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Oral ulcerations due to drug medications
Japanese Dental Science Review (2014) 50, 40—46
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/jdsr
Review Article
Oral ulcerations due to drug medications Yoshinori Jinbu a,*, Toshio Demitsu b a b
Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Tochigi, Japan Department of Dermatology Saitama Medical Center, Jichi Medical University, Saitama, Japan
Received 9 July 2013; received in revised form 4 December 2013; accepted 5 December 2013
KEYWORDS Oral ulceration; Drug medication; Differential diagnosis
Summary Ulcers are common symptoms observed in the oral cavity and some ulcerations are induced by drug medications. When ulcers show typical clinical findings differential diagnosis may be easy, but the exact diagnosis is often difficult. We reviewed differential diagnosis of oral ulcerative diseases, clinical characteristics of drug-induced oral ulcerations and drugs inducing oral ulcerations. Many kinds of drugs have been reported to cause oral ulcerations. Among them, non-steroidal anti-inflammatory drugs are popular and well-known. However, several recent reports have described oral ulceration associated with relatively new drugs for the treatment of chronic disorders such as, diabetes, angina pectoris, rheumatoid arthritis, and osteoporosis. We reviewed these new drugs and also reported typical cases of drug-induced oral ulcerations. # 2013 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . Oral ulcers . . . . . . . . . . . . . . . . . . . . . . . . . Differential diagnosis . . . . . . . . . . . . . . . . . . Clinical features of drug-induced oral ulceration . Drugs inducing oral ulcerations . . . . . . . . . . . . Treatment of drug-induced oral ulcerations . . . . Case presentation . . . . . . . . . . . . . . . . . . . . 7.1. Case 1. . . . . . . . . . . . . . . . . . . . . . . . 7.2. Case 2. . . . . . . . . . . . . . . . . . . . . . . . 7.3. Case 3. . . . . . . . . . . . . . . . . . . . . . . . 7.4. Case 4. . . . . . . . . . . . . . . . . . . . . . . . 7.5. Case 5. . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +81 285587390; fax: +81 285448669. E-mail address: [email protected] (Y. Jinbu). 1882-7616/$ — see front matter # 2013 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdsr.2013.12.001
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Oral ulcerations
41
1. Introduction
3. Differential diagnosis
Many kinds of adverse reactions induced by drug medications in the oral cavity are now well recognized [1—3]. Among these, the most frequent are dry mouth (hyposalivation), dysgeusia, and stomatitis. Stomatitis is a general term for disturbance of oral epithelial cells and covers several types of oral mucosal symptoms. Oral mucosal symptoms caused by drugs can be further divided as follows: (1) lichenoid reaction/lichen planus; (2) ulcers; (3) erythema multiforme; (4) pigmentation; (5) autoimmune vesiculo-bullous disease; (6) infections; (7) tumors (fibrovascular hyperplasia); (8) swellings (angioedema); and (9) keratosis [1]. This paper focuses on ulcers and/or erosions in the oral cavity induced by pharmacotherapy, with an emphasis on new drugs for the treatment of chronic diseases such as diabetes, angina pectoris, rheumatoid arthritis and osteoporosis.
Careful examination of the oral mucosa is the most important factor for determining a provisional diagnosis. Patients are often confused by the term stomatitis, and the precise nature of the complaint should be confirmed. The age, sex, and dental and medical histories of the patient may provide useful information, and the number, shape, size, and location of lesions must also be carefully observed [7,8]. Traumatic ulceration is caused by mechanical, thermal, or chemical irritants. The most frequent causes are ill-fitting dentures, sharp-edged crowns or bridges, and tooth decay. The ulcer floor is usually clear and ulcer margins do not typically show induration on palpation, but sometimes show bleeding, granular appearance, or induration resembling malignant tumor. Viral infection is generally associated with multiple small aphthous ulcerations. The initial presentation is fluid-filled vesicles, but these rapidly break down to form small, round, painful ulcers with ragged margins that often fuse to form large, irregular ulcers. Viral infections in the oral cavity are most commonly due to herpes simplex virus (HSV)-1, varicella-zoster virus (VZV), coxsackie virus and cytomegalovirus. Acute herpes zoster causes eruption of multiple small, painful vesicles that rapidly rupture to form punctate or confluent ulcers in a portion of the trigeminal nerve distribution [7]. Aphthous ulceration is the most common type of oral ulceration and improves within 10—14 days. The lesions usually occur in non-keratinizing epithelium and form small,
2. Oral ulcers Oral ulcers are common symptoms observed in the oral cavity and include traumatic, infective, aphthous, ulceration related to dermatoses, drug-induced, ulceration as a manifestation of systemic disease, and ulceration due to malignancy (Table 1) [4—6]. When ulcers show typical clinical findings, differential diagnosis may be easy; however, the exact diagnosis is difficult in most cases, and histopathological diagnosis may be needed.
Table 1
Chronic oral ulcers.
