests and a variety of stresstests (eg, rapid adrenocorticotropic hormone stimula-tion test, short synacthen test, low dose short synac-then test) have been used to evaluate tbe status of theHPA axis after a prednisone taper.™

Systemic steroid tberapy is a valuable option forMaRAS after topicai steroids bave failed to improvetbe ulcers. Unfortunately, it may not be eftective whenused alone, and steroid resistance may also develop.Other immunosuppressive drugs sbould be consideredunder these circumstances. Importantly, prior to use,tbe tberapeutic eftectiveness of eacb must be weigbedagainst its potential side effects. Steroid-sparing im-munosuppressant agents are typically considered forpatients in need of long-term tberapy or those who areunresponsive to steroids. Accordingly, azathioprine, asteroid sparing purinc analog,'' was added to the pred-nisone regimen for the above-mentioned patient, andprednisone was gradually discontinued,-** Therapywith dapsone, azathioprine, and other immunosup-pressants may result in nephrotoxicity, iiver toxicity, oranemia. Follow-up with complete blood counts beforeand during azatbioprine treatment is recommended, «

Dapsone'"" bas sbown some effectiveness for treat-ment of RAS in case studies and open trials. Leva-misole (150 mg/day), an immunotherapeutic drug.

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may aiso be an effective treatment for RAS, An openlabel study'" and several randomized, double-blindstudies""'" reported significant reduction in pain, num-ber and duration of ulcers, and frequency betweenepisodes after levamisole. However, at least three simi-lar studies'^-'* did not report any significant differencesin symptoms between treatment and placebo groups,Cyclosporine''"" has shown some effectiveness fortreatment of RAS in case studies and open trials.Pentoxifylhne"^' also has been reported to be effec-tive in treatment of aphthous stomatitis,

Thalidomide, a blocker of TNF-alpha, has beenshown to be an effective treatment for severeRAS."'* "* Thalidomide enhances human keratinocytemigration and proliferation, which is essential forre-epithelialization of skin wounds and could proveuseful for RAS.*' Use of thalidomide in children hasheen documented with some success, but long-term ef-fects bave not been established.^' Thalidomide therapyhas been more thoroughly researched in HIV-positivepatients.''' • ''•*'* One study" reported that HIV-infectedpatients with RAS experienced significant improve-ment, diminished pain, and an increased ability to catafter a 4-week course of thalidomide (200 mg/day)wben compared to placebo. However, the dose wasreduced or completely terminated in approximately20% of patients due to toxicity (eg, rash, somnolence,peripheral sensory neuropathy). Another mulficenter,double-blind, randomized, and placebo-controlledstudy of HIV-inlected patients "* reported significantlygreater healing of aphthous ulcération of the esopha-gus after 200 mg/day thalidomide treatment with asso-ciated diminished odynophagia and enhanced eatingability. Adverse events were minimal, and includedsomnolence, rash, and peripheral sensory neuropathy.

Inifial thalidomide treatment in either HIV-positiveor HIV-negative patients should be 100 to 200 mgdaily depending on the severity of lesions and patienttolerance. Once remission has been accomplished,therapy may be stopped until recurrence of ulcers. Ifrecurrence occurs, tbe initial regimen should be re-peated until remission, and then a maintenancedosage of 50 to 100 mg daily or 50 mg every other dayshould be attempted. The maintenance dosage shouldbe tapered as much as possible to minimize side ef-fects. Due to the established teratogenic capacity ofthalidomide, strict precautions must be taken inwomen of child-bearing age,"'^ All pafients must un-dergo an extensive educational program prior to drugtherapy according to recommended guidelines,'^''^ Inaddition, due to the risk of peripheral sensory neu-ropathies,"•'^•''•^^ concurrent management with med-ical and neurologic specialists is advised. Baseline sen-sory nerve action potenfiais (SNAP) may be obtainedprior to therapy. Follow-up amplitude decreases

greater tban 40% of baseline values may be used as atiindication for discontinuing thalidomide to preventneuropatby,*'

CONCLUSION

This case report describes an unusual case of major re-current aphtbous stomatitis that was refractory to multi-ple topical and systemic immunosuppressive therapies.Ultimately, thalidomide was selected despite itswell-re cognized adverse potential, and was successful inproducing remission of ulcers. Strict clinical protocolswere followed for this therapy in collaboration with nu-merous medical providers. This case illustrates the abil-ity of mulfiple oral health and medical providers to col-laborate in the diagnosis, management, and follow-up ofa patient with an oral vesiculoerosive disease.

