Adverse Drug Events In The Oral Cavity.pdf

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 control disease also exposes them to the risk for developing reactions to the medications. One definition put forward by Edwards and Aronson in 2000 for “adverse drug reaction” is “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”1 This definition attempts to address several important issues related to “appreciable harm and unpleasantness” and excludes minor reactions, addresses the issue of medication error, addresses injury from nonpharmaceutical agents (including contaminants and inactive ingredients), and does not assign disease mechanism. The authors make a distinction between an adverse effect (adverse outcome attributed to an action of the drug) and an adverse event (adverse outcome that occurs when a patient is on the drug but that may not be caused by the drug).1 The term used currently that satisfies both regulatory bodies as well as patient safety advocates is “adverse drug event” which includes (1) harm caused by a drug (commonly known as adverse drug reaction), (2) harm caused by appropriate drug use (usually referred to as a side effect), and (3) medication errors.2 This review will focus on common adverse drug events (ADEs), as defined 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 the annual meeting of the American Academy of Oral Medicine in 2013 in San Antonio, Texas. a Division of Oral Medicine, Brigham & Women’s Hospital, Boston, Massachusetts. b Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts. Received for publication Jun 4, 2014; returned for revision Aug 18, 2014; accepted for publication Sep 10, 2014. Ó 2015 Elsevier Inc. Open access under CC BY-NC-ND license. 2212-4403 http://dx.doi.org/10.1016/j.oooo.2014.09.009

whether the patients were significantly harmed by the event is probably subject to interpretation. Although the term “medication” is preferred over “drug,” we are using the term ADE because it is the convention. Diagnosis is based on history and chronology of the adverse oral reaction. Typically, these changes are detected within weeks or months after taking the medications. Some lesions, such as lichenoid drug reactions, may present asymptomatically initially but become symptomatic years later, making the relationship between start of drug use and development of ADE difficult to ascertain. The presence of the oral condition predating the administration of the medication must be excluded, and this may be difficult to determine if the patient has not seen a health care provider in a long time. Resolution should occur after discontinuation of the suspected medication, although this may necessitate the use of topical corticosteroids for inflammatory conditions. Recurrence with rechallenge confirms the diagnosis, although this may not be feasible if the ADEs are unpleasant, severe, or life-threatening. Concurrent medications must be noted. The benefits of using any particular medication must, of course, always be weighed against the side effects, and some considerations include the necessity for the medication and availability of substitute agents, how severe the side effects are (e.g., asymptomatic oral pigmentation vs highly morbid necrolytic syndromes),

Statement of Clinical Relevance Adverse drug events in the oral cavity are common and will likely increase as newer therapeutic agents are approved. Health care providers should familiarize themselves with such events. This review describes common and uncommon oral mucosal reactions to medications. 35

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ORAL MEDICINE 36 Yuan and Woo

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Table I. Drug-induced oral reactions Hyposalivation/xerostomia Lichenoid reaction/lichen planus Aphthous-like ulcers Bullous disorders Pigmentation Fibrovascular hyperplasia Keratosis/epithelial hyperplasia Dysesthesia Osteonecrosis of the jaws Infection Angioedema Malignancy

the frequency of occurrence of such ADEs, whether the ADE can be eliminated by lowering the dose, and whether the ADE may be easily treated.1,2 Drug-induced cutaneous reactions are common and varied in presentation, but only a limited number of reaction patterns occur in the oral cavity. This is likely due to the higher turnover rate in the oral mucosa compared with that on the skin, and this does not allow easy detection of the spectrum of subtle clinical changes on the skin. The oral lesions to be discussed fall into several categories (Table I).

