Vol. 119 No. 1 January 2015

Adverse drug events in the oral cavity

Anna Yuan, DMD,a,b and Sook-Bin Woo, DMD, MMSca,b

Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity.

Targeted therapies and the new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and

inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. Some examples

include osteonecrosis, seen with not only bisphosphonates but also antiangiogenic agents, and the distinctive ulcers caused by

mammalian target of rapamycin inhibitors. As newer therapeutic agents are approved, it is likely that more adverse drug events

will be encountered. This review describes the most common clinical presentations of oral mucosal reactions to medications,

namely, xerostomia, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, white lesions,

dysesthesia, osteonecrosis, infection, angioedema, and malignancy. Oral health care providers should be familiar with such

events, as they will encounter them in their practice. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:35-47)

A multitude of medications that patients take to controldisease also exposes them to the risk for developingreactions to the medications. One definition put forwardby Edwards and Aronson in 2000 for “adverse drugreaction” is “an appreciably harmful or unpleasant re-action, resulting from an intervention related to the useof a medicinal product, which predicts hazard fromfuture administration and warrants prevention or spe-cific treatment, or alteration of the dosage regimen, orwithdrawal of the product.”1 This definition attempts toaddress several important issues related to “appreciableharm and unpleasantness” and excludes minor re-actions, addresses the issue of medication error, ad-dresses injury from nonpharmaceutical agents(including contaminants and inactive ingredients), anddoes not assign disease mechanism. The authors make adistinction between an adverse effect (adverse outcomeattributed to an action of the drug) and an adverse event(adverse outcome that occurs when a patient is on thedrug but that may not be caused by the drug).1

The term used currently that satisfies both regulatorybodies as well as patient safety advocates is “adversedrug event” which includes (1) harm caused by a drug(commonly known as adverse drug reaction), (2) harmcaused by appropriate drug use (usually referred to as aside effect), and (3) medication errors.2 This review willfocus on common adverse drug events (ADEs), asdefined by Nebeker et al.2 from a clinical perspective.Most fall under the category of side effects, although

Portions of this were presented at the Jonathan A. Ship Lecture at theannual meeting of the American Academy of Oral Medicine in 2013in San Antonio, Texas.aDivision of Oral Medicine, Brigham & Women’s Hospital, Boston,Massachusetts.bDepartment of Oral Medicine, Infection and Immunity, HarvardSchool of Dental Medicine, Boston, Massachusetts.Received for publication Jun 4, 2014; returned for revision Aug 18,2014; accepted for publication Sep 10, 2014.� 2015 Elsevier Inc. All rights reserved.2212-4403/$ - see front matterhttp://dx.doi.org/10.1016/j.oooo.2014.09.009

whether the patients were significantly harmed by theevent is probably subject to interpretation. Although theterm “medication” is preferred over “drug,” we areusing the term ADE because it is the convention.

Diagnosis is based on history and chronology of theadverse oral reaction. Typically, these changes aredetected within weeks or months after taking themedications. Some lesions, such as lichenoid drugreactions, may present asymptomatically initially butbecome symptomatic years later, making the rela-tionship between start of drug use and development ofADE difficult to ascertain. The presence of the oralcondition predating the administration of the medi-cation must be excluded, and this may be difficult todetermine if the patient has not seen a health careprovider in a long time. Resolution should occur afterdiscontinuation of the suspected medication, althoughthis may necessitate the use of topical corticosteroidsfor inflammatory conditions. Recurrence withrechallenge confirms the diagnosis, although this maynot be feasible if the ADEs are unpleasant, severe, orlife-threatening. Concurrent medications must benoted.

The benefits of using any particular medication must,of course, always be weighed against the side effects,and some considerations include the necessity for themedication and availability of substitute agents, howsevere the side effects are (e.g., asymptomatic oralpigmentation vs highly morbid necrolytic syndromes),

Statement of Clinical Relevance

Adverse drug events in the oral cavity are commonand will likely increase as newer therapeutic agentsare approved. Health care providers should famil-iarize themselves with such events. This review de-scribes common and uncommon oral mucosalreactions to medications.

35

Table I. Drug-induced oral reactionsHyposalivation/xerostomiaLichenoid reaction/lichen planusAphthous-like ulcersBullous disordersPigmentationFibrovascular hyperplasiaKeratosis/epithelial hyperplasiaDysesthesiaOsteonecrosis of the jawsInfectionAngioedemaMalignancy

Fig. 1. Hyposalivation from polypharmacy.

ORAL MEDICINE OOOO

36 Yuan and Woo January 2015

the frequency of occurrence of such ADEs, whether theADE can be eliminated by lowering the dose, andwhether the ADE may be easily treated.1,2

Drug-induced cutaneous reactions are common andvaried in presentation, but only a limited number ofreaction patterns occur in the oral cavity. This is likelydue to the higher turnover rate in the oral mucosacompared with that on the skin, and this does not alloweasy detection of the spectrum of subtle clinicalchanges on the skin. The oral lesions to be discussedfall into several categories (Table I).

HYPOSALIVATION/XEROSTOMIAMedication use is one of the most common causes ofboth xerostomia and hyposalivation. Many middle-agedand older patients in the United States are on multiplemedications (“polypharmacy”), and even medicationswith small anticholinergic effects may act synergisti-cally in combination to cause oral symptoms of drynessand discomfort (Figure 1). Dry mouth is listed as anadverse effect for over 500 medications.3 In a system-atic review, xerostomia was reported to be one of themost common oral adverse effects associated with over80% of the 100 most prescribed medications in theUnited States.4 The most frequently reported medica-tion classes that result in hyposalivation are antide-pressants, antipsychotics, antihistamines, muscarinicreceptor and a-receptor antagonists, antihypertensives(e.g., diuretics, b-blockers, and angiotensin-convertingenzyme [ACE] inhibitors), bronchodilators, and skeletalmuscle relaxants.3,5 Other culprits include chemo-therapy agents, appetite suppressants, decongestants,antimigraine drugs, opioids, benzodiazepines, hyp-notics, histamine 2 (H2) receptor antagonists and protonpump inhibitors, systemic retinoids, antiehuman im-munodeficiency virus medications, and cytokinetherapy.3,5

A study of 601 patients reported that older in-dividuals were almost three times more likely to reportxerostomia, and patients taking one or more drugs were

more than twice as likely to do so compared withmedication-free patients; this prevalence increased withincreasing number of medications used (16.7% of pa-tients reported xerostomia with one medication daily vs33.3% with two to three medications daily vs 36.9% atgreater than three medications daily).6 Persistenthyposalivation can lead to infections, such as candidi-asis and dental caries, as well as bacterial sialadenitis.7

The loss of lubrication also results in erythema andsusceptibility of the mucosa to frictional trauma againstteeth; discomfort and burning may be profound.

LICHENOID REACTION/LICHEN PLANUSOne of the most common inflammatory conditionsaffecting the skin and oral mucosa is lichen planus (LP).LP is an immune-mediated process, where T cellsmediate the destruction of the basal cells of theepithelium.8 Oral LP presents as white striations orpapules often associated with erythema or erosion andulcers, most commonly in a bilaterally symmetricmanner, often on the buccal mucosa, tongue, andgingiva.9 Many medications are known to cause cuta-neous lichenoid hypersensitivity reactions (LHRs),which are often difficult to distinguish clinically andhistopathologically from idiopathic cutaneous LP.10,11

Cutaneous LHRs present as skin eruptions character-ized by purplish, pruritic keratotic papules and plaques,usually without the classic Wickham striae, on the trunkand extremities instead of the flexural regions.11-13 Ithas been postulated that active thiol groups found in thechemical structure of such medications as piroxicam,sulfasalazine, and glipizide play a role in inciting suchreactions.14,15 It is, therefore, likely that these same

Fig. 2. Lichenoid tissue reaction from rituximab.

OOOO REVIEW ARTICLE

Volume 119, Number 1 Yuan and Woo 37

medications may cause an oral LHR and that it canresemble idiopathic oral LP (Figure 2).

