Case Report

Stomatitis Medicamentosa‒a Case Report

Shaik Md. Asif1, Sultan Mohammed Kaleem1, Shefali Waghray2, Naheeda Shaheen3, and Renu Tanwar4

1Maxillo Facial Diagnostic Sciences, College of Dentistry, King Khalid University, Abha. Kingdom of Saudi Arabia.2Pananeya Dental College, Hyderabad, Andhra Pradesh, India.3Mamatha Dental College, Khammam. Andhra Pradesh, India.4SGT Dental College, Gurgaon, New Delhi, India.

Article History

Received 24 November 2011

Accepted � April 2012

Keywords :

stomatitis medicamentosa; IgE reac-

tion; eosinophils

Abstract

Mucosal allergies represent a growing problem and often go undiagnosed by health

professionals. The prevalence of mucosal allergies due to drugs routinely prescribed in

dental practice appears to be increasing. Ingestion of certain drugs by individuals with

idiosyncratic reactions or intolerance may result in allergic manifestations referred to as

stomatitis medicamentosa. The clinical features may vary from a burning sensation to

ulcerative lesions in the oral cavity. These lesions resolve with discontinuation of the

causative agent. However, antihistamines and steroids are the drugs of choice in severe

cases. We describe herein the case of a 45-year-old woman with an allergic reaction to an

Over- the- Counter drug, treated in the Department of Oral Medicine & Radiology at D.A.

Pandu Memorial R.V. Dental College, Bangalore, India. The pathogenesis, clinical features,

diagnosis and treatment are discussed.

Introduction

Drug allergy covers a variety of sensitivity reactions

following exposure to drugs and chemicals, but is unrelated

to any inherent pharmacological activity or toxicity of the

material. Practically every known drug has been recognized

at one time or another as capable of producing an allergic

reaction in a sensitive individual (1)). Certain drugs,

however, have a far great propensity for producing

reactions than others. It is impossible to list even a small

portion of the overwhelming number of drugs that have

been known to produce an allergic reaction (2). Several

categories of allergic reactions have significant oral and

facial involvements. These clinical entities are well defined

and frequently described in the medical and dental

literature(1, 2). The oral mucous membrane may be the

sole site of involvement or may be part of a more

generalized skin reaction to the offending drug. Mucosal

allergies represent a growing problem and often go

undiagnosed by health professionals(3). A mucosal allergic

reaction caused by systemic administration of drugs is

known as stomatitis medicamentosa. We present herein the

case of a 45-year-old woman with acute allergic reaction in

the oral cavity due to a Over- the-Counter drug.

Case report

A 45-year-old woman reported to the Department of Oral

Medicine & Radiology at D.A. Pandu Memorial R.V. Dental

College, Bangalore, India, with a 2-day history of a severe

burning sensation in the oral cavity. Initially the patient

experienced burning sensation within half an hour after

administration of an Over- the- Counter drug (ibuprofen)

she had obtained from the pharmacist for tooth pain. The

burning sensation became suddenly and severely aggra-

vated after administration of a second dose. There was no

history of fever following administration of this drug.. A

history of disturbed sleep and difficulty swallowing due to

the burning sensation was elicited. Her medical, dental and

family histories were non-contributory. The patient was

poorly nourished and of slight build, with no signs of anemia

or icterus. No cutaneous or ocular lesions were apparent.

Intraoral examination revealed multiple (10-12) ulcers at

the vermilion border of the lower lip and angle of the mouth

(Fig. 1). The ulcers were encrusted and showed varying

Int J Oral-Med Sci 11(1):57-61, 2012 57

Correspondence to :

Shaik Md. Asif.