HYPOSALIVATION/XEROSTOMIA Medication use is one of the most common causes of both xerostomia and hyposalivation. Many middle-aged and older patients in the United States are on multiple medications (“polypharmacy”), and even medications with small anticholinergic effects may act synergistically in combination to cause oral symptoms of dryness and discomfort (Figure 1). Dry mouth is listed as an adverse effect for over 500 medications.3 In a systematic review, xerostomia was reported to be one of the most common oral adverse effects associated with over 80% of the 100 most prescribed medications in the United States.4 The most frequently reported medication classes that result in hyposalivation are antidepressants, antipsychotics, antihistamines, muscarinic receptor and a-receptor antagonists, antihypertensives (e.g., diuretics, b-blockers, and angiotensin-converting enzyme [ACE] inhibitors), bronchodilators, and skeletal muscle relaxants.3,5 Other culprits include chemotherapy agents, appetite suppressants, decongestants, antimigraine drugs, opioids, benzodiazepines, hypnotics, histamine 2 (H2) receptor antagonists and proton pump inhibitors, systemic retinoids, antiehuman immunodeficiency virus medications, and cytokine therapy.3,5 A study of 601 patients reported that older individuals were almost three times more likely to report xerostomia, and patients taking one or more drugs were

Fig. 1. Hyposalivation from polypharmacy.

more than twice as likely to do so compared with medication-free patients; this prevalence increased with increasing number of medications used (16.7% of patients reported xerostomia with one medication daily vs 33.3% with two to three medications daily vs 36.9% at greater than three medications daily).6 Persistent hyposalivation can lead to infections, such as candidiasis and dental caries, as well as bacterial sialadenitis.7 The loss of lubrication also results in erythema and susceptibility of the mucosa to frictional trauma against teeth; discomfort and burning may be profound.

LICHENOID REACTION/LICHEN PLANUS One of the most common inflammatory conditions affecting the skin and oral mucosa is lichen planus (LP). LP is an immune-mediated process, where T cells mediate the destruction of the basal cells of the epithelium.8 Oral LP presents as white striations or papules often associated with erythema or erosion and ulcers, most commonly in a bilaterally symmetric manner, often on the buccal mucosa, tongue, and gingiva.9 Many medications are known to cause cutaneous lichenoid hypersensitivity reactions (LHRs), which are often difficult to distinguish clinically and histopathologically from idiopathic cutaneous LP.10,11 Cutaneous LHRs present as skin eruptions characterized by purplish, pruritic keratotic papules and plaques, usually without the classic Wickham striae, on the trunk and extremities instead of the flexural regions.11-13 It has been postulated that active thiol groups found in the chemical structure of such medications as piroxicam, sulfasalazine, and glipizide play a role in inciting such reactions.14,15 It is, therefore, likely that these same

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Fig. 2. Lichenoid tissue reaction from rituximab.

medications may cause an oral LHR and that it can resemble idiopathic oral LP (Figure 2). The two classes of medications historically associated with oral LHRs are nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive agents, including b-blockers, ACE inhibitors, and diuretics (in particular hydrochlorothiazide).7,16,17 Sulfonylurea antidiabetic medications (e.g., tolbutamide and glipizide), antifungals (e.g., ketoconazole), anticonvulsants (e.g., carbamazepine), immunomodulatory drugs (e.g., gold salts and penicillamine), sulfasalazine, allopurinol, and lithium have been reported to elicit oral LHRs.18,19 Of historical interest, Grinspan syndrome was introduced at the 1963 Congress of Dermatology as a clinical presentation of a triad of oral LP, diabetes mellitus, and hypertension; it is now generally accepted that drug therapy for hypertension in particular and likely diabetes mellitus is capable of provoking oral LHRs.11,20,21 One theory regarding the pathogenesis of LHRs is that susceptible patients have polymorphisms of the cytochrome P450 enzymes (CYPs), which results in poor or intermediate CYP metabolism of some medications. One group of investigators reported higher CYP2-D6 among females (P > .05) and higher CYP2D6*4 among patients with oral LP (50%) versus those in the general population (30%), although this is of questionable clinical significance.22,23 It is often difficult to reach a consensus on diagnostic criteria, in part due to the fact that LHRs, once wellestablished, may persist after cessation of the drug unless rigorously treated. However, McCartan et al. suggested that a history of the current use of an LHRinducing medication in combination with consistent histopathology is likely sufficient, although the authors also suggested that testing for the presence of circulating basal cell cytoplasmic autoantibodies may be helpful.24,25 LP has been associated with thyroid disease in several studies. Siponen et al. reported that 15% and