The two classes of medications historically associ-ated with oral LHRs are nonsteroidal anti-inflammatorydrugs (NSAIDs) and antihypertensive agents, includingb-blockers, ACE inhibitors, and diuretics (in particularhydrochlorothiazide).7,16,17 Sulfonylurea antidiabeticmedications (e.g., tolbutamide and glipizide), antifun-gals (e.g., ketoconazole), anticonvulsants (e.g., carba-mazepine), immunomodulatory drugs (e.g., gold saltsand penicillamine), sulfasalazine, allopurinol, andlithium have been reported to elicit oral LHRs.18,19 Ofhistorical interest, Grinspan syndrome was introducedat the 1963 Congress of Dermatology as a clinicalpresentation of a triad of oral LP, diabetes mellitus, andhypertension; it is now generally accepted that drugtherapy for hypertension in particular and likely dia-betes mellitus is capable of provoking oralLHRs.11,20,21

One theory regarding the pathogenesis of LHRs isthat susceptible patients have polymorphisms of thecytochrome P450 enzymes (CYPs), which results inpoor or intermediate CYP metabolism of some medi-cations. One group of investigators reported higherCYP2-D6 among females (P > .05) and higher CYP2-D6*4 among patients with oral LP (50%) versus thosein the general population (30%), although this is ofquestionable clinical significance.22,23

It is often difficult to reach a consensus on diagnosticcriteria, in part due to the fact that LHRs, once well-established, may persist after cessation of the drugunless rigorously treated. However, McCartan et al.suggested that a history of the current use of an LHR-inducing medication in combination with consistenthistopathology is likely sufficient, although the authorsalso suggested that testing for the presence of circu-lating basal cell cytoplasmic autoantibodies may behelpful.24,25

LP has been associated with thyroid disease inseveral studies. Siponen et al. reported that 15% and

13% of patients with oral LP and oral lichenoid lesions,respectively, had thyroid disease compared with 8% ofcontrols.26 This raises the question of whether the le-sions result from the disease or from the medicationsused to treat the disease. A subsequent study found thatpatients with oral LP were 3.4 times more likely to betaking levothyroxine than not (P ¼ .001).27 Lo Muzioet al. noted that oral LP occurred in 14.3% of patientswith Hashimoto thyroiditis versus 1% of the generalpopulation.28

Several other classes of medications are also asso-ciated with the development of cutaneous LP or LHRs.3-hydroxy-3-methylglutaryl-coenzyme A inhibitors,such as pravastatin, simvastatin, fluvastatin, and lova-statin, have been implicated in causing cutaneous LHRswith mucosal involvement.29-31 The tyrosine kinaseinhibitor imatinib has been implicated in LHRs,particularly in the oral cavity.32-36 In a study of thearomatase inhibitor letrozole used for breast cancer,32.4% of patients were noted to have an adverse cuta-neous reaction, and another group reported that 16patients (0.9%) developed lichenoid keratosis over an8-year study period.37,38 Antituberculosis drugs, suchas ethambutol, pyrazinamide, isoniazid, and rifampicin,also have been reported to cause cutaneous LHRs.39-41

A recent case report noted an association betweenantituberculosis medications and hyperpigmentedmacules and lichenoid papules in the oral cavity; theselesions were bilateral and symmetric, but classic LPreticulations were absent.42

Biologic agents are being used with increasing fre-quency for the management of rheumatoid arthritis,ankylosing spondylitis, and psoriatic arthritis and inoncology, and reports of LHRs have begun to appear inthe literature. The novel anti-CD20 monoclonal anti-body obinutuzumab was reported to cause LHRs on theskin and oral ulcers.43 Asarch et al. reported two casesof oral LP (more accurately, LHRs) in patients takingtumor necrosis factor alpha (TNF-a) inhibitors inflix-imab and adalimumab and 12 cases involving the TNFreceptor fusion proteins etanercept and abatacept.44

Infliximab and certolizumab used to treat Crohn diseasehave both been linked to biopsy-proven oral LP.45,46

This seems paradoxical, since oral LP is mediated byTNF-a. However, it has been suggested that there maybe upregulation of interferon alpha when TNF-alpha isinhibited.44 Interferon alpha then activates T cells anddendritic cells, causing an inflammatory response.44,47

Fixed drug eruptions (FDEs) in the oral cavity arelesions that recur at the same site each time theoffending medication is taken.48 Oral mucosal lesionsare infrequently reported and can be accompanied byskin or genital involvement.49,50 The presentation canrange from bullous to erosive, hyperpigmented, pruitic,or erythematous lesions.49 A number of first- and

Fig. 3. Sirolimus-induced aphthous-like ulcers. Fig. 4. Methotrexate-induced oral ulcer.

ORAL MEDICINE OOOO

38 Yuan and Woo January 2015

second-generation antihistamines have been known tocause FDEs on the skin.51,52 The third-generationantihistamine levocetirizine was reported in a case ofFDE involving the oral (lower lip and tongue) andgenital tissues (glans penis).53 Use of acetaminophenwas reported to result in erythematous and papularFDEs on the hard palate and skin; naproxen and oxi-cams have caused lesions on the lips48,54; and flucon-azole has caused lesions of the palatal mucosa and oralbullae.55,56 Co-trimoxazole, oxyphenbutazone, tetracy-cline, clarithromycin, and gabapentin have also beenimplicated in the occurrence of oral FDEs.50,57,58

Fig. 5. Ulcerative mucositis secondary to chemotherapy.

APHTHOUS-LIKE AND NONeAPHTHOUS-LIKE ULCERSIdiopathic aphthous ulcers usually begin in the first twodecades of life and appear as ovoid to round ulcersusually 1 cm or less with a yellowish fibrinous mem-brane and surrounding erythema involving the non-keratinized mucosa.5 “Aphthous-like” or aphtheiformulcers is the term used for oral ulcers where there is aknown etiology, as these resolve when the underlyingetiology is effectively managed.

NSAIDs were one of the earliest classes of drugsassociated with the development of aphthous-like ulcersin the oral cavity.59-61 Piroxicam, in particular, wasshown to cause such ulcers, possibly because it containsa thiol group.5,60,62,63 Naproxen, trimethoprim-sulfa-methoxazole, cyclooxygenase-2 inhibitors (e.g., refe-coxib), and the angiotensin receptor blocker losartanhave been implicated in the development of aphthous-like ulcers.49,64,65

More recently, aphthous-like ulcers have beendocumented in patients with metastatic tumors treatedwith mammalian target of rapamycin inhibitors,including sirolimus, temsirolimus, everolimus, andridaforolimus (Figure 3).66-68 However, unlike idio-pathic recurrent aphthous ulcers, on withdrawal oftherapy, these regress completely without recurrence.

Conventional chemotherapy agents, such as 5-fluo-rouracil, cisplatin, methotrexate, and hydroxyurea, arestomatotoxic and cause oral ulcers and ulcerativemucositis (Figure 4).69-71 These ulcers tend to be largerand more diffuse and do not have the ovoid, well-demarcated appearance of aphthous ulcers (Figure 5).

Mycophenolate mofetil has been reported to causeulcers on the tongue, palate, labial mucosa, and gingivain recipients of solid organ transplants, but these ulcersresolve on cessation of medication, as in the case oftacrolimus.72-77 Rare cases of ulcers associated withmultitargeted kinase inhibitors (MTKIs) have beenreported.78

BULLOUS DISORDERSMedication-induced autoimmune bullous disorders ofthe skin are not uncommon, whereas such disorderspresenting in the oral cavity are rare. The developmentof simultaneous oral and cutaneous pemphigus vulgarishas been noted with the use of thiol radicalecontainingdrugs,64,79,80 such as penicillamine81,82 and NSAIDs(see Figure 4).83 Cutaneous bullous pemphigoid hasbeen associated with antipsychotic medications,spironolactones, and sulfonamides.80,84-86 Lupus

Fig. 6. Palatal mucosal pigmentation associated withimatinib.

OOOO REVIEW ARTICLE

Volume 119, Number 1 Yuan and Woo 39

erythematosus of the skin has been observed in patientsusing procainamide, hydralazine, and biologic agents,such as anti-TNF inhibitors.87-89

Erythema multiforme (EM), major or minor, canaffect both the skin and mucous membranes. It presentsas irregular oral ulcers with diffuse erythema and targetlesions of the skin. It is a hypersensitivity reaction, mostcommonly to an infectious agent, such as herpes sim-plex virus and less commonly to Mycoplasma pneu-monia in children; approximately 18% of casesrepresent hypersensitivity reactions to medications.90-92

EM of the skin and oral mucous membranes has beenreported with the administration of infliximab andadalimumab.93,94

Steven Johnson syndrome (SJS) and toxicepidermal necrolysis (TEN) are severe necrolytic hy-persensitivity reactions, which, unlike EM, are muchmore commonly associated with the use of medica-tions and may be life-threatening.92 SJS and TENalmost always involve the mucous membranes of themouth, eye, and genitalia, sometimes extensively.Antimicrobials (amoxicillin/clavulanic acid)95 andanticonvulsants (phenytoin and lamotrigine) have beenimplicated.96,97 In the Han Chinese populations, SJSand TEN caused by anticonvulsants, such as pheno-barbital, phenytoin, and carbamazepine, are associatedwith HLA-B*1502 (odds ratio [OR] 1357), whereasreactions to allopurinol are associated with HLA-B*5801 (OR 580).98-100 In the Thai population, car-bamazepine is also associated with SJS and TEN in alarge number of patients (OR 75).99 In Europeans, SJSand TEN caused by sulfamethoxasole has been asso-ciated with HLA-B*38, NSAIDs with HLA-B*73,101

and HIV-1 reverse-transcriptase inhibitor abacavirwith HLA-B*5701.102 Other drugs implicated includelamotrigine, phenytoin, phenobarbital, lenalido-mide103; co-trimoxazole, sulfonamides, sulfasalazine,and oxicam104,105; nivirapine106; transexamic acid107;and rituximab.108

PIGMENTATIONMetabolites of such medications as the tetracyclines,minocyclines, antimalarial drugs (e.g., hydroxy-chloroquine, mepacrine, and quinacine), and phenazinedyes (e.g., clofazimine) may be deposited in the oralmucosa. Such drug metabolites chelate with iron andmelanin, which results in pigmentation of the hardpalatal mucosa, and have a specific histopathology(Figure 6).109-113 Tetracycline and minocycline are alsodeposited in teeth, bones, thyroid, and sclera and causemucosal and nail pigmentation.114,115 The tyrosine ki-nase inhibitor imatinib, used to treat chronic myeloge-nous leukemia and acute lymphoblastic leukemia, cancause hyper- or hypopigmentation of the skin, hyper-pigmentation of nails, and diffuse blue-gray pigmenta-tion on the palatal mucosa, with similar characteristichistopathology.116,117 It is unclear whether second-generation tyrosine kinase inhibitors such as dasatinib,nilotinib, and bosutinib will have the same effect.