E-mail : drasif_2002@rediffmail.com

sizes of 1-2mm. The dorsal surface of the tongue was

coated with yellowish slough and movements of the tongue

were restricted due to presence of ulcers on the tongue

(Fig. 2). Similar ulcerative lesions measuring 1×2mmwere

seen bilaterally over the entire buccal mucosa. Mouth

opening was restricted due to the presence of ulcers in the

retromolar area. Based on the chief complaint and drug

history, a provisional diagnosis of stomatitis medicamentosa

was made. Differential diagnoses for the lesions included

erythema multiforme (EM). Skin testing was performed on

the inner surface of the patientʼs forearm by intradermal

inoculation of the suspected allergen (ibuprofen). Skin

erythema was apparent at the site of inoculation within 20

min after inoculation. The patient was referred for further

investigations, and peripheral blood smears showed an

increase in relative eosinophil count to 15% (normal, 1-4%)

using Wrightʼs stain to count the eosinophils. The erythro-

cyte sedimentation rate was higher than normal, at 57mm/h

(normal, 0-20mm/h). Periodic acid Schiff staining of

scrapings from lesions was non contributory. An increase in

serum immunoglobulin (Ig) E levels to 1,120IU/ml sug-

gested a type I hypersensitivity reaction. Based on these

investigations, skin test results and the elicited history, we

reached a conclusive diagnosis of stomatitis medicamentosa.

The patient was instructed to discontinue usage of the drug

after diagnosing the condition and was later prescribed

systemic steroids (prednisolone, 60mg/day) for 1 week

along with topical antihistamines (benzydamine hydrochlor-

ide) and germicidal (chlorhexidine) mouthwash. To over-

come complications associated with steroid use, the dosage

was tapered to 30mg/day after the first week. After 3

weeks of therapy, all lesions had completely resolved (Figs.

3, 4) and the patient was referred to an endodontist for

evaluation of the tooth pain.

Discussion

The list of offending medications and their resultant side

effects appears endless. In a short and highly beneficial

article, Matthews listed more than 150 frequently pre-

scribed medications and related them to 46 oral and perioral

side effects(4). The oral mucosa is exposed to a wide range

of ingested medications(5). However, immediate and severe

reactions have been reported in the literature(4, 5).

Pathogenesis

The term“allergy”is used to define a specific immune

reaction to one or more exogenous substances, termed

“allergens”. The immune system is made up of two

functional components: an adaptive component; and an

innate component(6). The innate immune system is situated

in organs such as the skin and mucosa. When an antigen

enters the body, specialized helper T-cells (Th cells)

respond to foreign materials in two ways: Th1 responses;

and Th2 responses. IgE is associated with Th2 responses,

58 Int J Oral-Med Sci 11(1):57-61, 2012

Fig. 1. Multiple ulcers on the vermilion border of the lower lipand angle of the mouth.

Fig. 2. Yellow slough on the dorsal surface of the tongue, withmultiple ulcers on the tongue.

which generally occur immediately after exposure. The

clinical symptoms of IgE reactions are due to inflammatory

Th2 cytokines (7). IgE antibodies also initiate a series of

reactions that result in the release of inflammatory

mediators, such as histamine, C-reactive protein and other

chemicals from specialized cells called mast cells. The role of

mast cells in allergic tissue inflammation is well recognized.

Interleukin (IL)-4 in the presence of stem cell factor (SCF)

regulates the functional status of mast cells and increases

the release of IgE-dependent mediators(8, 9).

Clinical Features

Type I allergic reactions are characterized by Quinckeʼs

edema (angioedema), which can become life threatening for

patients if the upper respiratory tract becomes involved

(10). Type I also cause urticarial reactions on the skin, in the

form of erythematous papules accompanied by pruritus or a

tingling sensation. However, none of these findings were

observed in the present case. The affected mucosa exhibits a

diffuse distribution of lesions varying in appearance from

multiple areas of erythema, to extensive areas of erosion or

ulceration(11). Patients will complain of a burning sensation

with altered taste sensation and difficulty swallowing.

Although the lesions of the oral cavity resembled EM

clinically, this possibility was excluded as a diagnosis due to

absence of target lesions. Biopsy was not performed in this

patient, as the patient reported a severe burning sensation

and because the majority of severe cases of toxic epidermal

necrolysis are caused by drug reactions that usually result

in sloughing of the skin and mucosa in large sheets(12). EM

has been classified according to the degree of mucosal

involvement and the nature and distribution of skin lesions.