REFERENCES

1. Ship II, Epidemiologic aspects of recurrent aphthous ulcér-ations. Ora) Surg Oral Med Oral Pathol 1972;33:400-406,

2. Kleiriman DV, Swango PA, Niessen LC. Epidemiologie stud-ies of oral mucosal conditions-Methodologie issues. CommDent Oral Epidemiol 1991;19(3):129-140,

3. Field EA, Brookes V, lyideslcy WR. Recurrent aphthous tilcer-ation in ehjIdren-A review, lnt J Paediatr Dent 1992;2:l-10.

4. Pedersen A, Recurrenl aphthous ulcération: Virological andimmunologieal aspects. APMIS 1993;101(37 suppl):l--37.

5. Ship JA. Recurrent aphthous stomatitis-An update. OralSurg Oral Med Oral Pathol Oral Radioi Endod 1996;8l;141-147

6. Woo SB, Sonis ST. Recurrent aphthous ulcers: A review ofdiagnosis and treatment. J Am Dent Assoc 1996;127(8):1202-1213.

7. Rees TD, Binnie WH. Recurrent aphthous stomatitis. DermClin 1996; 14:243-256.

8. MaePhail L. Topical and systemic therapy for recurrent aph-thous stomatitis. Sera Cut Med Surg 1997;I6:301-307

9. Rogers RS 3rd. Recurrent aphthous stomatitis: Clinicalcharacteristics and associated systemic disorders. Sem CutMed Surg 1997; 16:278-283.

10. Eversole LR. Immunopathogenesis of oral lichen planus andrecurrent aphthous stomatitis, Sem Cut Med Surs 1997;16:284-294.

11. Porter SR, Scully C, Pedersen A, Recurrent aphthous stom-atitis. Crit Rev Oral Biol Med 1998;9:306-321.

12. Ship JA, Chavez EM, Doerr PA, Henson BS, Sarmadi M.Recurrent aphthous stomatitis. Quintessence Int 2000;31:95-112.

13. Miller MF, Garfunltel AA, Ram CA, Ship II, The inheritanceot recurrent aphthous stomatitis Ohservations on suscepti-bility. Oral Surg Oral Med Oral Pathoi 1980;49:409-412.

14. Lehner T Autoiramunity in oral diseases, with special refer-ence to recurrent oral ulcération. Proc Royal Soc Med1968;61:515-524.

46 Volume 35, Number 1, 2004

• Sarmadi/Ship

15. Menni S, Imondi D, Brancaleonc W, Croci S. Recurrentgiant aphfhous ulcers in a ehlfd: Protracted treatmenf withthalidomide. Pediatr Derm 1993; 10:283-285.

16. Rybakov AI, Kulikov VS, Terekhova NV. Metabolic reactionin patients with chronic relapsing aphthous stomatitis dur-ing their treafment with prodigiosan. Stomatologia 1975;54{5);8-12.

17. Paterson DL, Georghiou PR, Allworth AM, Kemp RJ.Thalidomide as treatment of refractory aphthous ulcérationrelated to human immunodeficiency virus infection. Clinlnfeet Dis 1995-,20:250-254.

18. MacPhail LA, Greenspan jS. Oral ulcération in HIV infec-tion: investigation and pathogenesis. Oral Diseases 1997;3(suppl l):S190-S193.

19. Rodenas JM, Ortego N, Herranz MT, Tercedor J, Pinar A,Quero JH. Cyclic neutropenia: A cause of recurrent aphf-hous stomatitis nol to be missed. Dermatology 1992;184:205-207.

20. Verpilleux fWP, Bastuji-Garin S, Revuz J. Comparativeanalysis of severe aphthosis and Behcet's disease: 104 cases.Dermatology 1999; 198:247-251.

21. Rizzi R, Bruno S, Dammacco R. Behcet's disease: An im-mune-mediated vascuhtis involving vessels of all sizes, lnt JClin Lab Res 1997;27(4):225-232.

22. Ghate JV, Jorizzo JL. Behcet's disease and complex aphtho-sis. J Am Acad Derm I999;40:l-18.

23. Maeda K, Okada M, Yao T, et al. Intestinal and extraintesti-nal complications of Crohn's disease: Predictors and cumula-tive probability of complications. J Gastro 1994;29:577-582.