Diagnosis
Clinical features
Drug-induced ulcers
Single, isolated ulcers, located on the side of the tongue, surrounded by an erythematous halo and resistant to usual treatments Areas of atrophy, erosions or painful ulcers, generally resistant to conventional treatments Bullae appear in oral cavity (posterior region), forming painful ulcers with necrotic fundus and erythematous halo Spontaneous onset of bullae that readily rupture, giving rise to a highly painful ulcerated area (most common areas are palate and gingiva) Erythema and oral ulcers, without induration and accompanied by whitish striae and a tendency to bleeding Arthritis, urethritis, conjunctivitis and oral ulcers similar to those of recurrent aphtous stomatitis Primary tuberculosis: deep, irregular, persistent and painful ulcer on the tongue, with rolled border and granulation tissue in the fundus Secondary tuberculosis: chronic ulcer, painful and indurated Mycoses give rise to chronic ulcers on the oral mucosa, most commonly in immunocompromised patients Klebsiella and Leishmania spp. can produce chronic oral ulcers in HIV-infected patients Large ulcer, generally in the tongue, with raised, indurated borders and white-yellowish fundus that may resemble a malignant lesion. Persists for weeks or months Can produce ulcers (exophytic, endophytic or mixed). Metastatic lesion can appear as ulcers in the oral cavity
Erosive lichen planus Pemphigus vulgaris Mucous membrane pemphigoid Lupus erythematosus Reiter’s syndrome Tuberculosis
Mycosis Other bacterial and parasitic diseases Eosinophilic ulcer Oral squamous cell carcinoma Munoz-Corcuera et al. [5]. HIV, human immunodeficiency virus.
42 round or oval ulcers covered with pseudomembrane surrounded by an erythematous halo. Similar lesions have been seen in association with various systemic conditions, such as Behc¸et’s disease, Crohn’s disease, celiac disease and ulcerative colitis [9—11]. Major-type aphtha appear as large, painful ulcers and healing may result in mucosal scarring; this type of ulceration can mimic other diseases, such as malignant lesions. The exact etiology of aphthous ulceration is unclear, but some altered local immune response is considered as a predisposing factor. Lichen planus varies in clinical appearance. The typical type of oral lichen planus (OLP) shows bilateral and symmetrical white lace-like patterns of buccal mucosa, but ulceration is frequently seen in the lesion [12,13]. This ulceration is usually surrounded by fine reticular white lines radiating from its border. Another type of ulceration involves focal red granular areas co-existing with a typical white reticular pattern. The etiology of OLP is unclear, but the mechanism appears to be immunologically mediated. Some drugs and metal allergies can cause similar lesions, known as oral lichenoid lesions (OLL), but both clinical and histopathological diagnosis is often very difficult. Quite similar lesions are seen in patients with graft-versus-host disease and collagenous diseases such as systemic lupus erythematosus. Pemphigus vulgaris is an autoimmune bullous disease with autoantibodies against desmosome-related proteins desmoglein 1 and/or 3 [14—16]. Oral lesions develop in about 70% of cases, and over 50% of cases show oral lesions as the initial manifestation. Painful, shallow, irregular ulcers with friable adjacent mucosa are a characteristic feature and lateral shearing force on the mucosa can produce a surface slough or induce vesicle formation (Nikolsky sign). Histologically, intraepithelial acantholysis is characteristic. Blood analysis for autoantibodies against desmoglein 1 and 3 using enzymelinked immunosorbent assay and immunofluorescence are useful for diagnosis. Bullous pemphigoid is also an autoimmune disease with autoantibody against BP180NC16a, a component of hemidesmosome [17]. Formation of firm blisters against an erythematous background is the main cutaneous symptom. In the oral cavity, multiple well-defined or diffuse ulcers are seen. Histopathologically, subepithelial blistering with numerous eosinophils is seen. The level of BP180 antibodies correlates with disease activity. Mucous membrane pemphigoid shows redness with erosions, gray-white vesicles or blisters on the oral mucosa [18,19]. Desquamation of the gingiva is a typical finding with this disease. Immunofluorescence microscopy reveals a linear arrangement along the basement membrane zone of immunoglobulin (Ig)G, C3 and occasionally IgA. Circulating autoantibodies are detected by indirect immunofluorescence microscopy, but the titer is usually very low. Autoantibody against the cellular fragment of BP180 may be pathogenic in some cases, while antibodies against laminin-332 may be pathogenic in others. In erythema multiforme or erythema exudative multiforme, oral mucosal lesions appear a few days after the onset of symmetrical target skin lesions [20,21]. Severe widespread painful erosions covered with a gray-white pseudomembrane associated with ocular and genital lesions are seen. Erosive and hemorrhagic cheilitis with bleeding crusts
Y. Jinbu, T. Demitsu is a characteristic symptom, induced by pharmacotherapy or viral infection. Triggering drugs include sulfonamides, piroxicam, non-steroidal antirheumatic agents, allopurinol, barbiturates, phenytoin, pyrazolone derivatives, and sulfones. Exposure of the oral cavity to radiation induces widespread mucosal erythema, atrophy, ulceration, and pseudomembrane formation. These pathologies are caused by destruction of the germinative layers of oral mucosal epithelium and enhanced by intraoral bacterial infection. Squamous cell carcinoma is the most frequent malignancy of the oral mucosa. In the early stages, white or red-white focal surface lesions are seen, while ulceration with induration and elevated margins is characteristic in later stages. The surface shows a granular and/or necrotic appearance with easy bleeding.