As the most common form, EM minor typically affects a

single mucous membrane and may be associated with

target lesions on the extremities(13). EM major is more

severe, typically involving two or more mucous membranes

with more variable skin involvement. This feature is used to

distinguish EM major from Stevens-Johnson syndrome,

which shows extensive skin involvement(13). The micro-

scopic appearance of EM is not diagnostic. Although

considerable variation occurs, corresponding to the varia-

tion in clinical appearance, cutaneous or mucosal lesions

generally exhibit intracellular edema of the stratum

spinosumof the epithelium and edema of the superficial

connective tissue, which may actually produce subepider-

mal vesicles with varying degrees of inflammatory cell

infiltration (chiefly by lymphocytes, but often including

neutrophils and eosinophils) (14). Anaphylactic stomatitis

arises after the drug enters the circulatory system and

binds to IgE-mast cell complexes (15). Oral lesions may

occur alone or in association with urticarial skin lesions or

other signs and symptoms of anaphylaxis (such as

Int J Oral-Med Sci 11(1):57-61, 2012 59

Fig. 3. Follow-up 3 weeks after starting steroid treatment,showing complete healing of lesions on the vermilion border ofthe lip.

Fig. 4. Follow-up 3 weeks after starting steroid treatment,showing healed lesions on the dorsal surface of the tongue.

hoarseness, respiratory distress and vomiting). The affected

mucosa exhibits diffuse distribution of lesions, varying in

appearance from multiple areas of erythema to extensive

areas of erosion or ulceration. The histopathological features

of anaphylactic stomatitis typically reveal a non-specific

pattern of subacute mucositis that contains lymphocytes

intermixed with eosinophils and neutrophils (15). Such

reactions in the oral mucosa are considerably less common

than cutaneous reactions, and present in various patterns.

Common reactions produced in the oral cavity are

stomatitis, ulceration, gingival hyperplasia, pigmentation,

altered salivary function and altered taste sensation(15, 16).

However, some authors believe that separation of these

entities leads to unnecessary confusion and that terms like

stomatitis medicamentosa should be discarded (16). The

final diagnosis in this case was confirmed based on skin

testing, increased eosinophil counts and an increased IgE

level suggestive of anaphylactic reaction. Various tests can

help in diagnosing type I hypersensitivity reaction, such as

radioallergosorbent tests (RASTs) to detect the amount of

IgE antibody reacting with the suspected or known allergen

(17), leukocyte histamine release assays, surface markers

for basophil activation and leukotriene release tests(18).

Mechanism of ulcer healing

Ulcer healing is a complex process that involves cell

migration, proliferation, re-epithelialization, angiogenesis

and matrix deposition leading to scar formation (19). All

these processes are controlled by growth factors, transcrip-

tion factors and cytokines. Granulation tissue develops at the

ulcer base within 48-72 h after ulceration. Epithelial cells at

the ulcer margin undergo dedifferentiation, express epider-

mal growth factors and start to actively proliferate. These

cells migrate from the ulcer margin on to the granulation

tissue to re-epithelialize the ulcer base. Granulation tissue

consists of macrophages, fibroblasts and proliferating

endothelial cells that form microvessels throughout the

process of angiogenesis(20). The growth of these structures

is stimulated by cytokines, IL-1 and tumor necrosis factor α.

As the granulation tissue matures, it becomes more fibrous

through condensation of collagen bundles and the surface of

the lesion becomes epithealized and leads to scar formation.

Diagnostic Testing

Diagnosis of an allergic reaction is typically based on the

medical history, clinical findings and the results of patch

testing. Some practitioners use patch tests to confirm the

diagnosis of type IV allergic reaction. Limits exist to the

utility of patch tests, due to their poor sensitivity and

relatively high rate of false-negative results(21). The skin

test (prick test) helps in diagnosis of type I allergic reaction.

This test involves intradermal inoculation of suspected

antigens. The results are then read within 15-30 min. If the

result is positive, red, papular or vesicular reactions will be

apparent on the skin. These tests are used in the diagnosis of

drug and food allergies, which may manifest as ulcerative

lesions of the oral mucosa(22).

Management

The causative agent should be discontinued and, if

necessary, replaced with another drug that provides a

similar therapeutic result. Mild localized lesions can be

relieved by administration of topical cortisone or antihist-

amines, while secondary infection can be prevented by use

of germicidal drugs. Generalized and severe lesions warrant

the use of adrenaline or systemic steroids.

