Oral Manifestation

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ORIGINAL ARTICLE

Keywords: Oral medicine, autoimmune diseases, aphthous stomatitis, Sjogren’s syndrome, systemic lupuserythematosus

Corresponding Author: Niki Moutsopoulos,

DDS, PhD, National Institutes of Health/

Nidcr Building 30, Room 327, 30 Convent

Dr Msc 4320, Bethesda, MD 20892-4320;

E-mail: [email protected]

J Evid Base Dent Pract 2012:S1:

[265-282]

1532-3382/$36.00

© 2012 Elsevier Inc . All rights reser ved.

Clinical Research Core, NationalInstitute of Dental and CraniofacialResearch, National Institutes ofHealth, Bethesda, MD 20892

ORAL MANIFESTATIONS OF SYSTEMIC

AUTOIMMUNE AND INFLAMMATORYDISEASES: DIAGNOSIS AND CLINICAL

MANAGEMENT Jacqueline W. Mays, DDS, PhD, Mojgan Sarmadi, DDS, MD, Niki M. Moutsopoulos DDS, PhD

ABSTRACT

Context: Systemic autoimmune and inammatory diseases often manifest oral le-sions in their earliest stages, and early diagnosis, which may be spurred by a dental

examination, is key for improved outcomes. After systemic diagnosis, oral lesionsbenet from specialized care by dentists in collaboration with the medical team.

This review aims to educate dental clinicians about the most relevant systemic

autoimmune and inammatory conditions with accompanying oral lesions, theirimplications for health, and management strategies supported by the biomedi-

cal literature and clinical experience. Ulcerative conditions including Behcet andCrohn diseases are discussed, along with rheumatic conditions including Sjögren

syndrome, lupus erythematosus, and rheumatoid arthritis.

Evidence Acquisition: Evidence was accumulated through PubMed searches usingpertinent keywords for each subsection. References were reviewed and originalpublications examined to verify the accuracy of the information. We focused on

evidence included in current reviews and randomized trials. Recommendations

were supported by multiple studies and consensus expert opinion.

Evidence Synthesis: Disease phenotypes described and clinical recommendations

were synthesized from best-quality evidence available for each disease. Effortswere made to describe evidence selection within each disease section.

Conclusions: Dentists play an important role in the early detection and multidis-ciplinary medical management of complex autoimmune diseases. It is important to recognize prevalent medical and dental issues and special needs of patients

with autoimmune conditions. The management of many inammatory conditions

is similar, and often begins with the use of topical steroids, analgesics, and antimi-

crobial treatments, in addition to careful attention to oral hygiene and appropriateuoride usage.

In this brief review, we aim to discuss the presentation/prevalence, diagnosis, and treatment of oral manifestations encountered in autoimmune, autoinammatory

and systemic chronic inammatory diseases. Systemic autoimmune conditions are

estimated to affect 5% to 8% of Americans.1 Oral manifestations are encountered

with high frequency, and are often the rst clinical signs or symptoms of the general

disease. Optimal management of complex autoimmune diseases requires a multi -

disciplinary medical team including dentists to care for lesions of the oral cavity. Thedental practitioner may be asked to play a primary role in the diagnosis of such


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266Volume 12, Supplement 1

JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE SPECIAL ISSUE— PERIODONTAL AND IMPLANT TREATMENT

on nonkeratinized mucosa of inner lips, cheeks, oor of the

mouth, ventral surface of the tongue, and the soft palate. Itspares keratinized surfaces like the hard palate and attached

gingival,6 which are more likely to be involved in intraoralviral (herpes simplex virus [HSV]) infection.7 There are noinitial blisters with RAS.8,9 Some patients notice a prodromal

tingling sensation in the local mucosa, which may correlatewith inammation in the preulcerative epithelium.10 Aph-

thous stomatitis without an underlying systemic disease orinfection is not a febrile condition but is often associated with

pain. When ulcers are closer to the oropharynx, the patientmay come in with a sore throat or even ear pain. Extraoral

examination is essential and generally normal.9 Mild ipsilateralregional lymphadenopathy may occasionally be found withlarge active ulcers of the tongue or oor of the mouth but it

is important to consider periodic fever, aphthous-stomatitis,pharyngitis, adenitis (PFAPA) or infection with nding of cer -

vical lymphadenopathy.11,12

Aphthous has been categorized based on physical presentation or morphology as minor (smaller than 1 cm in diameterand most often smaller than 5 mm) and major (larger than

1 cm in diameter and rarely several centimeters, may affectkeratinized gingiva).6 RAS lesions of different morphology can

clinically present as “simple” or “complex” forms of aphthosis.Simple minor aphthosis is the most typical clinical presenta-

tion of RAS. It usually heals in 5 to 10 days, leaves no scar,and has a prior history of similar uncomplicated ulcers since

childhood.13 The term complex aphthosis is used when thereare very frequent or continuous ulcers, concurrent genital

ulcers, or associated discomfort mounting to the level of dis-

ability.3,13

Complex RAS is more likely to involve major ulcers.An association between complex or simple aphthosis withother disorders may exist and highlights the importance offormulating a differential diagnosis. A systemic condition is

more likely when RAS is complex or recalcitrant.13

Diagnosis of RAS is by exclusion and largely relies on history,review of systems, and examination. History of present illnessmust address ulcer activity and pattern. Review of systems

should screen for gastrointestinal (GI), dermatological, andimmunological/hematological symptoms, including fever and

malaise, skin rash, GI disturbances, and pain. Family historyand recent smoking cessation are relevant, as they increase

the likelihood of RAS in an individual.4 Medications and re-cent infection exposure, history, diet, oral hygiene products,

and lifestyle practices should be reviewed, as they may beassociated with oral ulcers. Matute and Alonso6 provide a list

of more than 80 medications that produce oral ulcers in their2011 review article.

During the exam, adjacent mucosa, teeth, and denturesshould be examined to identify possible sources of local ir-

ritation. Recent exposure to nuts or spices may be reportedbut often no inciting factor is identied.13 Patients should be

conditions and to participate with other health professionals

working together to achieve effective clinical management.

To aid in this process, we discuss in this article the current

general knowledge of systemic autoimmune conditions thatpresent with prevalent oral manifestations. The focus is on

the diagnosis and management of the oral component of

each disease. Importantly, whereas the etiology and patho-genesis and systemic clinical presentation may vary, presentation in the oral cavity is often similar and many conditionsinvolve oral ulcerations. For this reason, we discuss the dif-

ferential diagnosis and management of the most commonoral ulcerations in a general section and subsequently ad -

dress individual conditions that present with oral ulcerations.Similarly, treatment of various autoimmune/inammatory

oral conditions is often common and involves modulation orsuppression of the immune response locally and/or systemi-

cally and will be therefore addressed in a common section aswell as individually for each disease when unique treatment

regimens are recommended. We present here our general treatment recommendations based on clinical experienceand literature review; however, it is critical that good clinical

judgment and specics of an individual case should deter -mine the appropriate dental/oral medicine intervention for

a specic patient.