Other medications that have been noted to cause oralmucosal pigmentation are zidovudine (on thetongue)118,119; oral contraceptives (on the maxillary andmandibular gingiva)120; and chemotherapy agents, suchas such as doxorubicin, docetaxel, and cyclophospha-mide (on the tongue dorsum, buccal mucosa, andnails).121-123 Pigmentation of the facial skin has beennoted with the use of amiodorone and phenothiazines(chlorpromazine).124,125 Stimulation of melanocyteswithout metabolite deposition is postulated to be themechanism, and, interestingly, pigmentation does notoccur on the palatal mucosa.

FIBROVASCULAR HYPERPLASIACalcium channel blockers, in particular, nifedipine andamlodipine, are antihypertensive agents that inducehyperplasia of the gingival tissues.126,127 This presentsas a diffuse, generalized, often nodular overgrowth ofdensely fibrous gingival tissue. The resulting gingivalenlargement is exacerbated by plaque-induced inflam-mation, and there may be a genetic predisposition.128 Ithas been suggested that the mechanism is due todecreased cellular folic acid uptake leading to decreasedactivity of matrix metalloproteinases and the failure toactivate collagenase.129-131

Calcineurin inhibitors, such as cyclosporine or, lessfrequently, tacrolimus, also induce inflammatory fibro-vascular hyperplasias in the oral cavity. However, thesepresent as localized polypoid fibrous tumors and aremore often seen on the tongue and buccal mucosa ratherthan on the gingiva (Figure 7).132,133 The increasedproduction of collagen is thought to be due to both thereduced activity of matrix metalloproteinases and theincreased activity of tissue inhibitors of metal-loproteinases.134-136 It has also been proposed that

Fig. 7. Fibrovascular hyperplasia with ulceration associatedwith tacrolimus.

ORAL MEDICINE OOOO

40 Yuan and Woo January 2015

phenytoin and cyclosporine cause an increase in theexpression of interleukins (IL-1, IL-6), which mayinduce oral mucosal mesenchymal stem cells todifferentiate toward a pro-fibrotic phenotype.137-139

KERATOSIS/EPITHELIAL HYPERPLASIAPalifermin is a recombinant keratinocyte growth factordelivered intravenously to reduce the incidence andseverity of mucositis related to autologous hematopoi-etic stem cell transplantation, chemotherapy, andradiotherapy.140,141 It has been associated with mouthor tongue thickness and white discoloration in 17% ofpatients.142 The diffuse, thickened white plaquesobserved in the mouth as a response to palifermin arelikely due to increased thickness of the oral epitheliumand/or keratin layer as a result of the proliferation ofepithelial cells.143

DYSESTHESIASOral dysesthesias, such as sensitivity, burning, dysgeu-sia, and other altered sensations without clinical signs,may be caused by medications. It must be noted thatdysgeusia can be secondary to hyposalivation instead ofbeing the direct effect of a drug.144 Damage to the sali-vary glands reduces the production of saliva, the solutionin which chemoreceptors in the taste buds of the tonguebind their receptor molecules.145 A study on dysgeusiaand dysosmia was reported for several drug classes,including macrolides, such as clarithromycin (17%);antimycotics, such as terbinafine (9%); and fluo-roquinolones (8%), as well as protein kinase inhibitors,ACE-inhibitors, statins, and proton pump inhibitors (3%-5% each).146 The mechanism is multifactorial and maybe a combination of drugereceptor inhibition, alterationof neurotransmitter function, disturbance of action po-tentials in neurons, and dysfunctional sensory modula-tion in the brain.146,147 Vismodegib, a first-in-class,small-molecule inhibitor of the hedgehog pathway

produced dysgeusia in 51% of participants in a phase 1trial for management of advanced basal cellcarcinomas.148

Neurologic complications of chemotherapy are welldescribed in the literature. The pathobiology of pe-ripheral neuropathy is complex and could be attributedto neuronopathy, axonopathy, myelinopathy, andintraepidermal nerve fiber degeneration.149 Chemo-therapy-associated peripheral neuropathies are oftenassociated with the use of taxanes,150 platinum com-pounds, thalidomide, bortezomib,151 and vinca alka-loids, such as vincristine and vinblastine.152-155

MTKIs (e.g., sunitinib and sorafenib) downregulate avariety of receptors, including vascular endothelialgrowth factor (VEGF), platelet-derived growth factor,fibroblast growth factor, c-kit, FMS-like tyrosine kinase3 (FLT-3), BRAF, and RET. The development of oraldysesthesias is significantly associated with the devel-opment and severity of palmareplantar eryth-rodysesthesia in patients on MTKIs.156,157 A study ofover 200 patients reported “stomatitis” symptoms in26% of patients on sorafenib and in 36% of patients onsunitinib in the absence of oral findings.157 Koll-mannsberger et al. reported oral toxicities in up to 60%of patients and noted that the type of “stomatitis”observed was characterized by oral mucosal sensitivity,taste changes, and xerostomia without noticeablephysical changes.158 They may fall within the spectrumof burning mouth syndrome or oral dysesthesiadisorders.

OSTEONECROSIS OF THE JAWSBisphosphonates and denosumab (monoclonal antibodyagainst receptor activator of nuclear factor kappa-Bligand) are antiresorptive medications that markedlyslow bone turnover and remodeling and therefore in-crease bone density; they are used to treat post-menopausal osteoporosis and reduce skeletal-relatedevents during cancer therapy (e.g., for plasma cellmyeloma and metastatic cancers).159-161 Osteonecrosisis an ADE presenting as either exposed bone or anonhealing extraction socket (Figure 8).162-164 A stage0 variant exists where bone is not exposed.159,165,166

Bisphosphonates also exhibit antiangiogenic activ-ity.167 Antiangiogenic agents, such as bevacizumab andsunitinib, which act againstVEGF, either used alone or incombination with bisphosphonates, also lead to thedevelopment of osteonecrosis in some patients.168-173 Infact, higher incidences of osteonecrosis have been seenwith combination of such anti-VEGF therapies andbisphosphonates thanwith bisphosphonates alone.174-177

It is unclear whether mammalian target of rapamycininhibitors alone may cause osteonecrosis, since it hasbeen recently reported that patients who developed thiscondition had also been on intravenous bisphosphonates

Fig. 9. Candidiasis from topical steroid therapy.Fig. 8. Osteonecrosis of the jaw associated with denosumab.

OOOO REVIEW ARTICLE

Volume 119, Number 1 Yuan and Woo 41

for years.177-179 The term “medication-induced osteo-necrosis” may be a more appropriate general term forsuch osteonecrotic lesions, since medications other thanantiresorptive agents may be involved.

INFECTIONPatients on long-term immunosuppressive therapy maydevelop a variety of opportunistic infections in the oralcavity (Figure 9). It is well established that immuno-suppressed patients frequently develop pseudomem-branous candidiasis,180 fungal infections,181-183 andviral infections.184-188 TNF-a therapy specifically hasbeen linked to an increased risk of serious infections,such as tuberculosis and meningitis, especially whencombined with other immunomodulatory agents.189,190

Patients receiving infliximab and adalimumab havebeen shown to be at an increased risk for tuberculosis(OR 2.0) as well as histoplasmosis and coccidiomy-cosis.191 Disease-modifying antirheumatic drugs, suchas methotrexate, abatacept, and alefacept, have beenassociated with herpes simplex or herpes zoster infec-tion, deep fungal infections, and tuberculosis.192

ANGIOEDEMAMedication-induced angioedema has been observedwith the use of multiple agents, most commonly ACEinhibitors.193,194 This abrupt-onset swelling of theorofacial region and lips can compromise the airwayand be life-threatening. Angioedema is mediated byinflammatory cytokines, complement activation, andvascular permeability. It has also been reported with theuse of other antihypertensive agents, such as angio-tensin receptor blockers,195 calcium channelblockers,196 and hydrochlorothiazide,197 as well as an-tiplatelet agents, such as thienopyridine and clopidog-rel.198 The use of the statin class of medications,including simvastatin, fluvastatin, atorvastatin, andpravastatin, is infrequently associated with this sideeffect.199-202

MALIGNANCYA number of chemotherapy and immunomodulatingagents have been shown to increase the risk of lympho-proliferative disorders and neoplasms.203 Patients takingmethotrexate for rheumatoid arthritis sometimes developlymphoproliferative diseases; in 23% of cases, the diseaseregressed after discontinuation of the medication204-206;these diseases are often associatedwith Epstein-Barr virusinfection and occur infrequently.205,207,208