4. Clinical features of drug-induced oral ulceration Typical oral ulcers due to drugs are clinically classified into two types. The first is widespread mucositis and ulceration, mainly caused by cytotoxic drugs used for anti-tumor chemotherapy. Widespread sloughing and ulceration arise within days of commencing therapy, with the associated pain often requiring opioid therapy and alteration or cessation of chemotherapy. Such cytotoxic drugs include 5-fluorouracil, methotrexate, bleomycin, and cisplatin. Immunosuppressive agents may also cause oral ulceration through opportunistic secondary infections involving organisms such as Gram-negative bacteria and fungi. The second type is fixed drug eruption, showing repeated development of treatment-resistant ulcers [22]. Single or multiple large ulcerations are seen on every site of the oral mucosa. Generally, the ulceration is larger than aphthous ulceration, with a flat surface showing slightly white appearance. The margin of the ulcer is clear and often slightly raised; however, the ulcers are unaccompanied by any induration. They often resemble traumatic and decubital ulcers, but no irritant factors are apparent in their vicinity. A multiple aphthous ulceration type has also been reported [8]. Topical steroids are ineffective for these forms of ulceration [8]. Histopathological examination usually reveals non-specific ulcer formation with marked infiltration of inflammatory cells. The molecular mechanisms involved with these types of oral ulceration have yet to be clarified, but immunological reactions may play some role in the process.
5. Drugs inducing oral ulcerations Many kinds of drugs cause oral ulcerations, including some bblockers, immunosuppressants, anticholinergic bronchodilators, platelet aggregation inhibitors, vasodilators, protease inhibitors, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), antiretrovirals, and antihypertensives (Table 2) [1]. Among these, NSAIDs are popular drugs that are wellknown to induce oral ulcerations [23—25]. Several recent reports have described oral ulceration associated with relatively new drugs for the treatment of chronic disorders such as diabetes, angina pectoris, rheumatoid arthritis, and osteoporosis.
Oral ulcerations Table 2
43
Drugs inducing oral ulceration.
Antibiotics Anticholinergic bronchodilators Anti-hypertensives Antiretrovirals Anti-rheumatic drug Anti-septics Bisphosphonate b-Blockers Corticosteroids
Gastric ulcer treatments Hypoglycemic agents Immunosuppressants Interferons Non-steroidal anti-inflammatory drugs (NSAIDs) Platelet aggregation inhibitors Potassium-channel activators Protease inhibitors Vasodilators
Dipeptidyl peptidase (DPP)-4 inhibitors: DPP-4 inhibitors (e.g., sitagliptin) are newly developed oral hypoglycemic agents that gained approval for release in 2009 in Japan [26]. DPP-4 inhibitors or incretin enhancers have been introduced for the treatment of type 2 diabetes mellitus (T2DM) [27,28]. This class of glucose-lowering agents enhances levels of endogenous glucagon-like peptide (GLP)-1 and glucosedependent insulinotropic polypeptide (GIP) by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors restore the deranged islet-cell balance in T2DM, by stimulating mealrelated insulin secretion and by decreasing postprandial glucagon levels. Moreover, DPP-4 inhibitors have demonstrated beneficial effects on the functional b-cell mass and pancreatic insulin contents. As prevention and treatment of T2DM and its complications represent major healthcare issues worldwide, DPP-4 inhibitors are already in wide use in clinics around the world. We recently provided the first report of oral ulceration due to DPP-4 [29]. Nicorandil. Nicorandil belongs to a relatively new class of potassium-channel activators that are available around the world and in use for the prevention and long-term treatment of angina pectoris. Adverse effects of nicorandil therapy may include cutaneous vasodilatation, nausea and vomiting, dizziness, myalgia and rash. Over the past few years, cases in which nicorandil has caused oral ulceration have been reported [30—35]. Low-dose methotrexate (MTX): MTX is an antifolic agent with a well-established history of use in the treatment of various neoplastic diseases. Low-dose MTX has been widely used for rheumatoid arthritis (RA) as a disease-modifying antirheumatic drug [36,37]. Since MTX was approved as an antirheumatic drug in 1999, use of low-dose MTX has become widespread in Japan. About 60,000 patients are estimated to be taking low-dose MTX for the treatment of RA. As general adverse effects, gastrointestinal toxicity (nausea, vomiting, abdominal discomfort, anorexia, dyspepsia, diarrhea), hepatotoxicity (hepatitis, fibrosis, cirrhosis), myelosuppression (leukocytopenia, thrombocytopenia, pancytopenia), hyperhomocysteinemia, hypersensitivity causing pulmonary toxicity, central nervous system events (headaches, depression) and osteoporosis have been described [37]. Some reports have described stomatitis and oral ulcerations due to lowdose MTX [38—41]. Alendronate (bisphosphonate). Alendronate is a drug belonging to the diphosphonate family that has recently been used in the treatment of osteoporosis and other bone
diseases [42]. This drug has been demonstrated to induce progressive and significant increases in bone mineral density in women with osteoporosis [43]. Bisphosphonate-related osteonecrosis of the jaw is a well-established adverse effect of bisphosphonates [44,45], but oral ulceration as a result of taking alendronate has also recently been reported [46—50]. These oral ulcerations are induced by incorrect use of the drugs and are caused by the drugs causing direct irritation.
6. Treatment of drug-induced oral ulcerations Topical steroids are ineffective against these ulcers [8]. If ulcers do not show improvement despite topical steroid treatment for 1—2 weeks, and no signs of malignancy are evident, drug exposures must be carefully checked. If a medication is suspected as a cause of oral ulceration, contact must be made with the prescribing medical doctor to discuss the possibility of alternative medications or dose reduction. After cessation, change, or dose reduction of the drug, ulcerations may improve in 1—2 weeks. It is further necessary to confirm that the drug is really a responsible drug, so restarting the drug may be important, but is very difficult.