ULCERATIVE CONDITIONS

Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis is an ulcerative oral mucosal

condition encountered in various ethnicities and geographi-

cal locations.2,3 In the literature it is referred to as RAS andin lay terms as the “canker sore.” RAS is not contagious andusually heals in 7 to 14 days without any treatment. Aphthousis painful and may cause signicant morbidity depending on

its location, duration, and frequency.4,5 RAS or RAS-like le-sions can also be indicative of an underlying illness or de-

ciency and may often be a presentation of a systemic auto-immune or inammatory disorder.3,5 Furthermore, although

the etiology and pathogenesis of RAS is not fully understoodand may involve multiple factors, the inammatory nature of

the disease makes it relevant to the audience of this article.Hence, in this article we review RAS followed by some sys-

temic autoimmune conditions that manifest with oral ulcers.Diagnosis

Aphthous is dened as a round to oval ulcer with well-de-ned margins and a shallow necrotic center. The ulcer base is

covered in a thin gray to white pseudomembrane or brin-ous clot and is surrounded by an erythematous halo fromlocalized vasculitis. Lesions form as “erosions” but involve the

entire epithelial lining and can affect the underlying connective tissue. The margins are red, and may feel slightly raised.6 There

is no associated drainage. Aphthous almost always develops


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manifestation of a process with several inter-related networks

that independently or together promote an ulcer. When oneof the contributing systems is signicantly impaired, a distinct

disease may be seen together with aphthous ulcers.19

Existence of genetic predisposition in RAS is generally ac-

cepted. The likelihood if both parents are affected is 90% and

with none affected it is only 20%.6 T-cell mediated immunityappears to play a key role.4 Tumor necrosis factor (TNF)-alpha inhibition appears to signicantly reduce RAS activity.5 Various connections to heat shock protein (HSP) 65–60

have been postulated,20 in addition to other immune-relatedaberrations in people with RAS, including primary antibody

deciencies,21 changes in interleukin (IL)-1β, IL-2, and IL-6.22 Hematological abnormalities, nutritional deciencies, hor -

monal inuence,18 and smoking status are other contributingfactors.6

The list of external factors associated with RAS is very longand contains many dietary items, including nuts, spices, gluten,

and acidic fruits; environmental agents like sodium lauryl sul-fate in toothpaste and nitrates in water 23; medications; and

local mechanical irritation.6 Educating patients about thesefactors may be helpful. A list of systemic conditions reported

in association with aphthous stomatitis appears in Ship et al,24 which includes multiple deciencies in addition to systemic

diseases.

Treatment

Clinical management of the disease may require more than

one agent or modality depending on severity of RAS. Prin-

ciples of treatment include:

• Ulcer management to promote healing

• Pain management

• Nutritional management

• Disease control. Currently this means reducing recur-

rence because there is no cure.4

A search in PubMed for controlled tr ials in treatment of RASidentied more than 100 modalities and agents evaluated.

This diversity is a testimony to the lack of an effective univer-sal treatment. A multipronged approach of combined simple

treatments may be more successful. The clinical form of RAS,comorbidities, age, previous treatments, and a patient’s ability

to comply with treatment should guide recommendations.3

The best time for intervention is before ulcer formation.9

Elimination of contributing factors like irritants and decien-cies is key. Supplementation with B12 may reduce RAS fre-quency in patients with or without B12 deciency.3,25 For re-currence of active ulcers not suspected of infectious etiology,local anti-inammatory or immunomodulatory treatments

as early as possible have been recommended. Maintenance therapy after resolution is indicated if the frequency and

burden of disease justies the continued treatment. Patient

asked to return for follow-up of simple aphthous ulcer if the

lesion lasts more than 2 weeks or if their RAS changes forworse. Under these circumstances, follow-up examination

and laboratory work-up are needed. In persistent lesionswith an unusual presentation, an infectious etiology shouldbe higher on the differential. Viral cultures of intraoral HSV

lesion have high false-negative results (unless blister uid isobtained), so polymerase chain reaction (PCR) and smear

testing are recommended. Fungal cultures are more important in immunocompromised patients but are low yield so

addition of potassium hydroxide fungal preparations and fun-gal smears may be helpful in their diagnosis.14 Steroids should

not be used if an infectious or malignant etiology is suspected.Biopsy of nonhealing ulcers that resemble RAS has been rec-

ommended after 3 weeks. Biopsy is also indicated if lesionsdo not respond to regular therapy after 3 to 6 weeks. It maybe done sooner in high-risk patients represented by males,

smokers, heavy alcohol users, and those older than 45.13 Evenrepeat biopsy of oral ulcers may be needed under certain

circumstances to verify the continued benign nature of a veryrecalcitrant lesion.

Epidemiology

The onset of RAS is in childhood. Incidence of ulcers increas-

es after the age of 5,7 peaks before the age of 30,6,13,15 and de-creases in advanced age.6,13 Reported rates of RAS in adults

vary from less than 0.5% in some ethnicities in Southeast Asiaup to 66% in some subpopulations in the United States.16,17

Within US rates of 6% to 66% have been reported in studiesof different segments of the population,16,17 but these rates

are often self-reported. For all Americans, RAS prevalence

was reported as 1030 per 100,000 people based on an anal-ysis of National Health and Nutrition Examination SurveyIII.3 Higher rates are noted among women, professionals andchildren of higher socioeconomic status, adults, whites, and

those with a positive family histor y of RAS. The most com-mon morphology is minor RAS.7

The presence of underlying systemic disorders with presentation of RAS varies among subpopulations. Association of

complex RAS with future development of Behcet disease,for example, depends on the ethnicity of patient (very high in

Korea and Turkey, low in Western Europe and Nor th Ameri-ca). Some systemic conditions associated with RAS, like ane-

mia, are prevalent and some conditions like systemic lupuserythematosus (SLE) are less common but potentially life-

threatening.3,18 Among other systemic conditions associatedwith higher rates of RAS are diabetes, rheumatoid arthritis,

cyclic neutropenia, and Reiter syndrome.

Etiology

RAS may not be a truly autoimmune disease but a dysregu-lation of the local immune response to a variety of irritants

or stimuli.6 Most cases of RAS occur in otherwise healthyindividuals.3 It may be best to consider RAS as the nal


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Patients with especially frequent or severe RAS may require

systemic immunosuppressive therapy. Systemic agents usedin treatment of RAS include oral corticosteroids, anti-TNF-

alpha agents, and calcineurin inhibitors.27 Systemic corticoste-roids are the best-studied group with proven efcacy. They

may be ineffective in certain cases or contraindicated in oth-ers for medical reasons like high risk of infection. Thalidomide

can clear aphthous ulcers and is used for recalcitrant lesions,particularly when associated with another disease.28 Of inter-est is that some immunomodulators may produce a period

of remission up to 12 months after therapy but potential sideeffects remain a concern.29

Pain management in RAS may be challenging. Typically, painis reduced concurrent with effective therapy for the lesion.

Topical anesthetics have been used with efcacy but need

frequent application. Diphenhydramine may be used as an

alternative topical anesthetic without bitter taste. Some over-

the-counter preparations may provide relief through ulcerprotection. Use of systemic analgesics like acetaminophenmay reduce the overall discomfort when pain is signicant.