Topical tacrolimus applied on the skin in the murinemodel exhibited development of squamous cell carci-nomas in 8.5% of cases and benign papillomas 91.5%of cases.209 There have been anecdotal reports ofsquamous cell carcinoma developing in patients withoral LP treated with tacrolimus ointment.210,211 Tacro-limus has been shown to have an effect on both theMAPK and the p53 pathways, which are important incancer signaling.211 In a long-term study of recipientsof liver transplants, 45% of de novo malignancies wereon the skin, with tacrolimus immunosuppression citedas a risk factor (hazard ratio 2.06).212 There have beenonly sporadic case reports of squamous cell carcinomasof the skin and cutaneous T-cell lymphomas occurringafter tacrolimus and pimecrolimus application.213-216

It has also been reported that 9.6% of patients oncombinations of immunomodulating agents, such asazathioprine, cyclophosphamide, cyclosporine, ormycophenolate mofetil, for pemphigus or pemphigoidmay develop a secondary malignancy.217

Malignancies induced by biologic agents have beenreported in the literature. Bongartz et al. analyzed ninerandomized, controlled trials of infliximab and adali-mumab used in 3493 patients and found a three-foldincrease of malignancy (OR 3.3).191 The secondarycancers were significantly more common in patientstreated with higher doses of anti-TNF antibodies andprimarily consisted of basal cell carcinomas and lym-phomas.191 However, another study evaluated 18 clin-ical trials using TNF-a inhibitors and found no increasein malignancy or infection.218

ORAL MEDICINE OOOO

42 Yuan and Woo January 2015

The issue of drug-induced malignancy is stillcontroversial, and it is difficult to remove confoundingfactors from studies that show an association. Someconditions themselves predispose the patient to devel-oping malignancy regardless of the therapy received(e.g., severe rheumatoid arthritis and the developmentof lymphoma219) and the use of powerful immuno-suppressive medications likely increase the risk.Furthermore, the patient may have received many yearsof other immunosuppressive therapies that predisposedthem to malignancy.210,220 In cases of oral LP, forexample, that are resistant to topical steroid therapy, theclinician should carefully weigh the benefit of usingtopical tacrolimus against the rare anecdotal cases ofsquamous cell carcinoma that developed as a result ofits use.

CONCLUSIONAdverse drug events in the oral cavity are common andmay have a variety of clinical presentations. With newtherapeutic agents being introduced into clinical prac-tice, it is likely that more ADEs will be encountered.The advent of targeted therapies in oncology has pro-duced a number of novel complications in the oralcavity. Oral health care providers should be aware ofthe manifestations of ADEs encountered in theirpractice.

The authors would like to thank Dr Jennifer Frustino for herassistance with this manuscript.

REFERENCES1. Edwards IR, Aronson JK. Adverse drug reactions: definitions,

diagnosis, and management. Lancet. 2000;356:1255-1259.2. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug

events: a clinician’s guide to terminology, documentation, andreporting. Ann Intern Med. 2004;140:795-801.

3. Femiano F, Rullo R, di Spirito F, Lanza A, Festa VM, Cirillo N.A comparison of salivary substitutes versus a natural sialogogue(citric acid) in patients complaining of dry mouth as an adversedrug reaction: a clinical, randomized controlled study. Oral SurgOral Med Oral Pathol Oral Radiol Endod. 2011;112:e15-e20.

4. Zavras AI, Rosenberg GE, Danielson JD, Cartsos VM. Adversedrug and device reactions in the oral cavity: surveillance andreporting. J Am Dent Assoc. 2013;144:1014-1021.

5. Scully C, Bagan JV. Adverse drug reactions in the orofacialregion. Crit Rev Oral Biol Med. 2004;15:221-239.

6. Villa A, Abati S. Risk factors and symptoms associated withxerostomia: a cross-sectional study. Aust Dent J. 2011;56:290-295.

7. Korstanje MJ. Drug-induced mouth disorders. Clin Exp Der-matol. 1995;20:10-18.

8. Lavanya N, Jayanthi P, Rao UK, Ranganathan K. Oral lichenplanus: an update on pathogenesis and treatment. J Oral Max-illofac Pathol. 2011;15:127-132.

9. Piboonniyom SO, Treister N, Pitiphat W, Woo SB. Scoringsystem for monitoring oral lichenoid lesions: a preliminary

study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2005;99:696-703.

10. Van den Haute V, Antoine JL, Lachapelle JM. Histopathologicaldiscriminant criteria between lichenoid drug eruption and idio-pathic lichen planus: retrospective study on selected samples.Dermatologica. 1989;179:10-13.

11. Lowell Goldsmith SK, Gilchrest Barbara, Paller Amy,Leffell David, Wolff Klaus, eds. Fitzpatrick’s Dermatology inGeneral Medicine. 8th ed. Boston, MA: McGraw-Hill Profes-sional; 2012.

12. Fessa C, Lim P, Kossard S, Richards S, Penas PF. Lichen pla-nus-like drug eruptions due to beta-blockers: a case report andliterature review. Am J Clin Dermatol. 2012;13:417-421.

13. Halevy S, Shai A. Lichenoid drug eruptions. J Am Acad Der-matol. 1993;29:249-255.

14. Reinhardt LA, Wilkin JK, Kirkendall WM. Lichenoid eruptionproduced by captopril. Cutis. 1983;31:98-99.

15. Breathnach SM. Mechanisms of drug eruptions: Part I. AustralasJ Dermatol. 1995;36:121-127.

16. Sugerman PB, Savage NW, Zhou X, Walsh LJ, Bigby M. Orallichen planus. Clin Dermatol. 2000;18:533-539.

17. Baricevic M, Mravak Stipetic M, Situm M, et al. Oral bullouseruption after taking lisinoprildcase report and literature re-view. Cent Eur J Med. 2013;125:408-411.

18. Schlosser BJ. Lichen planus and lichenoid reactions of the oralmucosa. Dermatol Ther. 2010;23:251-267.

19. Artico G, Bruno IS, Seo J, Hirota SK, Acay R, Migliari DA.Lichenoid reaction to carbamazepine in the oral mucosa: casereport. An Bras Dermatol. 2011;86:S152-S155.

20. Grinspan D, Diaz J, Villapol LO, et al. [Lichen ruber planus ofthe buccal mucosa. Its association with diabetes]. Bull Soc FrDermatol Syphiligr. 1966;73:898-899.

21. Aljabre SH. Grinspan’s syndrome. J Am Acad Dermatol.1994;30:671.

22. Kragelund C, Hansen C, Reibel J, et al. Polymorphic drugmetabolizing CYP-enzymesea pathogenic factor in oral lichenplanus? J Oral Pathol Med. 2009;38:63-71.

23. Kragelund C, Hansen C, Reibel J, et al. Can the genotype orphenotype of two polymorphic drug metabolising cytochromeP450-enzymes identify oral lichenoid drug eruptions? J OralPathol Med. 2010;39:497-505.

24. McCartan BE, McCreary CE. Oral lichenoid drug eruptions.Oral Dis. 1997;3:58-63.

25. Thornhill MH, Sankar V, Xu XJ, et al. The role of histopatho-logical characteristics in distinguishing amalgam-associated orallichenoid reactions and oral lichen planus. J Oral Pathol Med.2006;35:233-240.

26. Siponen M, Huuskonen L, Laara E, Salo T. Association of orallichen planus with thyroid disease in a Finnish population: aretrospective case-control study. Oral Surg Oral Med OralPathol Oral Radiol Endod. 2010;110:319-324.

27. Robledo-Sierra J, Mattsson U, Jontell M. Use of systemicmedication in patients with oral lichen planusda possible as-sociation with hypothyroidism. Oral Dis. 2012;19:313-319.

28. LoMuzio L, Santarelli A, Campisi G, LacaitaM, Favia G. PossiblelinkbetweenHashimoto’s thyroiditis andoral lichenplanus: a novelassociation found. Clin Oral Investig. 2013;17:333-336.

29. Pua VS, Scolyer RA, Barnetson RS. Pravastatin-inducedlichenoid drug eruption. Australas J Dermatol. 2006;47:57-59.

30. Roger D, Rolle F, Labrousse F, Brosset A, Bonnetblanc JM.Simvastatin-induced lichenoid drug eruption. Clin Exp Derma-tol. 1994;19:88-89.

31. Sebok B, Toth M, Anga B, Harangi F, Schneider I. Lichenoiddrug eruption with HMG-CoA reductase inhibitors (fluvastatinand lovastatin). Acta Derm Venereol. 2004;84:229-230.

OOOO REVIEW ARTICLE

Volume 119, Number 1 Yuan and Woo 43

32. Gomez Fernandez C, Sendagorta Cudos E, Casado Verrier B,Feito Rodriguez M, Suarez Aguado J, Vidaurrazaga Diaz deArcaya C. Oral lichenoid eruption associated with imatinibtreatment. Eur J Dermatol. 2010;20:127-128.

33. Pascual JC,Matarredona J,Miralles J, ConesaV, Borras-Blasco J.Oral and cutaneous lichenoid reaction secondary to imatinib:report of two cases. Int J Dermatol. 2006;45:1471-1473.

34. Lim DS, Muir J. Oral lichenoid reaction to imatinib (STI 571,Gleevec). Dermatology. 2002;205:169-171.

35. Wahiduzzaman M, Pubalan M. Oral and cutaneous lichenoidreaction with nail changes secondary to imatinib: report of a caseand literature review. Dermatol Online J. 2008;14:14.