24. Rehherger A, Puspok A, Stalhneister I , Jurecka W, Wolf K.Crohn's disease masquerading as aphlhous ulcers. Eur JDennl998;8(41:274-276.

25. Lorini R, Scaramuzza A, Vitali L, et al. Clinical aspects ofcoeiiac disease in children with insuhn-dcpcndent diabetesmellitus. J Pediatr Endo Metab 1996;9(suppl 1):1OI-111.

26. Skoglund A, Sunzel B, Lemer UH. Comparison of three testmethods used for the diagnosis of candidiasis. Scand J DentResl994;102(5):295-298.

27. Vazquez H, Cabanne A, Sugai E, et ai. Serological markersidentify histologically latent coeiiac disease among first-de-gree relatives. Eur J Gastro Hep 1996;8:15-21.

28. Maki M, Sulkanen S, CoUin P. Antibodies in relation togluten intake. Dig Dis 1998 ;16(6) :330-332.

29. Klein BS, Vergeront JM, Kaufman L, et a). Serologicai testsfor blastomycosis: Assessments during a large point-sourceoutbreak in Wisconsin. J Infect Dis 1987; 155:262-268.

30. Gonzalez C, Martin T, Arroyo T, Garcia-Isidoro M, Navajo JA,Gonzalez-Buitrago JM. Comparison and variation of differentmethodologies for the detection of autoantibodies to nuclearantigens (ANA]. J Clin Lab Analysis 1997;11:388-392.

31. Cordiali Fei P, D'Agosto G, Ameglio F, ef al. Determinationof antibodies to extractable nuclear antigens by commercialkits: A multicenter study. Int J Clin Lab Res 1998;28:29-33.

32. Reddel SW, Krilis SA. Testing for and clinical significance ofanticardiolipin antibodies. Clin Diag Lab Immun 1999;6:775-782.

33. Dieterich W, Laag E, Bruckner-Tuderman L, et al.Antibodies to tissue transglutaminase as seroiogic markersin patients with dermatitis herpetiformis. J Invest Derm1999;U3:133-I36.

34. Chaidemenos GC, Maltezos E, Chrysomallis F, et al. Valueof routine diagnostic criteria of bullous pemphigoid. Int JDerm 1998;37:206-210.

35. Lockhart PB. In hospital care of dental patient. OralMedicine and Hospital Practice, ed 4. Chicago: Federationof Special Care Organizations in Dentistry, 1997:2-1-2-65.

36. Gomella LG, Haist SA, Billeter M. Clinician's PocketReference, ed 8. Stamford, CT: Appleton and Lange, 1997

37 Todd P, Samarafunga IR, Pembroke A. Screening for glu-cose-6-phosphafe dehydrogenase deficiency prior to dap-sone therapy. Clin Exp Derm 1994;19:217-218.

38. Briggs JD. A critical review of immunosuppressive therapy.Immunol Ltr 1991;29(l-2):89-94.

39. Aranda-Michel }, Sherman KE. Tests of the liver: Use andmisuse. Gastroenterologist 1998;6:34-43.

40. Scheig R. Evaluation of tests used to screen patienfs withliver disorders. Prim Care Clin Off Pract 1996;23:551-560.

41. Johnston DE. Special considerations in interpreting liverfunction tests. Am Fam Phys 1999;59:2223-2230.

42. Glick M. Glucocorticosteroids. ¡n: Ciancio SG (ed) ADAGuide to Dental Therapeutics, ed 2. Chicago- ADAPublishing, 1999.

43. Wolverton SE. Glucocorlicosteroids. In: Wolverton SE,Wilkin JK ¡eds]. Systemic Drugs for Sidn Diseases. Phila-delphia: Saunders, 1991:86-124.

44. Palopoli J, Waxman J. Recurrent aphthous stomatitis and vi-tamin B12 deficiency. S Med J 1990 ;83:475-477

45. Nolan A, Mclntosh WB, Allam BE, Lamey PJ. Recurrentaphtbous ulcération: Vitamin Bl. B2 and B6 stafus and re-sponse ta replacement therapy. ] Oral Pathol Med 1991;20{8):389-391.

46. Haisraeli-Shalish M, Livneh A, Katz J, Doolman R, Sela BA.Recurrent aphthous stomatitis and thiamine deficiency. OralSurg Oral Med Oral Pathol Oral Radiol Endod 1996;82T634-636.