Behcet’s Disease

Behcet’s disease (BD) is a chronic, multisystem inammatory

disease that generally begins with ulcers of the oral mucosa,

and then is characterized by recurring mucocutaneous le-sions of the oral cavity, genitalia, and dermis, and involvement

of the ocular, vascular, digestive, and nervous systems. It is

education is important to improve effectiveness and reduce

side effects of any treatment. Two large classes of medications traditionally used for RAS are topical steroids and antimicro-

bials. Topical agents are considered the rst line of therapy.3

Topical corticosteroids are currently the rst-line therapy

for RAS. Topical corticosteroids vary in strength as well aspotency. They may be given as mouth rinses, sprays, oint-

ments, creams, pastes, or adhesive delivery systems. Almostall commercial corticosteroids have been formulated for skin

application, and their intraoral use is off label. Their long-termapplication promotes candidiasis, mucosal atrophy, and poses

the potential for systemic effects. For these reasons, often thesmallest effective dose is recommended in a form that canhave adequate contact with lesions. A detailed list of topical

steroids is provided by Ference and Last.26

We recommend that mucosa/ulcer is rst dried, as cor tico-

steroids are not water soluble. The topical medication is ap-plied and, if safely possible, the ulcer is covered with an avail-able dressing like gauze or intraoral patch at least for a few

minutes to reduce dilution by saliva and increase absorption.

The patient should later expectorate the excess medicineand avoid eating or drinking for 20 minutes.

Table 1 shows a limited list of topical treatments that havebeen used in RAS with demonstrated benet in randomized

control trials.

Table 1.

Local Anti-inammatory Treatments Formulation Dose

Nonsteroidal anti-infammatory

Viscous lidocaine-diphenhydramine-Maalox 1:1:1 Oral Rinse prn pain/discomfort

Diphenhydramine Syrup Rinse prn and before meals

Amlexanox 2-5% Paste ~2mg QID, apply to affected tissue

Steroids

Hydrocortisone 1.0% OTC gel or ointment QID

Dexamethasone Rinse (0.01%) Oral Rinse 5 mL TID or QID

Clobetasol ointment (0.05%) ointment or cream dry and apply with gauze

Treatment of Secondary Infections

Anti-Fungal

Nystatin Oral Rinse or troche 5 mL >1 min QID

Clotrimazole troches QID, melt on tongue

Diucan Pill 150 mg

Antimicrobial

Chlorhexidine Gluconate rinse, alcohol-free (0.12%) Oral Rinse

Minocycline 0.2% Oral Rinse 5 mL >1 min QID

Tetracycline Oral Rinse 5 mL >1 min QID

prn, as needed; QID, 4 times per day; TID, 3 times per day.


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with BD acquire hypersensitivity against streptococci in the

oral cavity, and often, an IL-12–mediated delayed-type hyper-

sensitivity (DTH) response is present in the various Behcetlesions. One theory postulates that antigen-presenting cells

uptake streptococcal agents, and during the trafcking pro-cess, are adhered to the damaged vessel walls to initiate a

local DTH-type response and subsequent clinical symptoms

characteristic of BD.32

Oral fndingsOral aphthosis is the most common and frequent symptom

of BD, reported to occur in 98.1% of patients with BD.31 Oralaphthous ulcers in patients with BD are identical to these

seen in other diseases and 25% of the healthy population.Lesions are well dened with a white to yellowish necrotic

base surrounded by a red rim. Often, clusters of ulcers arenoted in patients with BD (Fig. 1, B), and occur, in order offrequency, on the lips, cheeks, tongue, gingival, palate, tonsils,

and pharynx.31 Giant aphthous lesions are less frequent in the oral cavity than on the genital mucosa in BD. As with all

oral ulcers, it is important to establish a differential diagnosis

for suspected BD lesions. Infectious etiologies, pemphigus vul-garis, and oral lichen planus should be ruled out, particular ly if the initial BD diagnosis has not been well established.

Diagnosis

The diagnosis of BD relies on clinical examination, as pathog-

nomonic symptoms and laboratory ndings have not been

dened. Several sets of criteria are in use for diagnosis of

BD, however the most widely accepted are the criter ia from the International Study Group for Behcet’s Disease.33 For

diagnosis of BD, these criteria mandate that recurrent oral

generally a relapsing and remitting condition, and inammatory ares may occur.

Frequency

Patients with BD historically cluster along the ancient SilkRoad countries, with a higher incidence (1-10 per 10,000) in

the countries of the Far East, Mediterranean, and Middle East than in North America and the United Kingdom (1-2 per1,000,000).30 In 2008, the International Team for the Revision

of the International Criteria for Behcet’s Disease (ITR-ICBD)published data on 2488 patients with BD collected from 27

countries worldwide.31 In this cohort, 98.1% of patients ex-perienced oral aphthosis, 76.9% experienced genital aphtho-

sis, and skin manifestations were present in 71.9% of patients.Ocular manifestations, which can result in severe loss of vi-

sion or blindness, were found in 53.7% of patients. Joints wereaffected in 50.5% of patients, the nervous system was affect-ed in 15.3%, and vascular involvement (dened as thrombosis

of deep veins, large veins or arteries, pulse weakness as wellas aneurysms and supercial phlebitis) was seen in 18.2%

of cases. Fewer than 10% of the surveyed BD cohort had

pulmonary or cardiac manifestations, orchitis, or epididymitis.

Etiology and pathogenesis

The precise etiology of BD is unclear; however, the clinicalpresentation begins with oral aphthous ulceration and pro-gresses to systemic involvement. A close relationship between

genetic and external triggering factors is believed to exist inBD. More than 60% of patients with BD are associated with

a single genotype: HLA-B51.30,32 Many recent studies have fo-cused on the function of B and T cells, infectious agents, and

the mechanisms involved in thrombophilia.30 Most patients

Figure 1. Oral ulcers may be idiopathic or part of a larger autoimmune sequelae. Typical aphthous ulcers

(A) are single round or ovoid lesions that present most often on nonkeratinized mucosa of inner lips,

cheeks, oor of the mouth, ventral surface of the tongue and the soft palate. Behcet disease is typically

accompanied by oral aphthous ulcers that may present as singular or clustered (B) lesions. Oral cGVHD

ulcers do not have a typical form, but may present as large or small mucoid lesions, deep linear ulcerations

(C), or erosions of the oral mucosa most often on the buccal mucosa, palate, lips, labial mucosa, and the

lateral and ventral tongue. (Behcet disease photos courtesy of Dean Edwards, DDS.)

A B C


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for constant reinforcement of OHI in patients with BD tomaintain optimal oral health and minimize oral symptoms.

Crohn’s Disease

Inammatory bowel disease (IBD) is a complex inam-

matory disorder that has both genetic and environmentalpathogenic components. Two subsets have been identied,

including autoimmune Crohn’s disease (CD) and ulcerativecolitis, separated on the basis of their pathophysiology andclinical manifestations. CD is an idiopathic inammatory

bowel disease that may affect part or all of the alimentary

canal from the mouth to the anus. It results from defectsin mucosal immunity and intestinal epithelial barrier function.Characteristic chronic granulomatous lesions are present in

the gastrointestinal tract in CD, and may be accompaniedby strictures, adhesions, and stulae. These physical changes

result in clinical symptoms including frequent diarrhea, fever,

fatigue, anemia, reduced appetite, and weight loss. Manifesta-

tions may occur outside the alimentary tract, including skinrashes, arthritis, neurological complications, episcleritis, and

uveitis.