7. Case presentation 7.1. Case 1 The patient was a 76-year-old woman who presented with ulceration of the left tongue margin. Her medical history revealed articular rheumatism, diabetes, hypertension, and anemia. She had been treated with indomethacin (75 mg/ day) to control pain from articular rheumatism. Ulceration (20 mm 14 mm) on the left tongue margin with no induration was observed (Fig. 1). The surface was flat and clean, with no bleeding. The ulcer margin was slightly raised. Clinically, decubitus ulcer was suspected, but no improvement was observed after application of a topical steroid. We considered the denture was not a cause and instructed the patient to stop taking indomethacin after consulting with her physician. The oral ulceration showed re-epithelialization after 2 weeks [25].
Figure 1 Indomethacin-induced oral ulceration. Ulceration on the left tongue margin with no induration. Line shows the biopsy site.
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Y. Jinbu, T. Demitsu
Figure 2 Oral ulceration due to low-dose MTX. Ulceration on the left floor of the mouth with no induration.
7.2. Case 2 The patient was a 71-year-old man with oral mucosal ulceration of the floor of the mouth and a 6-year history of rheumatoid arthritis (RA). Medical history included RA, hypertension, prostatic hyperplasia, and cardiac disease. He had been treated with methotrexate (MTX) at 8 mg/week. Ulceration (22 mm 18 mm) on the left floor of the mouth was seen, showing no induration (Fig. 2). The surface of the ulceration was flat and clean, with no bleeding. Ulceration did not improve with corticosteroid treatment. We considered the denture was not a cause and contacted his physician. After the dose of MTX was reduced from 8 mg/week to 2 mg/week, oral ulceration greatly improved and re-epithelialization was achieved [40].
7.3. Case 3 The patient was a 77-year-old woman referred with oral ulceration. Medical history included type 2 diabetes mellitus and treatment with DPP-4 inhibitors for 1.5 years. Ulceration (10 mm 7 mm) was apparent on the left labial mucosa (Fig. 3). The surface of the ulcer was flat and clean, with no bleeding or induration. Ulcer margins were slightly raised. As the ulcer remained unimproved despite topical steroid
Figure 4 Oral ulcerations induced by incorrect use of alendronate. Several ulcerations on the lower lip, soft palate, and upper and lower gingiva.
treatment, the ulcer was surgically resected. However, the ulcer recurred 3 weeks after surgery. After consultation with her physician and cessation of DPP-4 inhibitor, re-epithelialization was completed within 16 days [29].
7.4. Case 4
Figure 3 Oral ulceration due to DPP-4 inhibitor. Ulceration on the left labial mucosa.
The patient was an 82-year-old woman who complained of oral ulcerations. She had been treated for osteoporosis with alendronate for 5 years. Several ulcerations on the lower lip, soft palate, and upper and lower gingiva were observed (Fig. 4). These ulcers showed irregular shape and were covered with pseudomembrane. Autoimmune bullous disease
Oral ulcerations
45
Conflict of interest None declared.
References
Figure 5 Oral ulcerations due to nicorandil. Multiple ulcers on bilateral buccal mucosa and bilateral tongue margins.
was clinically suspected, but blood examination showed negative results. We contacted her physician and alendronate was stopped. Ulcerations showed complete epithelialization within 7 days. On questioning, she was found to have been sucking the tablets instead of swallowing them [50].
7.5. Case 5 The patient was a 77-year-old man who complained of multiple oral ulcers. His medical history included angina pectoris and atrial fibrillation, and he had been treated with several drugs. After changing medication to nicorandil, he noticed multiple oral ulcerations. Multiple ulcers were seen on the bilateral buccal mucosa and bilateral tongue margins (Fig. 5). These ulcers were irregularly shaped and the surface was covered with pseudomembrane without induration. After contacting his physician, nicorandil was changed to another drug. Ulcerations subsequently improved within 2 weeks.
8. Conclusion Oral ulcers are common symptoms observed in the oral cavity and many kinds of drug have been reported to induce oral ulcerations. When drug-induced oral ulcerations are suspected after careful clinical observation and check of drug medications, contact must be made with the prescribing medical doctor to discuss the possibility of alternative medications or dose reduction.
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Y. Jinbu, T. Demitsu [37] Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001;8:729—35. [38] Deeming GMJ, Collingwood J, Pemberton MN. Methotrexate and oral ulceration. Br Dent J 2005;198:83—5. [39] Kalantzis A, Mashman Z, Falconer DT, Morgan PR, Odell EW. Oral effects of low-dose methotrexate treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:52—62. [40] Jinbu Y, Obi Y, Kawa R, Ikeda K, Kusama M, Tsukinoki K. Oral ulceration due to an antirheumatic drug (methotrexate): report of a case. Oral Med Pathol 2008;12:97—9. [41] Iwamoto O, Nakamura M, Koga C, Kusukawa J. A case of oral mucous membrane ulcer caused by disease modifying antirheumatic drug (DMARD). J Jpn Oral Muco Membr 2007;13: 43—6. [42] Selby P. Alendronate treatment for osteoporosis: a review of the clinical evidence. Osteoporos Int 1996;6:419—26. [43] Saag KG, Emkey R, Schnitzer TJ. Glucocorticoid-induced osteoporosis intervention study group. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998;339:292—9. [44] Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonateinduced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567—75. [45] Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005;23:8580—7. [46] Gonzales-Moles MA, Bagan-Sebastin JV. Alendronate-related oral mucosa ulcerations. J Oral Pathol Med 2000;29:514—8. [47] Demerjian N, Bolla G, Spreux A. Severe oral ulcerations induced by alendronate. Clin Rheumatol 1999;18:349—50. [48] Rubegni P, Finiami M. Bisphosphonate-associated contact stomatitis. N Engl J Med 2006;355:22. [49] Aleid W, Sidebottom A. Oral mucosal irritation with incorrect use of alendronate. Br J Oral Maxillofac Surg 2009;47: 166—71. [50] Jinbu Y, Ioka Y, Kawashima R, Kato R, Kusama M. Oral ulcerations induced by sucking the tablets of bisphosphonate (alendronate) in the oral cavity. J Jpn Oral Muco Membr 2010;16:24—7.