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13% of patients with oral LP and oral lichenoid lesions, respectively, had thyroid disease compared with 8% of controls.26 This raises the question of whether the lesions result from the disease or from the medications used to treat the disease. A subsequent study found that patients with oral LP were 3.4 times more likely to be taking levothyroxine than not (P ¼ .001).27 Lo Muzio et al. noted that oral LP occurred in 14.3% of patients with Hashimoto thyroiditis versus 1% of the general population.28 Several other classes of medications are also associated with the development of cutaneous LP or LHRs. 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors, such as pravastatin, simvastatin, fluvastatin, and lovastatin, have been implicated in causing cutaneous LHRs with mucosal involvement.29-31 The tyrosine kinase inhibitor imatinib has been implicated in LHRs, particularly in the oral cavity.32-36 In a study of the aromatase inhibitor letrozole used for breast cancer, 32.4% of patients were noted to have an adverse cutaneous reaction, and another group reported that 16 patients (0.9%) developed lichenoid keratosis over an 8-year study period.37,38 Antituberculosis drugs, such as ethambutol, pyrazinamide, isoniazid, and rifampicin, also have been reported to cause cutaneous LHRs.39-41 A recent case report noted an association between antituberculosis medications and hyperpigmented macules and lichenoid papules in the oral cavity; these lesions were bilateral and symmetric, but classic LP reticulations were absent.42 Biologic agents are being used with increasing frequency for the management of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis and in oncology, and reports of LHRs have begun to appear in the literature. The novel anti-CD20 monoclonal antibody obinutuzumab was reported to cause LHRs on the skin and oral ulcers.43 Asarch et al. reported two cases of oral LP (more accurately, LHRs) in patients taking tumor necrosis factor alpha (TNF-a) inhibitors infliximab and adalimumab and 12 cases involving the TNF receptor fusion proteins etanercept and abatacept.44 Infliximab and certolizumab used to treat Crohn disease have both been linked to biopsy-proven oral LP.45,46 This seems paradoxical, since oral LP is mediated by TNF-a. However, it has been suggested that there may be upregulation of interferon alpha when TNF-alpha is inhibited.44 Interferon alpha then activates T cells and dendritic cells, causing an inflammatory response.44,47 Fixed drug eruptions (FDEs) in the oral cavity are lesions that recur at the same site each time the offending medication is taken.48 Oral mucosal lesions are infrequently reported and can be accompanied by skin or genital involvement.49,50 The presentation can range from bullous to erosive, hyperpigmented, pruitic, or erythematous lesions.49 A number of first- and

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ORAL MEDICINE 38 Yuan and Woo

Fig. 3. Sirolimus-induced aphthous-like ulcers.

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Fig. 4. Methotrexate-induced oral ulcer.

second-generation antihistamines have been known to cause FDEs on the skin.51,52 The third-generation antihistamine levocetirizine was reported in a case of FDE involving the oral (lower lip and tongue) and genital tissues (glans penis).53 Use of acetaminophen was reported to result in erythematous and papular FDEs on the hard palate and skin; naproxen and oxicams have caused lesions on the lips48,54; and fluconazole has caused lesions of the palatal mucosa and oral bullae.55,56 Co-trimoxazole, oxyphenbutazone, tetracycline, clarithromycin, and gabapentin have also been implicated in the occurrence of oral FDEs.50,57,58 Fig. 5. Ulcerative mucositis secondary to chemotherapy.

APHTHOUS-LIKE AND NONeAPHTHOUSLIKE ULCERS Idiopathic aphthous ulcers usually begin in the first two decades of life and appear as ovoid to round ulcers usually 1 cm or less with a yellowish fibrinous membrane and surrounding erythema involving the nonkeratinized mucosa.5 “Aphthous-like” or aphtheiform ulcers is the term used for oral ulcers where there is a known etiology, as these resolve when the underlying etiology is effectively managed. NSAIDs were one of the earliest classes of drugs associated with the development of aphthous-like ulcers in the oral cavity.59-61 Piroxicam, in particular, was shown to cause such ulcers, possibly because it contains a thiol group.5,60,62,63 Naproxen, trimethoprim-sulfamethoxazole, cyclooxygenase-2 inhibitors (e.g., refecoxib), and the angiotensin receptor blocker losartan have been implicated in the development of aphthouslike ulcers.49,64,65 More recently, aphthous-like ulcers have been documented in patients with metastatic tumors treated with mammalian target of rapamycin inhibitors, including sirolimus, temsirolimus, everolimus, and ridaforolimus (Figure 3).66-68 However, unlike idiopathic recurrent aphthous ulcers, on withdrawal of therapy, these regress completely without recurrence.