Frequency

The highest frequency of CD is found in white Ashkenazi

Jewish individuals of Central European origin.36 According

to the Centers for Disease Control and Prevention (CDC),worldwide prevalence of CD varies between 0.1 and 16 per

100,000 persons.37 It is estimated that as many as 1.4 millionpersons in the United States suffer from IBD, with that num-

ber evenly split between CD and ulcerative colitis.

Etiology and pathogenesis

The cause of CD is multifactorial, although the precise rela- tionships among contributing factors are not well established.

Interaction between environmental risk factors and changesin the immune system are thought to tr igger the onset of thedisease in a genetically susceptible host.38 CD has a strong

genetic component, and more than 30 genes have beenassociated with the incidence and severity of CD. It is an

autoimmune disease, and emerging research indicates thatCD may result from an impaired innate immune response.

In this scenario, aberrant cytokine secretion by macrophagesimpairs the body’s natural antimicrobial defenses and leads

to a sustained proinammatory environment in the colon,

where the bacterial load is high. This theory is supported bya recent association between patients with CD and impairedgene expression, which may induce autophagy and dampen the body’s ability to attack invasive bacteria. So far, several

genetic associations with CD have been demonstrated asdisease modiers and susceptibility genes.36,39 An association

between CD and a specic bacterial species has not been

shown, although evidence clearly points to bacterial involve-

ment in CD development. There is an increased incidence ofCD in industrialized countries, pointing to an environmental

ulceration is present, plus at least 2 of the following: recur-

rent genital ulceration, eye lesions, skin lesions, or a positivepathergy test. The pathergy test entails the oblique insertion

of a sterile 20- to 22-gauge needle into the vascular skin toa depth of 5 mm. The test is considered positive if an erythematous papule develops at the test site after 48 hours. As

suggested by the criteria, this test is not positive in every BDpatient. Studies have found a higher rate of positive pathergy

test in patients with BD when the needle was rst dipped

in the patient’s own saliva, the majority of which contained

streptococci species, versus sterile-ltered saliva or saline.32 This nding was attributed to DTH response to streptococ-

cal species.

Clinical Management

Systemic management of BD typically involves systemic im-munosuppressive therapy or colchicine to manage disease-

related symptoms, including oral ulcers. Newer biologic therapies including anti–TNF-alpha therapies have been

tried with promising results.31 Not all Behcet patients requiresystemic management, and some rely on topical therapy asneeded to manage symptoms.31

Oral management of Behcet patients includes care of recur-

rent aphthous ulcers, meticulous attention to oral hygieneand frequent reinforcement of oral hygiene instruction. Local

antiseptics and local antibiotics may be helpful for symptom-atic ulcers, and these may be managed as standard aphthousulcers. Of interest, one single-center study found that patients

reported an improved oral health-related quality of life, as

assessed by the oral health impact prole-14, when on a sys-

temic immunosuppressive therapy versus those on colchi-

cine, which may warrant discussion with a patient’s medical team if oral symptoms are especially prevalent.34

As discussed previously, local infections may be an impor-

tant part of the pathogenesis of BD. The oral cavity is closely tied to BD pathogenesis, and oral ulcerations are typically the

rst clinical manifestation of BD. Many Behcet patients have

a heightened immune response to oral streptococci. Taken

together, these factors underscore the importance of goodoral hygiene in patients with BD. However, dental prophylaxisand other dental treatment may briey induce oral aphthous

ulcerations in susceptible populations. A 2009 prospective

clinical study followed patients with BD for 8 months to track the incidence of oral ulceration with and without dental andperiodontal treatments when all patients received oral hy-

giene instruction (OHI).35 In this cohort, the number of neworal ulcers increased in the 2 days following dental treatment,

but then signicantly decreased throughout the 6-month

posttreatment follow-up period when compared with the

OHI-only group. This report also noted that tooth-brushingfrequency increased after dental treatment, but had returned

to baseline values at the end of 6 months, indicating a need


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patients with potential inammatory bowel disease, particu-

larly when the diagnosis is not clear from other parts of theclinical examination.

Diagnosis

There are no gold standard criteria for the diagnosis of CD.

Diagnosis of CD relies on a constellation of clinical data from

the patient history, physical examination, and laboratory tests.This may include blood tests for anemia, autoimmune antibodies, and genotyping, although the latter 2 are not cur-rently endorsed by the American College of Gastroenterol-

ogy, and other tests to rule out infections and confoundingfactors. Endoscopic examination may include colonoscopy

for determination of the presence and extent of disease. This typically includes biopsy of the colon for histological evidence

of disease. Barium studies of the upper and lower GI tractand small bowel imaging may also be done.

Clinical Management

No cure exists for CD; thus, the goal of medical treatment

is to suppress the inammatory response. This allows the intestinal tissue to heal, and it typically relieves the symptoms

of fever, diarrhea, and abdominal pain. Once a patient is in astate of remission, treatment is focused on decreasing thefrequency of disease ares. Five major classes of drugs are

currently used to treat systemic CD. These include amino-

salicylates (5-ASA), corticosteroids, immunomodulators,including methotrexate and azathioprine, antibiotics, and

several newer biologic therapies including anti–TNF-alpha

therapies.

As with all autoimmune conditions discussed here, multidis-

ciplinary management of patients with CD is crucial so that they receive appropriate and comprehensive health care.Standard management of recurrent aphthous ulcers shouldbe used in this patient population. One case report in the

literature details successful use of thalidomide, which blocksproduction of TNF-alpha by monocytes, for the treatment of

recalcitrant RAS in a 13-year-old female patient with CD.45 This treatment strategy could conceivably be supplanted by

a newer biologic therapy to block TNF-alpha so as to avoid thalidomide-induced side effects. Patients with CD are prone to nutritional deciencies, and working with the patient and

medical team to correct areas of nutritional deciency may

help to decrease the incidence of ulceration. As CD involveschronic inammation of mucosal tissue, there is an increasedrisk for oral cancer. Patients with CD should receive regular

oral cancer screenings with biopsy of suspicious or nonheal-ing lesions along with their routine dental care. Other charac-

teristic oral manifestations of CD are reported to abate withsuccessful systemic management of CD.

Chronic Graft-Versis-Host-Disease

Allogeneic hematopoietic stem cell transplantation (al-loHSCT) is used with increasing frequency to treat

component that seems to include psychological stress, diet,

and tobacco smoking.37

In the oral cavity, less is known about why only some of the

CD population develops oral lesions. It is theorized that there

is an association between ileocolonic disease and CD; how-

ever, this is not supported by all population studies. Some

groups have found an association of oral CD in children withperianal disease; however, these lesions did not differ phe-notypically from children without oral CD.40 Little is known,mechanistically, about the immunological basis for oral CD,

although it seems to be a fur ther manifestation of the patho-logical processes occurring throughout the GI tract and may

result from similar impairments of the innate immune systemin patients with CD and other factors that promote general

oral inammatory disease.

Oral fndings

Oral lesions characteristic for CD are present in many cases,and the potential clinical relevance of these oral ndings is

emergent.40 Oral aphthous ulcerations are frequently pres-ent in patients with CD; however, these general ulcerations

also occur in patients with inammatory bowel disease and

in the general population. Jose et al41 reported from a large

cohort of patients (n = 1649) that aphthous ulceration was the most frequent extraintestinal manifestation of IBD before

diagnosis. Oral lesions that are characteristic for CD includeswelling of the lips, cobblestoning or edema of the buccal mu-cosa, deep linear ulcerations, mucosal tags, and mucogingivitis.