Conclusion

Almost all over- the- counter drugs are capable of causing

adverse reactions. The oral manifestations of pharmacother-

apy are often non-specific and vary in significance. These

undesirable effects can mimic many disease processes. To

avoid unnecessary diagnostic procedures and treatments,

clinicians need to recognize the disorder to allow quick and

accurate diagnosis.

References

1. Davis C, Squier CA, Lilly GE: Irritant contact stomatitis:

review of the condition. J Periodontal ,69: 620-631, 1998.

2. LeSuer BW, Yiannias AJ: Contact stomatitis. Dermatol Clin ,

21: 105-114, 2003.

3. Scott S, Rossi DE , Greenberg MS: Intraoral contact allergy. A

literature review and case reports. J Am Dent Assoc, 129:

1435-1441, 1998.

4. Matthews TG: Medication side effects of dental interest. J

Prosthet Dent , 64: 219-226, 1990.

5. Axell T: Hypersensitivity of the oral mucosa: clinics and

pathology. Acta Odontol Scand ,59: 315-319, 2001.

6. Greenberg PA: Immunotherapy update: mechanism of action.

Allergy Asthma Proc; 23: 373-376 2001.

7. Allison TJ, Winter CC, Fourrie JJ: Structure of a human

gamma delta T cell antigen receptor. Nature ,411: 820-824;

2001.

60 Int J Oral-Med Sci 11(1):57-61, 2012

8. Bischoff SC, Sellga G, Lorentz A, Reab R: IL-4 enhances

proliferation and mediator release in mature human mast

cells. Proc Nat Acad Sci U S A, 96: 8080-8085, 1999.

9. Gleich GJ, Adolphson CR: The eosinophilic leukocyte: struc-

ture and function. Adv Immunol, 39: 177-211, 1989.

10. Semenzato G, Bortoli M, Brunetta E: Agostinic. Immunology

and pathophysiology. Eur Respir Monograph ,10: 49-63, 2005.

11. Lankeranil L, Baron ED: Photosensitivity to exogenous

agents. J Cutan Med Surgn, 8: 424-431, 2004.

12. Roujeau JC, Kelly JP, Lugi Naldi MS, Rzany B, Stern R,

Anderson RN : Medication use and the risk of Stevens-

Johnson syndrome or toxic epidermal necrolysis. The New

England Journal of Medicine, 333: 1600-1608, 2005.

13. Kristina E, Archambault Ward R, Tracey L: Severe adverse

skin reactions to non steroidal anti inflammatory drugs: a

review of the literature. American Journal of Health-System

Pharmacy, 67: 206-213, 2010.

14. Rajendran R. Diseases of the skin. In: Rajendran R,

Sivapathasundaram B (eds.) Shaferʼs Textbook of Oral

Pathology, 6th ed. Elsevier, India: 2009. p 807.

15. SivapathaSundaram B: Allergic and immunological diseases of

the oral cavity. In: Rajendran R, Sivapathasundaram B (eds.)

Shaferʼs Textbook of Oral Pathology, 6th ed. Elsevier, India:

2009. p 673-674.

16. Greenberg MS: Ulcerative, vesicular and bullous lesions. In:

Lynch MA, Brightman VJ, Greenberg MS (eds.) Burketʼs

Oral Medicine. Diagnosis and Treatment. 9th ed. Lippincott,

Philadelphia: 2000. p 23.

17. Smith TF: Allergy testing in clinical practice. Ann Allergy, 68:

293-301, 1992

18. Primeau MN, Adkinson NF Jr: Recent advances in the

diagnosis of drug allergy. Curr Opin Allergy Clin Immunol, 1:

337-341, 2001.

19. Tarnawski A: Molecular mechanism of ulcer healing. Drug

News Perspect, 13: 158-168, 2000.

20. Risau W: Mechanisms of angiogenesis. Nature, 386: 671-673,

1997.

21. Forte G, Petrucci F, Bocca B: Metal allergens of growing

significance: epidemiology, immunotoxicology, strategies for

testing and prevention inflammation and allergy. Inflamm

Allergy Drug Targets, 7: 1-18, 2008.

22. Yamauchi R, Morita A, Tsuji T: Pacemaker dermatitis from

titanium. Contact Dermatitis ,42: 52-53, 2000.

Int J Oral-Med Sci 11(1):57-61, 2012 61