Conventional chemotherapy agents, such as 5-fluorouracil, cisplatin, methotrexate, and hydroxyurea, are stomatotoxic and cause oral ulcers and ulcerative mucositis (Figure 4).69-71 These ulcers tend to be larger and more diffuse and do not have the ovoid, welldemarcated appearance of aphthous ulcers (Figure 5). Mycophenolate mofetil has been reported to cause ulcers on the tongue, palate, labial mucosa, and gingiva in recipients of solid organ transplants, but these ulcers resolve on cessation of medication, as in the case of tacrolimus.72-77 Rare cases of ulcers associated with multitargeted kinase inhibitors (MTKIs) have been reported.78

BULLOUS DISORDERS Medication-induced autoimmune bullous disorders of the skin are not uncommon, whereas such disorders presenting in the oral cavity are rare. The development of simultaneous oral and cutaneous pemphigus vulgaris has been noted with the use of thiol radicalecontaining drugs,64,79,80 such as penicillamine81,82 and NSAIDs (see Figure 4).83 Cutaneous bullous pemphigoid has been associated with antipsychotic medications, spironolactones, and sulfonamides.80,84-86 Lupus

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Fig. 6. Palatal mucosal pigmentation associated with imatinib.

erythematosus of the skin has been observed in patients using procainamide, hydralazine, and biologic agents, such as anti-TNF inhibitors.87-89 Erythema multiforme (EM), major or minor, can affect both the skin and mucous membranes. It presents as irregular oral ulcers with diffuse erythema and target lesions of the skin. It is a hypersensitivity reaction, most commonly to an infectious agent, such as herpes simplex virus and less commonly to Mycoplasma pneumonia in children; approximately 18% of cases represent hypersensitivity reactions to medications.90-92 EM of the skin and oral mucous membranes has been reported with the administration of infliximab and adalimumab.93,94 Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe necrolytic hypersensitivity reactions, which, unlike EM, are much more commonly associated with the use of medications and may be life-threatening.92 SJS and TEN almost always involve the mucous membranes of the mouth, eye, and genitalia, sometimes extensively. Antimicrobials (amoxicillin/clavulanic acid)95 and anticonvulsants (phenytoin and lamotrigine) have been implicated.96,97 In the Han Chinese populations, SJS and TEN caused by anticonvulsants, such as phenobarbital, phenytoin, and carbamazepine, are associated with HLA-B*1502 (odds ratio [OR] 1357), whereas reactions to allopurinol are associated with HLAB*5801 (OR 580).98-100 In the Thai population, carbamazepine is also associated with SJS and TEN in a large number of patients (OR 75).99 In Europeans, SJS and TEN caused by sulfamethoxasole has been associated with HLA-B*38, NSAIDs with HLA-B*73,101 and HIV-1 reverse-transcriptase inhibitor abacavir with HLA-B*5701.102 Other drugs implicated include lamotrigine, phenytoin, phenobarbital, lenalidomide103; co-trimoxazole, sulfonamides, sulfasalazine, and oxicam104,105; nivirapine106; transexamic acid107; and rituximab.108