Patients with CD reported a poorer self-perception of oralhealth in one study, specically caries incidence and gingival

bleeding; however, a case-control study of 62 patients with

BD and 59 matched healthy controls found a minor increasein dentin caries in IBD, with no signicant change in clinical

attachment loss.42,43

Oral manifestations seem to be more prevalent in children than in adults. A recent retrospective char t review that was

followed up with a 3-year prospective study of oral mani-festations of CD at a pediatric hospital found 40% to 48%

of children had CD-specic oral lesions at the time of CD

diagnosis.40,44 Additionally, in clinically indicated biopsies, 75%

to 100% contained noncaseating granulomas, which are clas-sic oral CD lesions.40,44 Routine biopsies were not performedduring the study, so it is not known how frequent oral granu

-lomas are in patients with CD. The prospective study furthercompared the frequency of oral ndings in children with CD

when examined by a gastroenterologist in a clinical settingversus formal oral exam by a pediatric dentist. Even through

the gastroenterologists were reported to have an establishedinterest in oral lesions, the ability of the physicians to iden-

tify and accurately classify oral CD lesions was poor when the dentist’s exam was used as a comparator.40 Harty et al40

advocate that involvement of an experienced dental profes-sional can be a valuable adjunct during the diagnosis phase in


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indications for its use, cGVHD will continue to be seen in

the numbers of alloHSCT performed each year. Thirty per-cent to 65% of patients who sur vive longer than 1 year after

transplantation wil l develop cGVHD,46 which may be fatal inapproximately 15% of transplant recipients.48 In the UnitedStates, almost 6000 patients underwent HCT in 2009, an

increase of 30% since 2005. With this dramatic increase inHCT, the incidence of GVHD will also continue to increase.49

Although cGVHD can affect multiple organs, the oral cavityis the second most commonly involved organ system, and is

reported in approximately 45% to 83% of patients withcGVHD.50

Patients with cGVHD have specialized oral health needs that

can be addressed in a general practice setting with a well-educated clinician, and it is important that diligent care isavailable for patients with cGVHD, as their numbers continue

to increase.

Etiology and pathogenesisMajor known risk factors for developing cGVHD includeolder recipient age, major allele for human leukocyte antigen

(HLA) mismatch between donor and recipient, peripheralblood stem cell source, conditioning regimen, and GVHD

prophylaxis regimen.51 Grafts that include more donor Tcells are typically more effective at eradicating malignancy;

however, also lead to a higher incidence of severe cGVHD.The essential pathogenesis of cGVHD, in which donor im-

munocompetent cells recognize and attack host tissues in

immunocompromised recipients, remains current.52,53 ThecGVHD has many autoimmune and brotic features, and

current evidence demonstrates involvement of the patient’sown immune cells in the autoimmune attack. The process hasa strong proinammatory T-cell component, with additional

involvement of B cells and regulatory T cells.46,54,55

Oral fndings

Oral cGVHD has 3 components: mucosal involvement,salivary gland involvement, and sclerotic involvement of themouth and surrounding tissues.56 The oral mucosa presents

with classic ndings in cGVHD, including lichenoid changes,

erythema, ulcerations, hyperkeratotic patches, and mucosal

atrophy (Fig. 2). Limited mouth opening may be caused byinvolvement of the temporomandibular joints, or by sclerotic

changes in the perioral tissues. Salivary gland dysfunction mayresult from medication, inammation, and/or brosis of the

major and minor salivary glands. Individually, these changesmimic oral ndings in several classic autoimmune diseases.

The lichenoid lesions mirror those seen in oral lichen pla-nus, whereas the lymphocytic salivary gland inltrates and

resulting dry mouth are reminiscent of Sjögren’s syndrome.

Restricted oral opening and perioral brosis in patients with

GVHD are similar to changes observed in patients with

scleroderma.

malignancies of the blood, bone marrow, and lymphoid system; systemic immunodeciencies; and a variety of other dis-

orders. It is the only curative option for many hematologicalmalignancies.46 In alloHSCT, multipotent hematopoietic stem

cells from a non-self donor, harvested from bone marrow,peripheral blood, or umbilical cord blood, are transfused into

the patient.Graft-versus-host disease (GVHD) results from an immuno-

logical attack on the patient’s tissues by donor T cells that are transferred along with the graft. Chronic GVHD (cGVHD)

is a common complication after HCT. cGVHD was initiallydened as occurring at or beyond 100 days posttransplanta-

tion; however, its classication is now based on characteristic

clinical presentation, regardless of timing.47

Patients with cGVHD suffer from mild to severe morbidity,with variable manifestations in the skin, mouth, eyes, gut, liver,

lungs, joints, and genitourinary tract. These are painful, impairfunctional ability, and reduce quality-of-life. The disease pre-

sentation of cGVHD resembles many autoimmune disorders,including scleroderma, Sjögren’s syndrome, and oral lichenplanus. Furthermore, owing to the inammatory nature of

the condition and the use of immunosuppressive therapies

in its treatment, cGVHD is relevant in the context of auto-immune and inammatory conditions.

Frequency

The occurrence of GVHD is the limiting factor in the suc-

cess of alloHSCT. With increasing success and long-termsurvival of patients after alloHSCT, as well as the increasing

Figure 2. Oral chronic graft-versus-host-disease

typically manifests more than 100 days after

allogeneic stem cell transplantation. Common oral

ndings include mucoceles (A), atrophy, perioral

brosis (B) or TMJ involvement resulting in limited

mouth opening, mucosal edema (C), lichenoid

lesions (C), ulceration (C), and mucosal erythema

(D). (A and B courtesy of Carol Bassim, DMD, MS,and Dean Edwards, DDS.)

A B

C D


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September 2012273


saliva substitute products. Several studies support the use

of short-term or prolonged pilocarpine therapy for salivarystimulation in patients with cGVHD; however, pilocarpinealso increases secretion of gastric uids, which may be prob-lematic in patients with GI tract GVHD.59,60

ORAL BLISTERING DISEASES OF AUTOIMMUNEORIGIN

Most bullous autoimmune diseases affect the skin and/ormucosal sites, including the oral cavity. Major bullous condi-

tions that involve the oral cavity include pemphigus vulgar is(PV), mucosal pemphigoid (MP-cicatricial pemphigoid), bul-

lous pemphigoid, and oral lichen planus (OLP).61,62 Lesionsin many of these conditions appear similar clinically, and di-

agnosis may be difcult and denitive only after histological

evaluation and support from a multidisciplinary medical team.Furthermore, it is often that such conditions are rst mani-fested in the mouth, rendering the dentist practitioner key

for initial diagnosis.

Treatment of autoimmune bullous diseases is geared (as inmany autoimmune or inammatory based disorders) toward

the remission of the disease by modulating or suppressing

the overreactive immune response locally and/or systemical-ly.62 Although pathogenesis and treatment of these disordersis addressed in a separate article of this publication, many of

the immune suppressive therapies used for the treatmentof oral manifestations in autoimmunity are common and are

discussed in a following section of our ar ticle and in Table 1.