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Review Article
Oral ulcerations due to drug medications Yoshinori Jinbu a,*, Toshio Demitsu b a b
Department of Dentistry, Oral and Maxillofacial Surgery, Jichi Medical University, Tochigi, Japan Department of Dermatology Saitama Medical Center, Jichi Medical University, Saitama, Japan
Received 9 July 2013; received in revised form 4 December 2013; accepted 5 December 2013
KEYWORDS Oral ulceration; Drug medication; Differential diagnosis
Summary Ulcers are common symptoms observed in the oral cavity and some ulcerations are induced by drug medications. When ulcers show typical clinical findings differential diagnosis may be easy, but the exact diagnosis is often difficult. We reviewed differential diagnosis of oral ulcerative diseases, clinical characteristics of drug-induced oral ulcerations and drugs inducing oral ulcerations. Many kinds of drugs have been reported to cause oral ulcerations. Among them, non-steroidal anti-inflammatory drugs are popular and well-known. However, several recent reports have described oral ulceration associated with relatively new drugs for the treatment of chronic disorders such as, diabetes, angina pectoris, rheumatoid arthritis, and osteoporosis. We reviewed these new drugs and also reported typical cases of drug-induced oral ulcerations. # 2013 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . Oral ulcers . . . . . . . . . . . . . . . . . . . . . . . . . Differential diagnosis . . . . . . . . . . . . . . . . . . Clinical features of drug-induced oral ulceration . Drugs inducing oral ulcerations . . . . . . . . . . . . Treatment of drug-induced oral ulcerations . . . . Case presentation . . . . . . . . . . . . . . . . . . . . 7.1. Case 1. . . . . . . . . . . . . . . . . . . . . . . . 7.2. Case 2. . . . . . . . . . . . . . . . . . . . . . . . 7.3. Case 3. . . . . . . . . . . . . . . . . . . . . . . . 7.4. Case 4. . . . . . . . . . . . . . . . . . . . . . . . 7.5. Case 5. . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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* Corresponding author. Tel.: +81 285587390; fax: +81 285448669. E-mail address: [email protected] (Y. Jinbu). 1882-7616/$ — see front matter # 2013 Japanese Association for Dental Science. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdsr.2013.12.001
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Oral ulcerations
41
1. Introduction
3. Differential diagnosis
Many kinds of adverse reactions induced by drug medications in the oral cavity are now well recognized [1—3]. Among these, the most frequent are dry mouth (hyposalivation), dysgeusia, and stomatitis. Stomatitis is a general term for disturbance of oral epithelial cells and covers several types of oral mucosal symptoms. Oral mucosal symptoms caused by drugs can be further divided as follows: (1) lichenoid reaction/lichen planus; (2) ulcers; (3) erythema multiforme; (4) pigmentation; (5) autoimmune vesiculo-bullous disease; (6) infections; (7) tumors (fibrovascular hyperplasia); (8) swellings (angioedema); and (9) keratosis [1]. This paper focuses on ulcers and/or erosions in the oral cavity induced by pharmacotherapy, with an emphasis on new drugs for the treatment of chronic diseases such as diabetes, angina pectoris, rheumatoid arthritis and osteoporosis.
Careful examination of the oral mucosa is the most important factor for determining a provisional diagnosis. Patients are often confused by the term stomatitis, and the precise nature of the complaint should be confirmed. The age, sex, and dental and medical histories of the patient may provide useful information, and the number, shape, size, and location of lesions must also be carefully observed [7,8]. Traumatic ulceration is caused by mechanical, thermal, or chemical irritants. The most frequent causes are ill-fitting dentures, sharp-edged crowns or bridges, and tooth decay. The ulcer floor is usually clear and ulcer margins do not typically show induration on palpation, but sometimes show bleeding, granular appearance, or induration resembling malignant tumor. Viral infection is generally associated with multiple small aphthous ulcerations. The initial presentation is fluid-filled vesicles, but these rapidly break down to form small, round, painful ulcers with ragged margins that often fuse to form large, irregular ulcers. Viral infections in the oral cavity are most commonly due to herpes simplex virus (HSV)-1, varicella-zoster virus (VZV), coxsackie virus and cytomegalovirus. Acute herpes zoster causes eruption of multiple small, painful vesicles that rapidly rupture to form punctate or confluent ulcers in a portion of the trigeminal nerve distribution [7]. Aphthous ulceration is the most common type of oral ulceration and improves within 10—14 days. The lesions usually occur in non-keratinizing epithelium and form small,
2. Oral ulcers Oral ulcers are common symptoms observed in the oral cavity and include traumatic, infective, aphthous, ulceration related to dermatoses, drug-induced, ulceration as a manifestation of systemic disease, and ulceration due to malignancy (Table 1) [4—6]. When ulcers show typical clinical findings, differential diagnosis may be easy; however, the exact diagnosis is difficult in most cases, and histopathological diagnosis may be needed.