36. Ena P, Chiarolini F, Siddi GM, Cossu A. Oral lichenoid eruptionsecondary to imatinib (Glivec). J Dermatolog Treat. 2004;15:253-255.

37. Mann BS, Johnson JR, Kelly R, Sridhara R, Williams G,Pazdur R. Letrozole in the extended adjuvant treatment ofpostmenopausal women with history of early-stage breast cancerwho have completed 5 years of adjuvant tamoxifen. Clin CancerRes. 2005;11:5671-5677.

38. MedFacts.com. MedFacts meta-analysis covering adverse sideeffect reports of letrozole patients who developed lichenoid kera-tosis. 2013 [cited 2013 3/1/2014. Available at: http://medsfacts.com/study-LETROZOLE-causing-LICHENOIDKERATOSIS.php. Accessed March 1, 2014.

39. Grossman ME, Warren K, Mady A, Satra KH. Lichenoideruption associated with ethambutol. J Am Acad Dermatol.1995;33:675-676.

40. Choonhakarn C, Janma J. Pyrazinamide-induced lichenoidphotodermatitis. J Am Acad Dermatol. 1999;40:645-646.

41. Lehloenya RJ, Todd G, Mogotlane L, Gantsho N, Hlela C,Dheda K. Lichenoid drug reaction to antituberculosis drugstreated through with topical steroids and phototherapy.J Antimicrob Chemother. 2012;67:2535-2537.

42. Byun JW, Bang CY, Choi GS, Shin J. Lichenoid eruptionassociated with antituberculous drug: an unusual oral andfollicular involvement. Am J Dermatopathol. 2013;36:684-685.

43. Bakkour W, Coulson IH. GA101 (a novel anti-CD20 mono-clonal antibody)-induced lichenoid eruption. Dermatol Ther(Heidelb). 2012;2:3.

44. Asarch A, Gottlieb AB, Lee J, et al. Lichen planus-like erup-tions: an emerging side effect of tumor necrosis factor-alphaantagonists. J Am Acad Dermatol. 2009;61:104-111.

45. Moss AC, Treister NS, Marsee DK, Cheifetz AS. Clinicalchallenges and images in GI. Oral lichenoid reaction in a patientwith Crohn’s disease receiving infliximab. Gastroenterology.2007;132:488:829.

46. Mocciaro F, Orlando A, Renna S, Rizzuto MR, Cottone M. Orallichen planus after certolizumab pegol treatment in a patient withCrohn’s disease. J Crohns Colitis. 2011;5:173-174.

47. Fiorentino DF. The yin and yang of TNF-a inhibition. ArchDermatol. 2007;143:233-236.

48. Ozkaya-Bayazit E. Specific site involvement in fixed drugeruption. J Am Acad Dermatol. 2003;49:1003-1007.

49. Ozkaya E. Oral mucosal fixed drug eruption: characteristics anddifferential diagnosis. J Am Acad Dermatol. 2013;69:e51-e58.

50. Jain VK, Dixit VB. Archana. Fixed drug eruption of the oralmucous membrane. Ann Dent. 1991;50:9-11.

51. Pionetti CH, Kien MC, Alonso A. Fixed drug eruption due toloratadine. Allergol Immunopathol (Madr). 2003;31:291-293.

52. Inamadar AC, Palit A, Athanikar SB, Sampagavi VV,Deshmukh NS. Multiple fixed drug eruptions due to cetirizine.Br J Dermatol. 2002;147:1025-1026.

53. MahajanVK, SharmaNL, SharmaVC.Fixed drug eruption: a novelside-effect of levocetirizine. Int J Dermatol. 2005;44:796-798.

54. Gomez-Traseira C, Rojas-Perez-Ezquerra P, Sanchez-Morillas L, et al. Paracetamol-induced fixed drug eruption at anunusual site. Recent Pat Inflamm Allergy Drug Discov. 2013;7:268-270.

55. Mahendra A, Gupta S, Gupta S, Sood S, Kumar P. Oral fixeddrug eruption due to fluconazole. Indian J Dermatol VenereolLeprol. 2006;72:391.

56. Heikkila H, Timonen K, Stubb S. Fixed drug eruption due tofluconazole. J Am Acad Dermatol. 2000;42:883-884.

57. Alonso JC, Melgosa AC, Gonzalo MJ, Garcia CM. Fixed drugeruption on the tongue due to clarithromycin. Contact Derma-titis. 2005;53:121-122.

58. Gupta S, Gupta S, Mittal A, David S. Oral fixed drug eruptioncaused by gabapentin. J Eur Acad Dermatol Venereol. 2009;23:1207-1208.

59. Boulinguez S, Reix S, Bedane C, et al. Role of drug exposure inaphthous ulcers: a case-control study. Br J Dermatol. 2000;143:1261-1265.

60. Siegel MA, Balciunas BA. Medication can induce severe ul-cerations. J Am Dent Assoc. 1991;122:75-77.

61. Healy CM, Thornhill MH. An association between recurrentoro-genital ulceration and non-steroidal anti-inflammatory drugs.J Oral Pathol Med. 1995;24:46-48.

62. Lisi P, Hansel K, Assalve D. Aphthous stomatitis induced bypiroxicam. J Am Acad Dermatol. 2004;50:648-649.

63. Trujillo MJ, de Barrio M, Rodriguez A, et al. Piroxicam-inducedphotodermatitis. Cross-reactivity among oxicams. A case report.Allergol Immunopathol (Madr). 2001;29:133-136.

64. Bagan JV, Thongprasom K, Scully C. Adverse oral reactionsassociated with the COX-2 inhibitor rofecoxib. Oral Dis.2004;10:401-403.

65. Goffin E, Pochet JM, Lejuste P, De Plaen JF. Aphtous ulcers ofthe mouth associated with losartan. Clin Nephrol. 1998;50:197.

66. Martins F, de Oliveira MA, Wang Q, et al. A review of oraltoxicity associated with mTOR inhibitor therapy in cancerpatients. Oral Oncol. 2013;49:293-298.

67. de Oliveira MA, Martins EMF, Wang Q, et al. Clinical pre-sentation and management of mTOR inhibitor-associated sto-matitis. Oral Oncol. 2011;47:998-1003.

68. Sonis S, Treister N, Chawla S, Demetri G, Haluska F.Preliminary characterization of oral lesions associated withinhibitors of mammalian target of rapamycin in cancer patients.Cancer. 2010;116:210-215.

69. Susser WS, Whitaker-Worth DL, Grant-Kels JM. Mucocuta-neous reactions to chemotherapy. J Am Acad Dermatol.1999;40:367-398:quiz 399-400.

70. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST,Keefe DM. Is the pathobiology of chemotherapy-inducedalimentary tract mucositis influenced by the type of mucotoxicdrug administered? Cancer Chemother Pharmacol. 2009;63:239-251.

71. Sonis ST. Regimen-related gastrointestinal toxicities in cancerpatients. Curr Opin Support Palliat Care. 2010;4:26-30.

72. Apostolou T, Tsagalis G, Koutroubas G, Hadjiconstantinou V,Drakopoulos S. Mycophenolate mofetil and oral ulcerations.Transplantation. 2004;77:1911-1912.

73. Garrigue V, Canet S, Dereure O, et al. Oral ulcerations in a renaltransplant recipient: a mycophenolate mofetil-induced compli-cation? Transplantation. 2001;72:968-969.

74. Naranjo J, Poniachik J, Cisco D, et al. Oral ulcers produced bymycophenolate mofetil in two liver transplant patients. Trans-plant Proc. 2007;39:612-614.

75. Weng RR, Foster CE 3rd, Hsieh LL, Patel PR. Oral ulcersassociated with mycophenolate mofetil use in a renal transplantrecipient. Am J Health Syst Pharm. 2011;68:585-588.

ORAL MEDICINE OOOO

44 Yuan and Woo January 2015

76. Hernandez G, Jimenez C, Arriba L, Moreno E, Lucas M. Res-olution of oral ulcerations after decreasing the dosage of tacro-limus in a liver transplantation recipient. Oral Surg Oral MedOral Pathol Oral Radiol Endod. 2001;92:526-531.

77. Macario-Barrel A, Tanasescu S, Courville P, et al. Mouth ulcersin patients receiving tacrolimus. Ann Dermatol Venereol.2001;128:1327-1329.

78. Mignogna MD, Fortuna G, Leuci S, Pollio A, Ruoppo E.Sunitinib adverse event: oral bullous and lichenoid mucositis.Ann Pharmacother. 2009;43:546-547.

79. Wolf R, Brenner S. An active amide group in the molecule ofdrugs that induce pemphigus: a casual or causal relationship?Dermatology. 1994;189:1-4.

80. Vassileva S. Drug-induced pemphigoid: bullous and cicatricial.Clin Dermatol. 1998;16:379-387.

81. Weller R, White MI. Bullous pemphigoid and penicillamine.Clin Exp Dermatol. 1996;21:121-122.

82. Eisenberg E, Ballow M, Wolfe SH, Krutchkoff DJ, Tanzer JM.Pemphigus-like mucosal lesions: a side effect of penicillaminetherapy. Oral Surg Oral Med Oral Pathol. 1981;51:409-414.