47. Lear JT, English JS. Erosive and generalized lichen planusresponsive to azathioprine. Clin Exp Derm 1996;21:56-57

4S. Roloy P, Sigurjonsdottir HA, Remotfi H, et al. Role of im-munosuppressive therapy in refractory sprue-iike disease.Am J Gastro 1999:94:219-225.

49. Mangelsdorf HC, White WL, Jorizzo JL. Behcet's disease.Report of twenty-five patients from the United States withprominent mucocutaneous involvement. J Am Acad Derm1996;34(5 Pf l):745-750.

50. Sun A, Chiang CP, Chiou PS, Wang JT, Liu BY, Wu YC.Immunomodulation by levamisole in patients with recurrentaphtbous ulcers or oral lichen planus. J Orai Pathol Med1994;23(4):172-177

51. Diaz-Llopis M, Cervera M, Menezo JL. Cyclosporin A treat-menf of Bebcet's disease: A long-term study. Current EyeRes 1990;9:17-23.

52. Cbandrasekhar J, Liem AA, Cox NH, Paterson AW.Oxypentifylline in the management of recurrent aphthousoral ulcers: An open i:hnical trial. Oral Surg Oral Med OralPathol Oral Radiol Endod 1999:87:564-567

53. Jacobson JM, Greenspan JS, Spritzler ], et al. Thalidomidefor the treatment of oral aphfhous ulcers in patients witbhuman immunodeficiency virus infection. N Engl ] Med1997;356(21):1487-1493.

54. Jacobson JM, Spritzler J, fax L, et al. Tbalidomide for thetreatment of esophageal aphthous ulcers in patients withhuman immunodeficiency virus infection. National Instituteof Allergy and Infectious Disease AIDS Clinical TrialsGroup. J Infect Dis 1999;180:61-67

Quintessence international 47

• Sarmadi/Ship

55, United States Food and Drug Administration, ThalidomideInformation. Center for Drug Evaluation and Research2000. Available at: http;//www,fda,gov/cdcr/ncws/thalinfo/defaulthtm Accessed 10 Sept 2003.

56, Celgene, Thalidomide, Celgene Corporation 2000. Availableat; http;//www,celgene,com/CelgeneN2,nsf/Weh-i-Pages/home Accessed 10 Sept 2003.

57, Atra E, Sato El, Treatment of the cutaneous lesions of sys-temic lupus erythematosus with thalidomide. Clin ExperRheum 1993;n;487-493.

58, Wulff CH, Hoyer H, Asboe-Hansen G. tirodthagen H.Development of poly neuropathy during thalidomide ther-apy. Brit J Derm 1985;112:475-480,

59, Schüler U, Ehninger G, Thalidomide: Rationale for reneweduse in immunological disorders. Drug Safety 1995;12:364-369.

60, Glick M, Muzyka BC, I.urie D, Salldn LM. Oral manifesta-tions associated with HIV-related disease as markers for im-mune suppression and AIDS, Oral Surg Oral Med OralPathol 1994;77:344-349.

61, MacPhail LA, Greenspan D, Feigal DW, Lennette ET,Greenspan JS, Recurrent aphthous ulcers in associationwith HIV infection. Description of ulcer types and analysisof T-lymphocyte suhsets, Orai Surg Oral Med Oral Pathol1991;71:678-6S3.

62, MacPhail LA, Greenspan D, Greenspan JS. Recurrent apht-hous ulcers in association with HIV infection. Diagnosis andtreatment. Oral Surg Oral Med Oral Pathol 1992;73:283-288,

63, Bachtiar EW, Comain S, Siregar B, Raharjo TW. DecreasedCD4+/CD8-I- ratio in major type of recurrent aphthous ul-cers: Comparing major to minor types of ulcers, Asian Pac JAllei^ Immunol 1998:16(2-3):75-79.

64, Pedersen A, Ryder LP. Gamma delta T-cell fraction of pe-ripheral blood is increased in recurrent aphthous ulcération.Clin Immunol Immunopathol 1994;72:98-104,

65, Taylor LJ, Bagg J, Walker DM, Peters Tj, Increased produc-tion of ttimour necrosis factor hy peripheral hlood leuko-cytes in patients with recurrent oral aphthous ulcération, JOral Pathol Med 1992 ;21:21-25,

66, Phelan |A, Eisig S, Freedman PD, Newsome N, IOein RS.Major aphthous-like ulcers in patients witii AIDS, OralSurg Oral Med Oral Pathol 1991;71:68-72

67, Lozada-Nur F, Huang MZ, Zhou GA. Open preliminaryclinical trial of clobetasoi propionate ointment in adhesivepaste for treatment of chronic oral vesiculoerosive diseases.Oral Surg Oral Med Oral Pathol 1991 ;71:283-287.