Table 1
Chronic oral ulcers.
Diagnosis
Clinical features
Drug-induced ulcers
Single, isolated ulcers, located on the side of the tongue, surrounded by an erythematous halo and resistant to usual treatments Areas of atrophy, erosions or painful ulcers, generally resistant to conventional treatments Bullae appear in oral cavity (posterior region), forming painful ulcers with necrotic fundus and erythematous halo Spontaneous onset of bullae that readily rupture, giving rise to a highly painful ulcerated area (most common areas are palate and gingiva) Erythema and oral ulcers, without induration and accompanied by whitish striae and a tendency to bleeding Arthritis, urethritis, conjunctivitis and oral ulcers similar to those of recurrent aphtous stomatitis Primary tuberculosis: deep, irregular, persistent and painful ulcer on the tongue, with rolled border and granulation tissue in the fundus Secondary tuberculosis: chronic ulcer, painful and indurated Mycoses give rise to chronic ulcers on the oral mucosa, most commonly in immunocompromised patients Klebsiella and Leishmania spp. can produce chronic oral ulcers in HIV-infected patients Large ulcer, generally in the tongue, with raised, indurated borders and white-yellowish fundus that may resemble a malignant lesion. Persists for weeks or months Can produce ulcers (exophytic, endophytic or mixed). Metastatic lesion can appear as ulcers in the oral cavity
Erosive lichen planus Pemphigus vulgaris Mucous membrane pemphigoid Lupus erythematosus Reiter’s syndrome Tuberculosis
Mycosis Other bacterial and parasitic diseases Eosinophilic ulcer Oral squamous cell carcinoma Munoz-Corcuera et al. [5]. HIV, human immunodeficiency virus.
42 round or oval ulcers covered with pseudomembrane surrounded by an erythematous halo. Similar lesions have been seen in association with various systemic conditions, such as Behc¸et’s disease, Crohn’s disease, celiac disease and ulcerative colitis [9—11]. Major-type aphtha appear as large, painful ulcers and healing may result in mucosal scarring; this type of ulceration can mimic other diseases, such as malignant lesions. The exact etiology of aphthous ulceration is unclear, but some altered local immune response is considered as a predisposing factor. Lichen planus varies in clinical appearance. The typical type of oral lichen planus (OLP) shows bilateral and symmetrical white lace-like patterns of buccal mucosa, but ulceration is frequently seen in the lesion [12,13]. This ulceration is usually surrounded by fine reticular white lines radiating from its border. Another type of ulceration involves focal red granular areas co-existing with a typical white reticular pattern. The etiology of OLP is unclear, but the mechanism appears to be immunologically mediated. Some drugs and metal allergies can cause similar lesions, known as oral lichenoid lesions (OLL), but both clinical and histopathological diagnosis is often very difficult. Quite similar lesions are seen in patients with graft-versus-host disease and collagenous diseases such as systemic lupus erythematosus. Pemphigus vulgaris is an autoimmune bullous disease with autoantibodies against desmosome-related proteins desmoglein 1 and/or 3 [14—16]. Oral lesions develop in about 70% of cases, and over 50% of cases show oral lesions as the initial manifestation. Painful, shallow, irregular ulcers with friable adjacent mucosa are a characteristic feature and lateral shearing force on the mucosa can produce a surface slough or induce vesicle formation (Nikolsky sign). Histologically, intraepithelial acantholysis is characteristic. Blood analysis for autoantibodies against desmoglein 1 and 3 using enzymelinked immunosorbent assay and immunofluorescence are useful for diagnosis. Bullous pemphigoid is also an autoimmune disease with autoantibody against BP180NC16a, a component of hemidesmosome [17]. Formation of firm blisters against an erythematous background is the main cutaneous symptom. In the oral cavity, multiple well-defined or diffuse ulcers are seen. Histopathologically, subepithelial blistering with numerous eosinophils is seen. The level of BP180 antibodies correlates with disease activity. Mucous membrane pemphigoid shows redness with erosions, gray-white vesicles or blisters on the oral mucosa [18,19]. Desquamation of the gingiva is a typical finding with this disease. Immunofluorescence microscopy reveals a linear arrangement along the basement membrane zone of immunoglobulin (Ig)G, C3 and occasionally IgA. Circulating autoantibodies are detected by indirect immunofluorescence microscopy, but the titer is usually very low. Autoantibody against the cellular fragment of BP180 may be pathogenic in some cases, while antibodies against laminin-332 may be pathogenic in others. In erythema multiforme or erythema exudative multiforme, oral mucosal lesions appear a few days after the onset of symmetrical target skin lesions [20,21]. Severe widespread painful erosions covered with a gray-white pseudomembrane associated with ocular and genital lesions are seen. Erosive and hemorrhagic cheilitis with bleeding crusts
Y. Jinbu, T. Demitsu is a characteristic symptom, induced by pharmacotherapy or viral infection. Triggering drugs include sulfonamides, piroxicam, non-steroidal antirheumatic agents, allopurinol, barbiturates, phenytoin, pyrazolone derivatives, and sulfones. Exposure of the oral cavity to radiation induces widespread mucosal erythema, atrophy, ulceration, and pseudomembrane formation. These pathologies are caused by destruction of the germinative layers of oral mucosal epithelium and enhanced by intraoral bacterial infection. Squamous cell carcinoma is the most frequent malignancy of the oral mucosa. In the early stages, white or red-white focal surface lesions are seen, while ulceration with induration and elevated margins is characteristic in later stages. The surface shows a granular and/or necrotic appearance with easy bleeding.