REVIEW ARTICLE Yuan and Woo 39

PIGMENTATION Metabolites of such medications as the tetracyclines, minocyclines, antimalarial drugs (e.g., hydroxychloroquine, mepacrine, and quinacine), and phenazine dyes (e.g., clofazimine) may be deposited in the oral mucosa. Such drug metabolites chelate with iron and melanin, which results in pigmentation of the hard palatal mucosa, and have a specific histopathology (Figure 6).109-113 Tetracycline and minocycline are also deposited in teeth, bones, thyroid, and sclera and cause mucosal and nail pigmentation.114,115 The tyrosine kinase inhibitor imatinib, used to treat chronic myelogenous leukemia and acute lymphoblastic leukemia, can cause hyper- or hypopigmentation of the skin, hyperpigmentation of nails, and diffuse blue-gray pigmentation on the palatal mucosa, with similar characteristic histopathology.116,117 It is unclear whether secondgeneration tyrosine kinase inhibitors such as dasatinib, nilotinib, and bosutinib will have the same effect. Other medications that have been noted to cause oral mucosal pigmentation are zidovudine (on the tongue)118,119; oral contraceptives (on the maxillary and mandibular gingiva)120; and chemotherapy agents, such as such as doxorubicin, docetaxel, and cyclophosphamide (on the tongue dorsum, buccal mucosa, and nails).121-123 Pigmentation of the facial skin has been noted with the use of amiodorone and phenothiazines (chlorpromazine).124,125 Stimulation of melanocytes without metabolite deposition is postulated to be the mechanism, and, interestingly, pigmentation does not occur on the palatal mucosa. FIBROVASCULAR HYPERPLASIA Calcium channel blockers, in particular, nifedipine and amlodipine, are antihypertensive agents that induce hyperplasia of the gingival tissues.126,127 This presents as a diffuse, generalized, often nodular overgrowth of densely fibrous gingival tissue. The resulting gingival enlargement is exacerbated by plaque-induced inflammation, and there may be a genetic predisposition.128 It has been suggested that the mechanism is due to decreased cellular folic acid uptake leading to decreased activity of matrix metalloproteinases and the failure to activate collagenase.129-131 Calcineurin inhibitors, such as cyclosporine or, less frequently, tacrolimus, also induce inflammatory fibrovascular hyperplasias in the oral cavity. However, these present as localized polypoid fibrous tumors and are more often seen on the tongue and buccal mucosa rather than on the gingiva (Figure 7).132,133 The increased production of collagen is thought to be due to both the reduced activity of matrix metalloproteinases and the increased activity of tissue inhibitors of metalloproteinases.134-136 It has also been proposed that

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ORAL MEDICINE 40 Yuan and Woo

Fig. 7. Fibrovascular hyperplasia with ulceration associated with tacrolimus.

phenytoin and cyclosporine cause an increase in the expression of interleukins (IL-1, IL-6), which may induce oral mucosal mesenchymal stem cells to differentiate toward a pro-fibrotic phenotype.137-139

KERATOSIS/EPITHELIAL HYPERPLASIA Palifermin is a recombinant keratinocyte growth factor delivered intravenously to reduce the incidence and severity of mucositis related to autologous hematopoietic stem cell transplantation, chemotherapy, and radiotherapy.140,141 It has been associated with mouth or tongue thickness and white discoloration in 17% of patients.142 The diffuse, thickened white plaques observed in the mouth as a response to palifermin are likely due to increased thickness of the oral epithelium and/or keratin layer as a result of the proliferation of epithelial cells.143 DYSESTHESIAS Oral dysesthesias, such as sensitivity, burning, dysgeusia, and other altered sensations without clinical signs, may be caused by medications. It must be noted that dysgeusia can be secondary to hyposalivation instead of being the direct effect of a drug.144 Damage to the salivary glands reduces the production of saliva, the solution in which chemoreceptors in the taste buds of the tongue bind their receptor molecules.145 A study on dysgeusia and dysosmia was reported for several drug classes, including macrolides, such as clarithromycin (17%); antimycotics, such as terbinafine (9%); and fluoroquinolones (8%), as well as protein kinase inhibitors, ACE-inhibitors, statins, and proton pump inhibitors (3%5% each).146 The mechanism is multifactorial and may be a combination of drugereceptor inhibition, alteration of neurotransmitter function, disturbance of action potentials in neurons, and dysfunctional sensory modulation in the brain.146,147 Vismodegib, a first-in-class, small-molecule inhibitor of the hedgehog pathway

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produced dysgeusia in 51% of participants in a phase 1 trial for management of advanced basal cell carcinomas.148 Neurologic complications of chemotherapy are well described in the literature. The pathobiology of peripheral neuropathy is complex and could be attributed to neuronopathy, axonopathy, myelinopathy, and intraepidermal nerve fiber degeneration.149 Chemotherapy-associated peripheral neuropathies are often associated with the use of taxanes,150 platinum compounds, thalidomide, bortezomib,151 and vinca alkaloids, such as vincristine and vinblastine.152-155 MTKIs (e.g., sunitinib and sorafenib) downregulate a variety of receptors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, fibroblast growth factor, c-kit, FMS-like tyrosine kinase 3 (FLT-3), BRAF, and RET. The development of oral dysesthesias is significantly associated with the development and severity of palmareplantar erythrodysesthesia in patients on MTKIs.156,157 A study of over 200 patients reported “stomatitis” symptoms in 26% of patients on sorafenib and in 36% of patients on sunitinib in the absence of oral findings.157 Kollmannsberger 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 noticeable physical changes.158 They may fall within the spectrum of burning mouth syndrome or oral dysesthesia disorders.