83. Matz H, Bialy-Golan A, Brenner S. Diclofenac: a new trigger ofpemphigus vulgaris? Dermatology. 1997;195:48-49.

84. Wijeratne C, Webster P. Risperidone and bullous pemphigoid.Am J Psychiatry. 1996;153:735.

85. Downham TF 3rd. Spironolactone-induced lichen planus.JAMA. 1978;240:1138.

86. Heydenreich G, Pindborg T, Schmidt H. Bullous dermatosisamong patients with chronic renal failure of high dose fruse-mide. Acta Med Scand. 1977;202:61-64.

87. Price EJ, Venables PJ. Drug-induced lupus. Drug Saf. 1995;12:283-290.

88. Subramanian S, Yajnik V, Sands BE, Cullen G, Korzenik JR.Characterization of patients with infliximab-induced lupus ery-thematosus and outcomes after retreatment with a second anti-TNF agent. Inflamm Bowel Dis. 2011;17:99-104.

89. Perez-Alvarez R, Perez-de-Lis M, Ramos-Casals M. Biologics-induced autoimmune diseases. Curr Opin Rheumatol. 2013;25:56-64.

90. Ayangco L, Rogers RS 3rd. Oral manifestations of erythemamultiforme. Dermatol Clin. 2003;21:195-205.

91. Schalock PC, Brennick JB, Dinulos JG. Mycoplasma pneumo-niae infection associated with bullous erythema multiforme.J Am Acad Dermatol. 2005;52:705-706.

92. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O,Schroder W, Roujeau JC. Correlations between clinical patternsand causes of erythema multiforme majus, Stevens-Johnsonsyndrome, and toxic epidermal necrolysis: results of an inter-national prospective study. Arch Dermatol. 2002;138:1019-1024.

93. Edwards D, Boritz E, Cowen EW, Brown RS. Erythema mul-tiforme major following treatment with infliximab. Oral SurgOral Med Oral Pathol Oral Radiol. 2013;115:e36-e40.

94. Ahdout J, Haley JC, Chiu MW. Erythema multiforme duringanti-tumor necrosis factor treatment for plaque psoriasis. J AmAcad Dermatol. 2010;62:874-879.

95. Abou-Elhamd KE. Two cases of Stevens-Johnson syndromefollowing intake of klavox with review of literature. Eur ArchOtorhinolaryngol. 2009;266:1327-1330.

96. Kandil AO, Dvorak T, Mignano J, Wu JK, Zhu JJ. MultifocalStevens-Johnson syndrome after concurrent phenytoin and cra-nial and thoracic radiation treatment, a case report. RadiatOncol. 2010;5:49.

97. Hilas O, Charneski L. Lamotrigine-induced Stevens-Johnsonsyndrome. Am J Health Syst Pharm. 2007;64:273-275.

98. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility tocarbamazepine-induced cutaneous adverse drug reactions.Pharmacogenet Genomics. 2006;16:297-306.

99. Kulkantrakorn K, Tassaneeyakul W, Tiamkao S, et al. HLA-B*1502 strongly predicts carbamazepine-inducedStevens-Johnsonsyndrome and toxic epidermal necrolysis in Thai patients withneuropathic pain. Pain Pract. 2012;12:202-208.

100. Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as agenetic marker for severe cutaneous adverse reactions caused byallopurinol. Proc Natl Acad Sci U S A. 2005;102:4134-4139.

101. Lonjou C, Borot N, Sekula P, et al. A European study of HLA-Bin Stevens-Johnson syndrome and toxic epidermal necrolysisrelated to five high-risk drugs. Pharmacogenet Genomics.2008;18:99-107.

102. Mallal S, Nolan D, Witt C, et al. Association between presenceof HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensi-tivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet.2002;359:727-732.

103. Allegra A, Alonci A, Penna G, et al. Stevens-Johnson syndromeafter lenalidomide therapy for multiple myeloma: a case reportand a review of treatment options. Hematol Oncol. 2012;30:41-45.

104. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the riskof Stevens-Johnson syndrome or toxic epidermal necrolysis.N Engl J Med. 1995;333:1600-1607.

105. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnsonsyndrome and toxic epidermal necrolysis: assessment of medi-cation risks with emphasis on recently marketed drugs. TheEuroSCAR-study. J Invest Dermatol. 2008;128:35-44.

106. Reddy RB, Shekar PC, Chandra KL, Aravind R. Oral lesionsassociated with Nevirapine-induced Stevens-Johnson syndromeand toxic epidermal necrolysis: a report of 10 cases. J OralMaxillofac Pathol. 2013;17:431-435.

107. Pretel Irazabal M, Marques Martin L, Aguado Gil L, IdoateGastearena MA. Tranexamic acid-induced toxic epidermalnecrolysis. Ann Pharmacother. 2013;47:e16.

108. Lowndes S, Darby A, Mead G, Lister A. Stevens-Johnsonsyndrome after treatment with rituximab. Ann Oncol. 2002;13:1948-1950.

109. Treister NS, Magalnick D, Woo SB. Oral mucosal pigmentationsecondary to minocycline therapy: report of two cases and areview of the literature. Oral Surg Oral Med Oral Pathol OralRadiol Endod. 2004;97:718-725.

110. Okada N, Sato S, Sasou T, Aoyama M, Nishida K,Yoshikawa K. Characterization of pigmented granules in min-ocycline-induced cutaneous pigmentation: observations usingfluorescence microscopy and high-performance liquid chroma-tography. Br J Dermatol. 1993;129:403-407.

111. Giansanti JS, Tillery DE, Olansky S. Oral mucosal pigmentationresulting from antimalarial therapy. Oral Surg Oral Med OralPathol. 1971;31:66-69.

112. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosalhyperpigmentation secondary to antimalarial drug therapy. OralSurg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:189-194.

113. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation ofthe hard palate. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2009;107:8-12.

114. Chiappinelli JA, Walton RE. Tooth discoloration resulting fromlong-term tetracycline therapy: a case report. Quintessence Int.1992;23:539-541.

115. Westbury LW, Najera A. Minocycline-induced intraoral phar-macogenic pigmentation: case reports and review of the litera-ture. J Periodontol. 1997;68:84-91.

OOOO REVIEW ARTICLE

Volume 119, Number 1 Yuan and Woo 45

116. Arora B, Kumar L, Sharma A, Wadhwa J, Kochupillai V.Pigmentary changes in chronic myeloid leukemia patientstreated with imatinib mesylate. Ann Oncol. 2004;15:358-359.

117. Li CC, Malik SM, Blaeser BF, et al. Mucosal pigmentationcaused by imatinib: report of three cases. Head Neck Pathol.2012;6:290-295.

118. Tadini G, D’Orso M, Cusini M, Alessi E. Oral mucosapigmentation: a new side effect of azidothymidine therapy inpatients with acquired immunodeficiency syndrome. Arch Der-matol. 1991;127:267-268.

119. Ficarra G, Shillitoe EJ, Adler-Storthz K, et al. Oral melanoticmacules in patients infected with human immunodeficiency vi-rus. Oral Surg Oral Med Oral Pathol. 1990;70:748-755.

120. Hertz RS, Beckstead PC, Brown WJ. Epithelial melanosis of thegingiva possibly resulting from the use of oral contraceptives.J Am Dent Assoc. 1980;100:713-714.

121. Blaya M, Saba N. Images in clinical medicine. Chemotherapy-induced hyperpigmentation of the tongue. N Engl J Med.2011;365:e20.

122. Alfreijat M. Tongue hyperpigmentation associated withchemotherapy. J Community Hosp Intern Med Perspect. 2013;3.

123. Casamiquela KM, Cohen PR. Chemotherapy-associated tonguehyperpigmentation and blue lunula. J Drugs Dermatol. 2013;12:223-226.

124. Gonzalez-Arriagada WA, Silva AR, Vargas PA, de Almeida OP,Lopes MA. Facial pigmentation associated with amiodarone.Gen Dent. 2013;61:e15-e17.

125. Wolf ME, Richer S, Berk MA, Mosnaim AD. Cutaneous andocular changes associated with the use of chlorpromazine. Int JClin Pharmacol Ther Toxicol. 1993;31:365-367.

126. Pradhan S, Mishra P. Gingival enlargement in antihypertensivemedication. JNMA J Nepal Med Assoc. 2009;48:149-152.

127. Westbrook P, Bednarczyk EM, Carlson M, Sheehan H,Bissada NF. Regression of nifedipine-induced gingival hyper-plasia following switch to a same class calcium channel blocker,isradipine. J Periodontol. 1997;68:645-650.

128. Seymour RA, Thomason JM, Ellis JS. The pathogenesis of drug-induced gingival overgrowth. J Clin Periodontol. 1996;23:165-175.

129. Brown RS, Beaver WT, Bottomley WK. On the mechanism ofdrug-induced gingival hyperplasia. J Oral Pathol Med. 1991;20:201-209.

130. Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Folic acid sup-plementation prevents phenytoin-induced gingival overgrowthin children. Neurology. 2011;76:1338-1343.

131. Vahabi S, Salman BN, Rezazadeh F, Namdari M. Effects ofcyclosporine and phenytoin on biomarker expressions ingingival fibroblasts of children and adults: an in vitro study.J Basic Clin Physiol Pharmacol. 2014;25:167-173.