4. Clinical features of drug-induced oral ulceration Typical oral ulcers due to drugs are clinically classified into two types. The first is widespread mucositis and ulceration, mainly caused by cytotoxic drugs used for anti-tumor chemotherapy. Widespread sloughing and ulceration arise within days of commencing therapy, with the associated pain often requiring opioid therapy and alteration or cessation of chemotherapy. Such cytotoxic drugs include 5-fluorouracil, methotrexate, bleomycin, and cisplatin. Immunosuppressive agents may also cause oral ulceration through opportunistic secondary infections involving organisms such as Gram-negative bacteria and fungi. The second type is fixed drug eruption, showing repeated development of treatment-resistant ulcers [22]. Single or multiple large ulcerations are seen on every site of the oral mucosa. Generally, the ulceration is larger than aphthous ulceration, with a flat surface showing slightly white appearance. The margin of the ulcer is clear and often slightly raised; however, the ulcers are unaccompanied by any induration. They often resemble traumatic and decubital ulcers, but no irritant factors are apparent in their vicinity. A multiple aphthous ulceration type has also been reported [8]. Topical steroids are ineffective for these forms of ulceration [8]. Histopathological examination usually reveals non-specific ulcer formation with marked infiltration of inflammatory cells. The molecular mechanisms involved with these types of oral ulceration have yet to be clarified, but immunological reactions may play some role in the process.
5. Drugs inducing oral ulcerations Many kinds of drugs cause oral ulcerations, including some bblockers, immunosuppressants, anticholinergic bronchodilators, platelet aggregation inhibitors, vasodilators, protease inhibitors, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), antiretrovirals, and antihypertensives (Table 2) [1]. Among these, NSAIDs are popular drugs that are wellknown to induce oral ulcerations [23—25]. Several recent reports have described oral ulceration associated with relatively new drugs for the treatment of chronic disorders such as diabetes, angina pectoris, rheumatoid arthritis, and osteoporosis.
Oral ulcerations Table 2
43
Drugs inducing oral ulceration.
Antibiotics Anticholinergic bronchodilators Anti-hypertensives Antiretrovirals Anti-rheumatic drug Anti-septics Bisphosphonate b-Blockers Corticosteroids
Gastric ulcer treatments Hypoglycemic agents Immunosuppressants Interferons Non-steroidal anti-inflammatory drugs (NSAIDs) Platelet aggregation inhibitors Potassium-channel activators Protease inhibitors Vasodilators
Dipeptidyl peptidase (DPP)-4 inhibitors: DPP-4 inhibitors (e.g., sitagliptin) are newly developed oral hypoglycemic agents that gained approval for release in 2009 in Japan [26]. DPP-4 inhibitors or incretin enhancers have been introduced for the treatment of type 2 diabetes mellitus (T2DM) [27,28]. This class of glucose-lowering agents enhances levels of endogenous glucagon-like peptide (GLP)-1 and glucosedependent insulinotropic polypeptide (GIP) by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors restore the deranged islet-cell balance in T2DM, by stimulating mealrelated insulin secretion and by decreasing postprandial glucagon levels. Moreover, DPP-4 inhibitors have demonstrated beneficial effects on the functional b-cell mass and pancreatic insulin contents. As prevention and treatment of T2DM and its complications represent major healthcare issues worldwide, DPP-4 inhibitors are already in wide use in clinics around the world. We recently provided the first report of oral ulceration due to DPP-4 [29]. Nicorandil. Nicorandil belongs to a relatively new class of potassium-channel activators that are available around the world and in use for the prevention and long-term treatment of angina pectoris. Adverse effects of nicorandil therapy may include cutaneous vasodilatation, nausea and vomiting, dizziness, myalgia and rash. Over the past few years, cases in which nicorandil has caused oral ulceration have been reported [30—35]. Low-dose methotrexate (MTX): MTX is an antifolic agent with a well-established history of use in the treatment of various neoplastic diseases. Low-dose MTX has been widely used for rheumatoid arthritis (RA) as a disease-modifying antirheumatic drug [36,37]. Since MTX was approved as an antirheumatic drug in 1999, use of low-dose MTX has become widespread in Japan. About 60,000 patients are estimated to be taking low-dose MTX for the treatment of RA. As general adverse effects, gastrointestinal toxicity (nausea, vomiting, abdominal discomfort, anorexia, dyspepsia, diarrhea), hepatotoxicity (hepatitis, fibrosis, cirrhosis), myelosuppression (leukocytopenia, thrombocytopenia, pancytopenia), hyperhomocysteinemia, hypersensitivity causing pulmonary toxicity, central nervous system events (headaches, depression) and osteoporosis have been described [37]. Some reports have described stomatitis and oral ulcerations due to lowdose MTX [38—41]. Alendronate (bisphosphonate). Alendronate is a drug belonging to the diphosphonate family that has recently been used in the treatment of osteoporosis and other bone
diseases [42]. This drug has been demonstrated to induce progressive and significant increases in bone mineral density in women with osteoporosis [43]. Bisphosphonate-related osteonecrosis of the jaw is a well-established adverse effect of bisphosphonates [44,45], but oral ulceration as a result of taking alendronate has also recently been reported [46—50]. These oral ulcerations are induced by incorrect use of the drugs and are caused by the drugs causing direct irritation.