RHEUMATIC DISORDERS

Sjögren’s Syndrome

Sjögren syndrome (SS) is a fairly common chronic auto-

immune disorder, affecting 0.5% to 5.0% of the general popu-lation, but most commonly females (at a 9:1 ratio) in theirfth decade. This large reported range of disease prevalence

may be attributed to differences in the denition and application of diagnostic criteria among the studies, the diverse geo-

graphic study origin, as well as the different initial sample size

and sex distribution.63,64 The hallmark of SS is the lymphocytic

inltration of the exocrine glands, particularly the periductal

areas of mainly the lacrimal and salivary glands. This resultsin impaired secretory function and consequently xerostomia(dry mouth) and xerophalmia (dry eyes) (Table 2).64,65 Si-

multaneously, systemic features of cutaneous, respiratory, re-nal, hepatic, neurologic, and vascular nature often occur. The

syndrome can present either alone (as primary SS) or in thecontext of underlying connective tissue disease (as second-ary SS).

Diagnosis

The multiple aspects of the syndrome make it difcult to

diagnose. As a consequence, SS commonly remains either

Clinically detectable oral cGVHD was present in 24% of pa-

tients from a referral-based multinational cohort of patientsseverely affected with cGVHD assessed at the National In-

stitutes of Health (NIH). In this cohort, most patients withoral cGVHD presented with erythema (54%) and lichenoidchanges of the oral mucosa, whereas only a few presented

with ulcerations (4%) and mucoceles (7%). Many of these patients reported subjective oral dryness (66.7%), pain (45.6%),

and sensitivity (59.3%).57

Clinical Management

Goals of therapy for patients with oral cGVHD include painmanagement, healing of lesions, and suppression of inam-

mation in the oral cavity. Early detection and diagnosis, ap-propriate therapeutic management, and regular follow-up

are essential to ensure optimal outcomes and improvedquality of life of patients with oral cGVHD. The NIH con-

sensus conference on ancillary therapy and supportive carefor cGVHD has provided recommendations for the man-

agement of symptoms and guidelines for the prevention ofinfections and other common complications of treatment re-lated to cGVHD.56 Although oral cGVHD symptoms reduce

quality of life and, in severe cases, lead to malnutrition, they

are generally not life-threatening.58 Treatment, particularly any

systemic therapy, should be coordinated in conjunction with the medical team.

Most therapy currently recommended for the managementof mucosal manifestations of oral cGVHD is directed at the

use of topical high- and ultra–high-potency corticosteroids(Table 1), calcineurin inhibitors, and analgesics. These topical

treatments are not always effective, and also carry the risk

of systemic absorption owing to a breakdown in mucosalintegrity in some patients with oral cGVHD. Efcacy may be

improved by compounding some of the topical agents to a

rinse formulation; however, clinical trials are lacking to sup-port specic agents and dosing schedules.

Patients with cGVHD should be regularly screened for oralcancer, as oral squamous cell carcinoma has been reported

in this population. Suspicious lesions should be biopsied. Pa- tients on systemic or oral topical corticosteroids are prone

to overgrowth of oral Candida, and it is impor tant to differ-entiate cGVHD-related hyperkeratosis and erythema from

an ongoing oral fungal infection before starting an aggres-sive course of treatment. Although patients with cGVHDare regularly screened for serum antibodies to viruses, virus-

related oral ulcers may still occur in serum-negative patients,and PCR-based screening or biopsy is recommended when

clinically indicated. The cGVHD induces changes in both thequality and quantity of saliva, which leaves patients suscep-

tible to dental decay. Excellent professional and home oralhygiene, use of supplemental uoride and mild dentifrice are

strongly indicated in patients with cGVHD. Patients shouldbe counseled on use of sugar-free beverages, sialagogues, and


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undiagnosed or is diagnosed years after the onset of symp-

toms. Early recognition of this disease is of pivotal importance to prevent delay in appropriate diagnostic evaluation,and optimize therapeutic intervention. Diagnosis of SS is

based on the concurrent presence of various signs and symptoms of the disease (see Table 3 for diagnostic criteria).66-69

The role of dentists in the diagnosis and treatment of SS iscrucial. Patients often present rst to their dentists because

of their predominantly oral symptomatology. Proper education of the general dentist to recognize signs and symptoms

of xerostomia, to include SS in their differential diagnosis, and to refer patients for evaluation with a rheumatologist in a

timely fashion, is key in the proper diagnosis and treatmentof the condition.

Etiology and Pathogenesis

The etiology of SS remains unknown to date. As for many

autoimmune diseases, it is believed for SS as well that aninitial unknown environmental trigger, in genetically suscep-

tible individuals, leads to aberrant activation of the immunesystem. Although genetic susceptibility has been speculated, there are limited studies investigating genetic linkage in SS.

Studies to date have focused on associations between HLAalleles and SS and genes that are known risk factors for

other autoimmune conditions, including polymorphisms in type I interferon (IFN)-related genes.63 Beyond susceptibility,

various triggers that initiate disease progression have beenspeculated and are under investigation. Viral triggers includ-

ing Epstein Barr, human T lymphotropic virus 1, hepatitis C,and enteroviruses have been previously proposed as poten-

tial initiating factors.63 Stress and hormonal factors have also

been linked to disease susceptibility and initiation. Followingdisease initiation in SS, there is compelling evidence of activation of the epithelium in target organs that appears todrive and/or perpetuate the inammatory response. In this

context, epithelial cells may act as antigen-presenting cells aswell as proinammatory immune cells by expressing major

histocompatibility complex (MHC) molecules and costimula- tory molecules and producing high levels of proinammatory

cytokines.63,65 Finally, the aberrant immune response leads toglandular immunopathology, dysfunction in glandular secre-

tion, and increase prevalence of lymphoma transformation inpatients with SS.63

Oral fndingsThe oral manifestations observed in patients with SS are at-

tributable to the involvement of salivar y glands, which leads to decreased salivary secretion. Loss of the lubricating, buff-

ering, and antimicrobial capacities of saliva leads to an in-creased incidence of oral/dental infection, mucosal friability,and subjective symptoms of dryness, irritation, and burning

sensation.64,65 Most common oral ndings are dental caries(often rampant) with the uncommon presentation of root

and incisal caries. Most often mucosal infections are fungal(primarily candidiasis/oral thrush), which can be manifested

Table 2. Common Oral Lesions of Systemic

Autoimmune Disorders

Bechet’s Disease

1. Minor recurrent apthous ulceration

2. RAS

Crohn’s Disease

1. Recurrant apthous ulcers

2. Swelling of the lips

3. Cobblestoning of the buccal mucosa

4. Deep linear ulceration

5. Mucosal tags

6. Mucogingivitis

7. Noncaseating granulomas in biopsy specimins

GVHD

1. Lichenoid changes

2. Ulcerations

3. Mucosal atrophy

3. Salivary gland dysfunction

4. Xerostomia

5. Restricted oral opening – Perioral brosis

– TMJ involvement

6. Hyperkeratosis (white patches)

7. Mucoceles

8. Buccal edema

Sjogren’s syndrome

1. Xerostomia (Dry Mouth)2. Rampant caries/Root caries

3. Oral Candidiasis

4. Unilateral parotid gland enlargement

Rheumatoid Arthritis

1. TMJ involvement (mostly in juvenile arthritis)

2. Increased prevelance of periodontal disease

Lupus Erythematosus

1-RAS

2-mucosal discoid lesion

3-white plaques/Lichen planus-like lesions

4-red plaques or macules

5-mucosal autoimmune ulcers with or without surroundingstraiae or telngiectasia

6-Transformation to squamous cell carcinoma

7-Secondary Sjogren’s oral sequela

8-Secondary Steven-Johnson’s syndrome

9-Secondary activation of HSV

10-Secondary fungal infections

11-Secondary light brown pigmentation from antimalarials


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September 2012275


and mucosal infections are common, the prevalence and se-verity of periodontal disease has not been reported to be

increased in SS. Mucosal friability in SS often leads to soft

as pseudomembranous or erythematous mucosal lesions,median rhomboid glossitis and tongue ssuration, denture-

associated stomatitis, or angular cheilitis.64,65 Although dental

Table 3.