OSTEONECROSIS OF THE JAWS Bisphosphonates and denosumab (monoclonal antibody against receptor activator of nuclear factor kappa-B ligand) are antiresorptive medications that markedly slow bone turnover and remodeling and therefore increase bone density; they are used to treat postmenopausal osteoporosis and reduce skeletal-related events during cancer therapy (e.g., for plasma cell myeloma and metastatic cancers).159-161 Osteonecrosis is an ADE presenting as either exposed bone or a nonhealing extraction socket (Figure 8).162-164 A stage 0 variant exists where bone is not exposed.159,165,166 Bisphosphonates also exhibit antiangiogenic activity.167 Antiangiogenic agents, such as bevacizumab and sunitinib, which act against VEGF, either used alone or in combination with bisphosphonates, also lead to the development of osteonecrosis in some patients.168-173 In fact, higher incidences of osteonecrosis have been seen with combination of such anti-VEGF therapies and bisphosphonates than with bisphosphonates alone.174-177 It is unclear whether mammalian target of rapamycin inhibitors alone may cause osteonecrosis, since it has been recently reported that patients who developed this condition had also been on intravenous bisphosphonates

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REVIEW ARTICLE Yuan and Woo 41

Fig. 8. Osteonecrosis of the jaw associated with denosumab.

Fig. 9. Candidiasis from topical steroid therapy.

for years.177-179 The term “medication-induced osteonecrosis” may be a more appropriate general term for such osteonecrotic lesions, since medications other than antiresorptive agents may be involved.

MALIGNANCY A number of chemotherapy and immunomodulating agents have been shown to increase the risk of lymphoproliferative disorders and neoplasms.203 Patients taking methotrexate for rheumatoid arthritis sometimes develop lymphoproliferative diseases; in 23% of cases, the disease regressed after discontinuation of the medication204-206; these diseases are often associated with Epstein-Barr virus infection and occur infrequently.205,207,208 Topical tacrolimus applied on the skin in the murine model exhibited development of squamous cell carcinomas in 8.5% of cases and benign papillomas 91.5% of cases.209 There have been anecdotal reports of squamous cell carcinoma developing in patients with oral LP treated with tacrolimus ointment.210,211 Tacrolimus has been shown to have an effect on both the MAPK and the p53 pathways, which are important in cancer signaling.211 In a long-term study of recipients of liver transplants, 45% of de novo malignancies were on the skin, with tacrolimus immunosuppression cited as a risk factor (hazard ratio 2.06).212 There have been only sporadic case reports of squamous cell carcinomas of the skin and cutaneous T-cell lymphomas occurring after tacrolimus and pimecrolimus application.213-216 It has also been reported that 9.6% of patients on combinations of immunomodulating agents, such as azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil, for pemphigus or pemphigoid may develop a secondary malignancy.217 Malignancies induced by biologic agents have been reported in the literature. Bongartz et al. analyzed nine randomized, controlled trials of infliximab and adalimumab used in 3493 patients and found a three-fold increase of malignancy (OR 3.3).191 The secondary cancers were significantly more common in patients treated with higher doses of anti-TNF antibodies and primarily consisted of basal cell carcinomas and lymphomas.191 However, another study evaluated 18 clinical trials using TNF-a inhibitors and found no increase in malignancy or infection.218