68, LaRochelle GE Jr, LaRochelle AG, Ratner RE, BorensteinDG, Recovery of the hvpothalamic-pitiiitary-adrenal {HPA)axis in patients with rheumatic diseases receiving low-doseprednisone. Am J Med 1993;95:258-264,

69, Friedman RJ, Schiff CF, Bromberg JS, Use of supplementalsteroids in patients having orthopaedic operations, J BaneJoint Surg Am 1995;77(12);1801-1806,

70, Abdu TA, Elhadd TA. Neary R, Clayton RN, Comparison ofthe low dose short synacthen test (1 micro"), the conven-tional dose short synacthen test [250 micro"), and the in-sulin tolerance test for assessment of the hypothalamo-pitu-itary-adrenal axis in patients with pituitary disease, J ClinEndod Metah I999;84:838-843,

71, Muzyka BC, Glick M, Major aphthous ulcers in patientswith HIV disease. Oral Surg Oral Med Oral Pathol 1994;77:116-120.

72, Lehner T, Wilton JM, Ivanyi L, Double blind crossover trialof levamisole in recurrent aphthous ulcération. Lancet1976;2[7992):926-929,

73, Van de Hayning J, Levamisole in the treatment of recurrentaphthous stomatitis. Laryngoscope 1978;88(3):522-527

74, Meyer JD, Degraeve M, Clarysse J, De Loose F, PeremansW, Levamisole in aphthous stomatitis: Evaluation of threeregimens, BritMedJ 1977;l(6062):671-674,

75, Kaplan B, Cardarelh C, Pinnell SR. Double-blind study otlevamisole in aphthous stomatitis. J Oral Pathol 1978;7(6);400-404,

76, Zissis NP, Hatzioti AJ, Antoniadis D, Ninika A, HatziotisJC, "ITierapeutic evaluation of levamisole in recurrent apht-hous stomatitis. Double-blind comparison of two dosageschedules of levamisole and placebo, J Oral Med 1983;38(4);161-163,

77 Olson JA, Silverman S Jr, Double-blind study of levamisoletherapy in recurrent aphthous stomatitis. J Oral Pathol1978;7:393-399,

78, Miller M¥, Silvert ME, Laster LL, Green P, Ship II, Effect oflevamisole on the incidence and prevalence of recurrentaphthous stomatitis, A doubie-blind clinical trial, J OralPathol 1978;7:387-392,

79, Drinnan AJ, Fischman SL, Randomized, double-blind studyof levamisole in reeurrent aphthous stomatitis, J Oral Pathol1978;7:414-417

80, Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M,Inaha G, Double-masked trial of cyclosporin versuscolehicine and long-term open study of cyelosporin inBehcet's disease. Lancet 1989:l(8647):1093-1096,

81, Wahba-Yahav AV, Pentoxifylline in intractable recurrentaphthous stomatitis. J Am Acad Derm 1995;33;680-682.

82, Grinspan D, Significant response of oral aphthosis to thalido-mide treatment, J Am Acad Derm 1985;12(1 Ptl):85-90,

83, Grinspan D, Blanco GF, Agüero S. Treatment of aphthaewith thalidomide, J Am Acad Derm 1989;20Í6):1060-1063,

84, Revuz J, Guillaume JC, Janier M, et al. Crossover study cftbalidomide vs placebo in severe recurrent aphthous stom-atitis. Arch Derm 1990; 126:923-927

85, Gardner-Medwin JM, Smith NJ, Powell RJ, Clinical experi-ence with thalidomide in the management of severe oraland genital ulcération in conditions such aa Behcet's dis-ease: Use of n euro physiological studies to detect thalido-mide neuropathy, Ann Rheum Dis 1994;53íl2):828-832,

86, Bonnetblanc JM, Royer C, Bédane C, Thalidomide and re-current aphthous stomatitis: A follow-up study. Derma-tology 1996;193(4):321-323,

87 Nasca MR, O'Toole EA, Palicharla P, West DP, WoodleyDT, Thalidomide increases human keratinocyte migrationand proliferation, J Invest Derm 1999;113:720-724,

88, Weidle PJ, Thalidomide for aphthous ulcers in patients in-fected with the htiman immunodeficiency virus. Am ]Health Sys Pharm 1996 ;53:371-372,

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