132. Lee L, Miller PA, Maxymiw WG, Messner HA, Rotstein LE.Intraoral pyogenic granuloma after allogeneic bone marrowtransplant. Report of three cases. Oral Surg Oral Med OralPathol. 1994;78:607-610.

133. Al-Mohaya M, Treister N, Al-Khadra O, Lehmann L, Padwa B,Woo SB. Calcineurin inhibitor-associated oral inflammatorypolyps after transplantation. J Oral Pathol Med. 2007;36:570-574.

134. Kataoka M, Shimizu Y, Kunikiyo K, et al. Cyclosporin A de-creases the degradation of type I collagen in rat gingival over-growth. J Cell Physiol. 2000;182:351-358.

135. Schincaglia GP, Forniti F, Cavallini R, Piva R, Calura G, delSenno L. Cyclosporin-A increases type I procollagen productionand mRNA level in human gingival fibroblasts in vitro. J OralPathol Med. 1992;21:181-185.

136. Woo SB, Allen CM, Orden A, Porter D, Antin JH. Non-gingivalsoft tissue growths after allogeneic marrow transplantation. BoneMarrow Transplant. 1996;17:1127-1132.

137. Iacopino AM, Doxey D, Cutler CW, et al. Phenytoin andcyclosporine A specifically regulate macrophage phenotype andexpression of platelet-derived growth factor and interleukin-1 invitro and in vivo: possible molecular mechanism of drug-inducedgingival hyperplasia. J Periodontol. 1997;68:73-83.

138. Bostanci N, Ilgenli T, Pirhan DC, et al. Relationship between IL-1 A polymorphisms and gingival overgrowth in renal transplantrecipients receiving cyclosporin A. J Clin Periodontol. 2006;33:771-778.

139. Morton RS, Dongari-Bagtzoglou AI. Regulation of gingivalfibroblast interleukin-6 secretion by cyclosporine A.J Periodontol. 1999;70:1464-1471.

140. Le QT, Kim HE, Schneider CJ, et al. Palifermin reduces severemucositis in definitive chemoradiotherapy of locally advancedhead and neck cancer: a randomized, placebo-controlled study.J Clin Oncol. 2011;29:2808-2814.

141. Lauritano D, Petruzzi M, Di Stasio D, Lucchese A. Clinicaleffectiveness of palifermin in prevention and treatment of oralmucositis in children with acute lymphoblastic leukaemia: acase-control study. Int J Oral Sci. 2013;6:27-30.

142. Beaven AW, Shea TC. Recombinant human keratinocyte growthfactor palifermin reduces oral mucositis and improves patientoutcomes after stem cell transplant. Drugs Today (Barc).2007;43:461-473.

143. Lerman MA, Treister NS. Generalized white appearance of theoral mucosa. Hyperkeratosis secondary to palifermin. J Am DentAssoc. 2010;141:867-869.

144. Boer CC, Correa ME, Miranda EC, de Souza CA. Taste disor-ders and oral evaluation in patients undergoing allogeneic he-matopoietic SCT. Bone Marrow Transplant. 2010;45:705-711.

145. Epstein JB, Phillips N, Parry J, Epstein MS, Nevill T, Steven-son-Moore P. Quality of life, taste, olfactory and oral functionfollowing high-dose chemotherapy and allogeneic hematopoieticcell transplantation. Bone Marrow Transplant. 2002:785-792.

146. Tuccori M, Lapi F, Testi A, et al. Drug-induced taste and smellalterations: a case/non-case evaluation of an italian database ofspontaneous adverse drug reaction reporting. Drug Saf. 2011;34:849-859.

147. Henkin RI. Drug-induced taste and smell disorders. Incidence,mechanisms and management related primarily to treatment ofsensory receptor dysfunction. Drug Saf. 1994;11:318-377.

148. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety ofvismodegib in advanced basal-cell carcinoma. N Engl J Med.2012;366:2171-2179.

149. Han Y, Smith MT. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Front Pharmacol.2013;4:156.

150. Hershman DL, Weimer LH, Wang A, et al. Association betweenpatient reported outcomes and quantitative sensory tests formeasuring long-term neurotoxicity in breast cancer survivorstreated with adjuvant paclitaxel chemotherapy. Breast CancerRes Treat. 2011;125:767-774.

151. Park SB, Goldstein D, Krishnan AV, et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA CancerJ Clin. 2013;63:419-437.

152. Dorchin M, Masoumi Dehshiri R, Soleiman S, Manashi M.Evaluation of neuropathy during intensive vincristine chemo-therapy for non-Hodgkin’s lymphoma and acute lymphoblasticleukemia. Iran J Ped Hematol Oncol. 2013;3:138-142.

153. Dixit G, Dhingra A, Kaushal D. Vincristine induced cranialneuropathy. J Assoc Physicians India. 2012;60:56-58.

ORAL MEDICINE OOOO

46 Yuan and Woo January 2015

154. Burns BV, Shotton JC. Vocal fold palsy following vinca alka-loid treatment. J Laryngol Otol. 1998;112:485-487.

155. Naithani R, Dolai TK, Kumar R. Bilateral vocal cord paralysisfollowing treatment with vincristine. Indian Pediatr. 2009;46:68-69.

156. Lipworth AD, Robert C, Zhu AX. Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus onsorafenib and sunitinib. Oncology. 2009;77:257-271.

157. Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects inpatients treated with the multitargeted kinase inhibitors sorafeniband sunitinib. Br J Dermatol. 2009;161:1045-1051.

158. Kollmannsberger C, Bjarnason G, Burnett P, et al. Sunitinib inmetastatic renal cell carcinoma: recommendations for manage-ment of noncardiovascular toxicities. Oncologist. 2011;16:543-553.

159. Ruggiero SL, Mehrotra B. Bisphosphonate-related osteonecrosisof the jaw: diagnosis, prevention, and management. Annu RevMed. 2009;60:85-96.

160. Otto S, Baumann S, Ehrenfeld M, Pautke C. Successful surgicalmanagement of osteonecrosis of the jaw due to RANK-ligandinhibitor treatment using fluorescence guided bone resection.J Craniomaxillofac Surg. 2013;41:694-698.

161. Rachner TD, Platzbecker U, Felsenberg D, Hofbauer LC.Osteonecrosis of the jaw after osteoporosis therapy with deno-sumab following long-term bisphosphonate therapy. Mayo ClinProc. 2013;88:418-419.

162. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws:risk factors, recognition, prevention, and treatment. J OralMaxillofac Surg. 2005;63:1567-1575.

163. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteo-necrosis of the jaws associated with the use of bisphosphonates:a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527-534.

164. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review:Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med.2006;144:753-761.

165. Woo SB, Mawardi H, Treister N. Comments on Osteonecrosis ofthe jaws in intravenous bisphosphonate use: proposal for a modi-fication of the clinical classification. Oral Oncol. 2009;45:740.

166. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE,Mehrotra B. American Association of Oral and MaxillofacialSurgeons position paper on bisphosphonate-related osteonec-rosis of the jawsd2009 update. J Oral Maxillofac Surg.2009;67:2-12.

167. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effectsof the bisphosphonate compound zoledronic acid. J PharmacolExp Ther. 2002;302:1055-1061.

168. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G 3rd,Huryn JM. Osteonecrosis of the jaw related to bevacizumab.J Clin Oncol. 2008;26:4037-4038.

169. Guarneri V, Miles D, Robert N, et al. Bevacizumab and osteo-necrosis of the jaw: incidence and association with bisphosph-onate therapy in three large prospective trials in advanced breastcancer. Breast Cancer Res Treat. 2010;122:181-188.

170. Katsenos S, Christophylakis C, Psathakis K. Osteonecrosis ofthe jaw in a patient with advanced non-small-cell lung cancerreceiving bevacizumab. Arch Bronconeumol. 2012;48:218-219.

171. Hoefert S, Eufinger H. Sunitinib may raise the risk ofbisphosphonate-related osteonecrosis of the jaw: presentation ofthree cases. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2010;110:463-469.

172. Koch FP, Walter C, Hansen T, Jager E, Wagner W. Osteonec-rosis of the jaw related to sunitinib. Oral Maxillofac Surg.2011;15:63-66.

173. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosisof jaw: a case report. Oral Surg Oral Med Oral Pathol OralRadiol. 2012;113:e1-e3.

174. Smidt-Hansen T, Folkmar TB, Fode K, Agerbaek M,Donskov F. Combination of zoledronic acid and targeted ther-apy is active but may induce osteonecrosis of the jaw in patientswith metastatic renal cell carcinoma. J Oral Maxillofac Surg.2013;71:1532-1540.

175. Agrillo A, Nastro Siniscalchi E, Facchini A, Filiaci F, Ungari C.Osteonecrosis of the jaws in patients assuming bisphosphonatesand sunitinib: two case reports. Eur Rev Med Pharmacol Sci.2012;16:952-957.

176. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy andsafety of sunitinib in patients with advanced gastrointestinalstromal tumour after failure of imatinib: a randomised controlledtrial. Lancet. 2006;368:1329-1338.