6. Treatment of drug-induced oral ulcerations Topical steroids are ineffective against these ulcers [8]. If ulcers do not show improvement despite topical steroid treatment for 1—2 weeks, and no signs of malignancy are evident, drug exposures must be carefully checked. If a medication is suspected as a cause of oral ulceration, contact must be made with the prescribing medical doctor to discuss the possibility of alternative medications or dose reduction. After cessation, change, or dose reduction of the drug, ulcerations may improve in 1—2 weeks. It is further necessary to confirm that the drug is really a responsible drug, so restarting the drug may be important, but is very difficult.
7. Case presentation 7.1. Case 1 The patient was a 76-year-old woman who presented with ulceration of the left tongue margin. Her medical history revealed articular rheumatism, diabetes, hypertension, and anemia. She had been treated with indomethacin (75 mg/ day) to control pain from articular rheumatism. Ulceration (20 mm 14 mm) on the left tongue margin with no induration was observed (Fig. 1). The surface was flat and clean, with no bleeding. The ulcer margin was slightly raised. Clinically, decubitus ulcer was suspected, but no improvement was observed after application of a topical steroid. We considered the denture was not a cause and instructed the patient to stop taking indomethacin after consulting with her physician. The oral ulceration showed re-epithelialization after 2 weeks [25].
Figure 1 Indomethacin-induced oral ulceration. Ulceration on the left tongue margin with no induration. Line shows the biopsy site.
44
Y. Jinbu, T. Demitsu
Figure 2 Oral ulceration due to low-dose MTX. Ulceration on the left floor of the mouth with no induration.
7.2. Case 2 The patient was a 71-year-old man with oral mucosal ulceration of the floor of the mouth and a 6-year history of rheumatoid arthritis (RA). Medical history included RA, hypertension, prostatic hyperplasia, and cardiac disease. He had been treated with methotrexate (MTX) at 8 mg/week. Ulceration (22 mm 18 mm) on the left floor of the mouth was seen, showing no induration (Fig. 2). The surface of the ulceration was flat and clean, with no bleeding. Ulceration did not improve with corticosteroid treatment. We considered the denture was not a cause and contacted his physician. After the dose of MTX was reduced from 8 mg/week to 2 mg/week, oral ulceration greatly improved and re-epithelialization was achieved [40].
7.3. Case 3 The patient was a 77-year-old woman referred with oral ulceration. Medical history included type 2 diabetes mellitus and treatment with DPP-4 inhibitors for 1.5 years. Ulceration (10 mm 7 mm) was apparent on the left labial mucosa (Fig. 3). The surface of the ulcer was flat and clean, with no bleeding or induration. Ulcer margins were slightly raised. As the ulcer remained unimproved despite topical steroid
Figure 4 Oral ulcerations induced by incorrect use of alendronate. Several ulcerations on the lower lip, soft palate, and upper and lower gingiva.
treatment, the ulcer was surgically resected. However, the ulcer recurred 3 weeks after surgery. After consultation with her physician and cessation of DPP-4 inhibitor, re-epithelialization was completed within 16 days [29].
7.4. Case 4
Figure 3 Oral ulceration due to DPP-4 inhibitor. Ulceration on the left labial mucosa.
The patient was an 82-year-old woman who complained of oral ulcerations. She had been treated for osteoporosis with alendronate for 5 years. Several ulcerations on the lower lip, soft palate, and upper and lower gingiva were observed (Fig. 4). These ulcers showed irregular shape and were covered with pseudomembrane. Autoimmune bullous disease
Oral ulcerations
45
Conflict of interest None declared.
References
Figure 5 Oral ulcerations due to nicorandil. Multiple ulcers on bilateral buccal mucosa and bilateral tongue margins.
was clinically suspected, but blood examination showed negative results. We contacted her physician and alendronate was stopped. Ulcerations showed complete epithelialization within 7 days. On questioning, she was found to have been sucking the tablets instead of swallowing them [50].
7.5. Case 5 The patient was a 77-year-old man who complained of multiple oral ulcers. His medical history included angina pectoris and atrial fibrillation, and he had been treated with several drugs. After changing medication to nicorandil, he noticed multiple oral ulcerations. Multiple ulcers were seen on the bilateral buccal mucosa and bilateral tongue margins (Fig. 5). These ulcers were irregularly shaped and the surface was covered with pseudomembrane without induration. After contacting his physician, nicorandil was changed to another drug. Ulcerations subsequently improved within 2 weeks.
8. Conclusion Oral ulcers are common symptoms observed in the oral cavity and many kinds of drug have been reported to induce oral ulcerations. When drug-induced oral ulcerations are suspected after careful clinical observation and check of drug medications, contact must be made with the prescribing medical doctor to discuss the possibility of alternative medications or dose reduction.
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