Revised International Classication Criteria for Diagnosis of Sjogren’s Syndrome [73]

I. Ocular symptoms: a positive response to at least one of the following questions:

1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?

2. Do you have a recurrent sensation of sand or gravel in the eyes?

3. Do you use tear substitutes more than 3 times a day?II. Oral symptoms: a positive response to at least one of the following questions:

1. Have you had a daily feeling of dry mouth for more than 3 months?

2. Have you had recurrently or persistently swollen salivary glands as an adult?

3. Do you frequently drink liquids to aid in swallowing dry food?

III. Ocular signs—that is, objective evidence of ocular involvement dened as a positive result for at least one of the following two tests:

1. Schirmer’s I test, performed without anesthesia (≤5 mm in 5 minutes)

2. Rose bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system)

IV. Histopathology: In minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialoadenitis, evaluated byan expert histopathologist, with a focus score ≥1, dened as a number of lymphocytic foci (which are adjacent to normal-appearing

mucous acini and contain more than 50 lymphocytes) per 4 mm2 of glandular tissue

V. Salivary gland involvement: objective evidence of salivary gland involvement dened by a positive result for at least one of the follow-ing diagnostic tests:

1. Unstimulated whole salivary ow (≤1.5 mL in 15 minutes)

2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary, or destructive pattern), without evidence ofobstruction in the major ducts

3. Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer

VI. Autoantibodies: presence in the serum of the following autoantibodies:

1. Antibodies to Ro(SSA) or La(SSB) antigens, or both

Revised Rules for Classication [73]

For primary SS

In patients without any potentially associated disease, primary SS may be dened as follows:

a. The presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV (Histopathology) or VI (Serology) is

positive

b. The presence of any 3 of the 4 objective criteria items (that is, items III, IV, V, VI)

c. The classication tree procedure represents a valid alternative method for classication, although it should be more properly used

in clinical-epidemiological survey

For secondary SS

In patients with a potentially associated disease (for instance, another well dened connective tissue disease), the presence of item I or

item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary SS

Exclusion criteria:

Past head and neck radiation treatment

Hepatitis C infection

Acquired immunodeciency disease (AIDS)

Preexisting lymphoma

Sarcoidosis

Graft-versus-host disease

Use of anticholinergic drugs (since a time shor ter than fourfold the half-life of the drug)

SS, Sjogren’s Syndrome .


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in preserving the natural dentition in patients with SS, inves-

tigating the possibility of dental implant treatment is of greatimportance. Unfortunately, there is very limited evidence in

the literature regarding the success of dental implants in patients with SS.

Treatment of Candidiasis For the treatment of oral candidia-

sis, topical antifungal treatment (see Table 1) can be followedby systemic antifungal agents for persistent or recurrent epi-sodes. A typical regimen includes nystatin cream and a pastilleor oral suspension of nystatin 3 to 4 times daily for 1 week,

followed by systemic treatment with an azole. For prevention

of candidiasis, wearing dentures overnight should be discour-

aged and dentures should be cleaned with 2% chlorhexidine.A biopsy should be undertaken in individuals with the hy-

perplastic variant of Candida infection, because of the risk ofmalignant transformation.64

Treatment of Xerostomia Traditional treatment of xerosto-mia in SS has focused on palliative measures using salivary

substitutes, which can improve lubrication and hydration oforal tissues, despite the transient nature of their activity. Lu-

bricating agents in the form of gels, mouthwashes, lozenges,

and toothpastes have been used, with various results. Tran-

sient comfort can also be achieved by sipping water andother sugar-free uids.

For patients with SS who have residual salivary gland function,stimulation of saliva ow with a secretagogue is the treat-

ment of choice and is, at present, the most efcacious means

of preventing long-term oral complications. Nonpharmaco-

logical secretagogues might be useful in patients with reason-

able levels of sal ivary ow, such as stimulation with sugar-freegums.

Two muscarinic acetylcholine receptor agonists (pilocarpine

and cevimeline) are licensed and have been widely used for the treatment of sicca symptoms in SS. These agents stimulate

the muscarinic acetylcholine receptors M1 and M3 presenton salivary glands, leading to increased secretory function.69

Management of the glandular and extraglandular manifestations of SS may often involve the use of immunomodulatory/

suppressive, antimalarial, and/or biologic agents, depending ondisease presentation and severity of symptoms. In all cases, though, successful management of patients with SS requires a

multidisciplinary approach with involvement of primary carephysicians, rheumatologists, ophthalmologists, dentists, gyne-

cologists, and hematologists.

Lupus Erythematosus

Lupus erythematosus refers to a group of autoimmune dis-eases with a wide range of presentations from cutaneous to

systemic.70 The term lupus is often used as short for systemiclupus or SLE, which is the most common form. Systemic lu-pus is a serious illness usually with ares and intermittent

tissue lesions in patients with SS. Such signs include oral mu-

cosal scores, dry and cracked lips, and tongue depapillation(Fig. 3). Finally, another fairly common oral manifestation is

the asymptomatic and self-limiting enlargement of the pa-rotid gland or another major salivar y gland (Fig. 3). Persistentenlargement should be carefully followed to exclude bacte-

rial super infection and, more importantly, the developmentof lymphoma.

Clinical Management

Treatment of Dental Caries Aggressive routine and preven-

tive dental care and use of uoride is crucial for patientswith SS. Fluoride gels, prescription-strength toothpaste, and/

or oral rinses containing 0.40% to 1.25% uoride should be

used. The provider should keep in mind the additional chal-

lenges of treating dental caries in patients with xerostomia.The commercially available agents are often acidic and can

cause irritation of the oral mucosa, resulting in poor com-pliance. Also, in extreme cases of hyposalivation, destruction

of the tooth enamel might theoretically occur because ofinsufcient remineralization, even in the presence of uoride,

resulting from the lack of saliva.64 Finally, given the difculties

Figure 3. Common manifestations of Sjögren

syndrome include benign lymphoepithelial lesion of

the parotid gland (A) and dry and ssured tongue

(B). (Photos courtesy of Clio Mavragani, MD.)

A

B


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September 2012277


Diagnosis and Oral Findings

Signs and symptoms of lupus depend on which organ is af-fected and often include fever, fatigue, oral ulcers, weight loss,

malar rash, photosensitivity, and joint pain. Circular (disc-like)plaques, renal failure, arthritis, coronary artery disease, pul-monary hypertension, hemolysis, stroke, seizures, or psycho-

sis may be seen. Early treatment could be critical, and familiar-ity with unique association of oral ndings in lupus may help

clinicians in recognizing lupus earlier.