177. Christodoulou C, Pervena A, Klouvas G, et al. Combination ofbisphosphonates and antiangiogenic factors induces osteonec-rosis of the jaw more frequently than bisphosphonates alone.Oncology. 2009;76:209-211.

178. Okui T, Shimo T, Fukazawa T, et al. Antitumor effect of tem-sirolimus against oral squamous cell carcinoma associated withbone destruction. Mol Cancer Ther. 2010;9:2960-2969.

179. Giancola F, Campisi G, Russo LL, Muzio LL, Di Fede O.Osteonecrosis of the jaw related to everolimus and bisphosph-onate: a unique case report? Ann Stomatol (Roma). 2013;4:20-21.

180. Scully C, el-Kabir M, Samaranayake LP. Candida and oralcandidosis: a review. Crit Rev Oral Biol Med. 1994;5:125-157.

181. Dreizen S, Keating MJ, Beran M. Orofacial fungal infections.Nine pathogens that may invade during chemotherapy. PostgradMed. 1992;91:349-350, 353-354, 357-360 passim.

182. Al Akhrass F, Debiane L, Abdallah L, et al. Palatal mucormy-cosis in patients with hematologic malignancy and stem celltransplantation. Med Mycol. 2011;49:400-405.

183. Marsot-Dupuch K, Quillard J, Meyohas MC. Head and necklesions in the immunocompromised host. Eur Radiol. 2004;14:E155-E167.

184. Schubert MM. Oral manifestations of viral infections in immu-nocompromised patients. Curr Opin Dent. 1991;1:384-397.

185. Triantos D, Porter SR, Scully C, Teo CG. Oral hairy leukopla-kia: clinicopathologic features, pathogenesis, diagnosis, andclinical significance. Clin Infect Dis. 1997;25:1392-1396.

186. Pinheiro RS, de Franca TR, Rocha B, et al. Human papilloma-virus coinfection in the oral cavity of HIV-infected children.J Clin Pathol. 2011;64:1083-1087.

187. Samonis G, Mantadakis E, Maraki S. Orofacial viral infectionsin the immunocompromised host. Oncol Rep. 2000;7:1389-1394.

188. Stoopler ET, Greenberg MS. Update on herpesvirus infections.Dent Clin North Am. 2003;47:517-532.

189. Deepak P, Stobaugh DJ, Ehrenpreis ED. Infectious complica-tions of TNF-alpha inhibitor monotherapy versus combinationtherapy with immunomodulators in inflammatory bowel disease:analysis of the Food and Drug Administration Adverse EventReporting System. J Gastrointestin Liver Dis. 2013;22:269-276.

190. Delabaye I, De Keyser F. 74-wk follow-up of safety of inflix-imab in patients with refractory rheumatoid arthritis. ArthritisRes Ther. 2010;12:R121.

191. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL,Montori V. Anti-TNF antibody therapy in rheumatoid arthritisand the risk of serious infections and malignancies: systematicreview and meta-analysis of rare harmful effects in randomizedcontrolled trials. JAMA. 2006;295:2275-2285.

OOOO REVIEW ARTICLE

Volume 119, Number 1 Yuan and Woo 47

192. Salvana EM, Salata RA. Infectious complications associatedwith monoclonal antibodies and related small molecules. ClinMicrobiol Rev. 2009;22:274-290, Table of Contents.

193. Hom KA, Hirsch R, Elluru RG. Antihypertensive drug-inducedangioedema causing upper airway obstruction in children. Int JPediatr Otorhinolaryngol. 2012;76:14-19.

194. Rafii MS, Koenig M, Ziai WC. Orolingual angioedema associ-ated with ACE inhibitor use after rtPA treatment of acute stroke.Neurology. 2005;65:1906.

195. Shino M, Takahashi K, Murata T, Iida H, Yasuoka Y,Furuya N. Angiotensin II receptor blocker-induced angioe-dema in the oral floor and epiglottis. Am J Otolaryngol.2011;32:624-626.

196. Southward J, Irvine E, Rabinovich M. Probable amlodipine-induced angioedema. Ann Pharmacother. 2009;43:772-776.

197. Ruscin JM, Page RL 2nd, Scott J. Hydrochlorothiazide-inducedangioedema in a patient allergic to sulfonamide antibiotics: ev-idence from a case report and a review of the literature. Am JGeriatr Pharmacother. 2006;4:325-329.

198. Fischer TC, Worm M, Groneberg DA. Clopidogrel-associatedangioedema. Am J Med. 2003;114:77-78.

199. Nisly SAAK, Knight TB. Simvastatin: a risk factor for angioe-dema? J Pharmacy Technol. 2013;29:149-152.

200. Liebhaber MI, Wright RS, Gelberg HJ, Dyer Z, Kupperman JL.Polymyalgia, hypersensitivity pneumonitis and other reactionsin patients receiving HMG-CoA reductase inhibitors: a report often cases. Chest. 1999;115:886-889.

201. Insert P. Lipitor (atorvastatin). 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s057lbl.pdf. Accessed April 1, 2014.

202. Hampson JP, Smith D, Cowell R, Baker A. Hypotension andeosinophilia with atorvastatin. Pharm World Sci. 2005;27:279-280.

203. Bagg A, Dunphy CH. Immunosuppressive and immunomodu-latory therapy-associated lymphoproliferative disorders. SeminDiagn Pathol. 2013;30:102-112.

204. Hoshida Y, Xu JX, Fujita S, et al. Lymphoproliferative disordersin rheumatoid arthritis: clinicopathological analysis of 76 casesin relation to methotrexate medication. J Rheumatol. 2007;34:322-331.

205. Hanakawa H, Orita Y, Sato Y, Uno K, Nishizaki K, Yoshino T.Large ulceration of the oropharynx induced by methotrexate-associated lymphoproliferative disorders. Acta Med Okayama.2013;67:265-269.

206. Ichikawa A, Arakawa F, Kiyasu J, et al. Methotrexate/iatrogeniclymphoproliferative disorders in rheumatoid arthritis: histology,Epstein-Barr virus, and clonality are important predictors ofdisease progression and regression. Eur J Haematol. 2013;91:20-28.

207. Kikuchi K, Miyazaki Y, Tanaka A, et al. Methotrexate-relatedEpstein-Barr virus (EBV)-associated lymphoproliferativedisorderdso-called “Hodgkin-like lesion”dof the oral cavity ina patient with rheumatoid arthritis. Head Neck Pathol. 2010;4:305-311.

208. Kalantzis A, Marshman Z, Falconer DT, Morgan PR, Odell EW.Oral effects of low-dose methotrexate treatment. Oral Surg OralMed Oral Pathol Oral Radiol Endod. 2005;100:52-62.

209. Niwa Y, Terashima T, Sumi H. Topical application of theimmunosuppressant tacrolimus accelerates carcinogenesis inmouse skin. Br J Dermatol. 2003;149:960-967.

210. Mattsson U, Magnusson B, Jontell M. Squamous cell carcinomain a patient with oral lichen planus treated with topical appli-cation of tacrolimus. Oral Surg Oral Med Oral Pathol OralRadiol Endod. 2010;110:e19-e25.

211. Becker JC, Houben R, Vetter CS, Brocker EB. The carcinogenicpotential of tacrolimus ointment beyond immune suppression: ahypothesis creating case report. BMC Cancer. 2006;6:7.

212. Wimmer CD, Angele MK, Schwarz B, et al. Impact of cyclo-sporine versus tacrolimus on the incidence of de novo malig-nancy following liver transplantation: a single center experiencewith 609 patients. Transpl Int. 2013;26:999-1006.

213. Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ,Frieden IJ. The use of topical calcineurin inhibitors in derma-tology: safety concerns. Report of the American Academy ofDermatology Association Task Force. J Am Acad Dermatol.2006;54:818-823.

214. Tennis P, Gelfand JM, Rothman KJ. Evaluation of cancer riskrelated to atopic dermatitis and use of topical calcineurin in-hibitors. Br J Dermatol. 2011;165:465-473.

215. Fischer G, Bradford J. Topical immunosuppressants, genitallichen sclerosus and the risk of squamous cell carcinoma: a casereport. J Reprod Med. 2007;52:329-331.

216. Langeland T, Engh V. Topical use of tacrolimus and squamouscell carcinoma on the penis. Br J Dermatol. 2005;152:183-185.

217. Mabrouk D, Gurcan HM, Keskin DB, Christen WG,Ahmed AR. Association between cancer and immunosuppres-sive therapydanalysis of selected studies in pemphigus andpemphigoid. Ann Pharmacother. 2010;44:1770-1776.

218. Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: metaand exposure-adjusted pooled analyses of serious adverseevents. Ann Rheum Dis. 2009;68:1136-1145.

219. Baecklund E, Backlin C, Iliadou A, et al. Characteristics ofdiffuse large B cell lymphomas in rheumatoid arthritis. ArthritisRheum. 2006;54:3774-3781.

220. Mawardi H, Elad S, Correa ME, et al. Oral epithelial dysplasiaand squamous cell carcinoma following allogeneic hematopoi-etic stem cell transplantation: clinical presentation and treatmentoutcomes. Bone Marrow Transplant. 2011;46:884-891.

Reprint requests:

Anna YuanDivision of Oral Medicine and DentistryBrigham and Women’s HospitalBoston, MAannayuan@post.harvard.edu