INFECTION Patients on long-term immunosuppressive therapy may develop a variety of opportunistic infections in the oral cavity (Figure 9). It is well established that immunosuppressed patients frequently develop pseudomembranous candidiasis,180 fungal infections,181-183 and viral infections.184-188 TNF-a therapy specifically has been linked to an increased risk of serious infections, such as tuberculosis and meningitis, especially when combined with other immunomodulatory agents.189,190 Patients receiving infliximab and adalimumab have been shown to be at an increased risk for tuberculosis (OR 2.0) as well as histoplasmosis and coccidiomycosis.191 Disease-modifying antirheumatic drugs, such as methotrexate, abatacept, and alefacept, have been associated with herpes simplex or herpes zoster infection, deep fungal infections, and tuberculosis.192 ANGIOEDEMA Medication-induced angioedema has been observed with the use of multiple agents, most commonly ACE inhibitors.193,194 This abrupt-onset swelling of the orofacial region and lips can compromise the airway and be life-threatening. Angioedema is mediated by inflammatory cytokines, complement activation, and vascular permeability. It has also been reported with the use of other antihypertensive agents, such as angiotensin receptor blockers,195 calcium channel blockers,196 and hydrochlorothiazide,197 as well as antiplatelet agents, such as thienopyridine and clopidogrel.198 The use of the statin class of medications, including simvastatin, fluvastatin, atorvastatin, and pravastatin, is infrequently associated with this side effect.199-202

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ORAL MEDICINE 42 Yuan and Woo

The issue of drug-induced malignancy is still controversial, and it is difficult to remove confounding factors from studies that show an association. Some conditions themselves predispose the patient to developing malignancy regardless of the therapy received (e.g., severe rheumatoid arthritis and the development of lymphoma219) and the use of powerful immunosuppressive medications likely increase the risk. Furthermore, the patient may have received many years of other immunosuppressive therapies that predisposed them to malignancy.210,220 In cases of oral LP, for example, that are resistant to topical steroid therapy, the clinician should carefully weigh the benefit of using topical tacrolimus against the rare anecdotal cases of squamous cell carcinoma that developed as a result of its use.

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10.

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13. 14. 15. 16.

CONCLUSION Adverse drug events in the oral cavity are common and may have a variety of clinical presentations. With new therapeutic agents being introduced into clinical practice, it is likely that more ADEs will be encountered. The advent of targeted therapies in oncology has produced a number of novel complications in the oral cavity. Oral health care providers should be aware of the manifestations of ADEs encountered in their practice.

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

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OOOO Volume 119, Number 1 192. Salvana EM, Salata RA. Infectious complications associated with monoclonal antibodies and related small molecules. Clin Microbiol Rev. 2009;22:274-290, Table of Contents. 193. Hom KA, Hirsch R, Elluru RG. Antihypertensive drug-induced angioedema causing upper airway obstruction in children. Int J Pediatr Otorhinolaryngol. 2012;76:14-19. 194. Rafii MS, Koenig M, Ziai WC. Orolingual angioedema associated 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 angioedema in the oral floor and epiglottis. Am J Otolaryngol. 2011;32:624-626. 196. Southward J, Irvine E, Rabinovich M. Probable amlodipineinduced angioedema. Ann Pharmacother. 2009;43:772-776. 197. Ruscin JM, Page RL 2nd, Scott J. Hydrochlorothiazide-induced angioedema in a patient allergic to sulfonamide antibiotics: evidence from a case report and a review of the literature. Am J Geriatr Pharmacother. 2006;4:325-329. 198. Fischer TC, Worm M, Groneberg DA. Clopidogrel-associated angioedema. Am J Med. 2003;114:77-78. 199. Nisly SAAK, Knight TB. Simvastatin: a risk factor for angioedema? J Pharmacy Technol. 2013;29:149-152. 200. Liebhaber MI, Wright RS, Gelberg HJ, Dyer Z, Kupperman JL. Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten 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 and eosinophilia with atorvastatin. Pharm World Sci. 2005;27: 279-280. 203. Bagg A, Dunphy CH. Immunosuppressive and immunomodulatory therapy-associated lymphoproliferative disorders. Semin Diagn Pathol. 2013;30:102-112. 204. Hoshida Y, Xu JX, Fujita S, et al. Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in 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 methotrexateassociated lymphoproliferative disorders. Acta Med Okayama. 2013;67:265-269. 206. Ichikawa A, Arakawa F, Kiyasu J, et al. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol. 2013;91: 20-28. 207. Kikuchi K, Miyazaki Y, Tanaka A, et al. Methotrexate-related Epstein-Barr virus (EBV)-associated lymphoproliferative disorderdso-called “Hodgkin-like lesion”dof the oral cavity in a patient with rheumatoid arthritis. Head Neck Pathol. 2010;4: 305-311.

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