The classical oral lupus lesion is a whitish plaque with ery -

thema in the center and keratotic str iae in the periphery at times with telangiectasia.70 Patterns of oral lesions may differ

among different types of lupus.82 Diagnosis of lupus-relatedlesions requires biopsy; intraoral biopsy is generally preferred

over skin biopsy when there is a choice to avoid scarring.

It may be difcult to delineate oral lesions of different forms

of lupus.76 Overall, red mucosal macules and plaques (ery - thematous lesions), mucosal ulcers and RAS, and lesions that

resemble lichen-planus or leukoplakia are described.76 Lichen-oid mucositis with acanthosis and deep perivascular inltrate

on histology have been reported.70,76 In DLE, discoid lesionscan occur intraorally and are seen on buccal mucosa, gingival,

and lips.74 Some other histological characteristics frequently

reported are hyperkeratosis with keratotic plugs, liquefaction/

vascular degeneration of the basal epithelial cells, thickeningof the basement membrane, atrophy of rete ridges, edema in the lamina propria, subepithelial mononuclear inltrate, and

at times periodic acid-Schiff –positive deposits.70,76 Direct im-munouorescence is often positive and shows linear deposits

of immunoglobulin (Ig)G or IgM and/or C3 in the basement

membrane. CD4+ T lymphocytes prevail in the ulcer base,which is also inltrated by other immune cells.70,74

RAS and oral ulcers are not only common in SLE but also

correlate well with the underlying systemic disease activity.New onset of RAS in adults or sudden unexplained worsen-

ing of preexisting RAS may be the earliest manifestation of asystemic disorder, including lupus.

Like worsening RAS, appearance of oral lupus lesions maysignal increased disease activity in a lupus patient. Pediatric

patients with discoid cutaneous lupus and mucosal involve-ment, including RAS lesions, are more likely to transition to

SLE and may benet from closer follow-up.83

Patients with lupus on systemic therapy with immunosuppres-

sant agents are prone to secondary infections. Viral and fungalinfections are common in the oral cavity. Some of these may

be mistaken for RAS or lupus ulcer but must not be treatedwith steroids. Stevens-Johnson syndrome is a rare but serious

complication of HSV that may appear a few weeks after anoutbreak. Skin and any of the mucosal surfaces, including eyes,

may be involved with ulcers in Stevens-Johnson syndrome.84

remissions. In SLE, internal organs are affected. The other

main category of lupus is cutaneous lupus erythematosus(CLE), which has various forms with different signs and se-

verity presenting as acute to chronic. Chronic CLE includesdiscoid lupus or DLE, with disc-like lesions of skin and/or mu-cosa.71 CLE can be mild or severe. It may remain limited to

skin or progress to SLE.

70,71

Neonatal lupus is secondary tomaternal autoantibodies,72 and drug-induced lupus produces

symptoms of lupus but usually resolves after the inciting factor is removed. Most literature on oral lesions in lupus per-

tains to SLE and DLE.

Oral lesions are among the most common ndings in lupus73

and provide an opportunity for early diagnosis and intervention. Oral lesions may be found in systemic or cutaneous

lupus and may be the only lesion in some patients.74 Lupusis often difcult to diagnose because presentations vary and

mimic other diseases.

Epidemiology

According to the Lupus Foundation of America, 1.5 millionindividuals in the United States have lupus and16,000 new

cases are reported annually. Systemic lupus is the most com-mon presentation. CLE is less prevalent74 and DLE is the most

common cutaneous form.71 A higher rate of lupus has beennoted in Asian, Hispanic, and Native American individuals. Lu-

pus can occur at any age in both sexes but it is diagnosed inwomen more than men and often during the child-bearingyears. Lupus is also 2 to 3 times more likely to affect Ameri-

can black females.70,75

Prevalence of oral manifestation in lupus has been reported

at various rates from low to more than 50% of cases andusually more than 1 lesion is present on examination.70 Thevariation in reported rates may reect the fact that many

medical examinations do not include a complete routine oral

exam, and rates that are repor ted pertain only to some typesof ulcers in different forms of lupus. Systemic therapy may re-

duce prevalence in treated patients.76 The mouth is the mostcommonly affected site in lupus.77

Etiology/ Pathogenesis

Immunological factors, genetics, environmental exposures,

smoking, infection, vaccines, and UV light, as well as hormonalfactors, are each reported to play a role in the development

of lupus.78,79 Neutrophil extracellular traps induce innateimmunity early on in the disease.80 Activation of type I IFN

pathways, B- and T-cell dysfunction, as well as presence ofantinuclear antibodies are seen.70 Many other autoantibodies

have been reported.79 A number of genetic loci that increaselupus susceptibility have been established but none has beenidentied as the cause of the disease. Instead, they appear to

correlate with the variations seen in lupus and may work byepigenetic modulation.80 Cer tain alleles of STAT4 were found

to correlate with protection from oral ulcers in patients withlupus.81


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September 2012279


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specialized treatment may also be necessary. TMJ signs and

symptoms should be treated by a trained specialist with traditional measures effective for other forms of TMJ dysfunction,

including physical medicine, jaw appliance, and biobehavioral therapy. If medical management is not effective, surgical treat-ment may be necessary, as it is for other joints in the body.98

Increased prevalence of periodontitis It has been speculated that the existence of systemic inammatory conditions, such

as RA, may contribute to the initiation and progression of the inammatory nature of periodontal disease. Although

the etiologic factors of the 2 diseases may be both commonand distinct (genetic predisposition, bacterial triggers, envi-

ronment factors), the mechanisms that lead to inammatory

bone loss appear to be shared between the 2 disease enti-

ties. To date, a large number of clinical studies have shownan association between periodontitis and RA.99-111 Unfortu-

nately, the studies investigating the association between RAand periodontitis have had a great variability in their selection

criteria, denition of periodontitis and RA, and selection ofcontrols throughout the study populations, so it is difcult

to conclude on the level of association between the 2 con-

ditions. However, most studies conducted to date report alevel of association between periodontitis and RA that range

from an odds ratio of 1.8 to 6.99. The studies performed todate show increased tooth loss and presence and severity

of periodontitis in patients with RA compared with healthysubjects.112 Some, but not all, studies have evaluated the level

of oral hygiene in patients, by recording plaque index. The im-paired manual dexterity in patients with RA may conceivably

contribute to increased oral health issues in this population.

Secondary SS: Close to a third of patients with RA sufferfrom secondary SS,113 and therefore timely diagnosis and ap-propriate management of SS-related disease is important in

this population (see SS section).

Clinical management recommendations:

Successful management of RA-related oral disease dependson accurate diagnosis and referral to appropriate dental spe-

cialists. Knowledge of the potential involvement of the TMJ joint, particularly in juvenile arthritis will help the generaldentist suspect and recognize potential signs and symptoms

of TMJ dysfunction. Additionally, careful and clinical examina-

tion with a particular focus on the evaluation of periodontalhealth and signs/symptoms of xerostomia will aid in the di-agnosis and treatment of disease-related periodontitis or SS.

Finally, the dental provider should address difculties in per -forming oral hygiene in patients with RA that are related to

their impaired manual dexterity and recommend appropriatemeasures, including the use of an electrical tooth brush, sup-

portive oral rinses, and more frequent dental visits.


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