Pathology

Psychobiologic views on stress-related oral ulcersFrancesco Chiappelli, PhDVOIivia S. Cajulis,

Recurrent aptithous stomatitJs (RAS) and oral lichen planus (OLP), two of the most common stress-relatedulcérations of tbe oral mucosa, fiave distinct etiologies, courses, and histopathologic features. In ligbt of in-CTeased underslanding of ttie psycbobiology of stress, the authors propose that RAS and OLP fundamen-tally differ from the perspective of tbe psychobiologic response to stress. This article presents possibledinical implications. (Quintessence tnt 2004:35:223-227)

Key words: allostatic load, oral \kiien pianus, recurrent aphthous stomatitis, stress

A s tbe most cotnmon inflammatory ulcerative condi-i i t i o n of the oral mucosa in the United States (US),recurrent aphtbous stomatitis (RAS), commonly re-ferred to as "eanker sores." clinically manifests as recur-rent oral ulcers, recurrent aphthous ulcers, or simple orcomplex aphthosis. Ciinicai evaluation of the ulcers ¡soften done on the basis of morphologj' (eg. minor ver-sus major apbtbous ulcers} and severity' (simple versuscomplex). Sores appear as recurring, self-limited ulcersof the nonkeratinized oral mucosa and oropharynx, areusuaily minor, shallow, painful ulcers less than 5 mm ¡ndiameter, and generally heal in 10 to 14 days (minorRAS). Major ulcers can spread over tbe oral mucosa,heal in a period of weeks, and actually leave significantscarring. Differential diagnosis exeludes associated sys-temic disorders, such as Behcet's disease and complexaphthosis variants, such as ulcus vulvae acutum, mouthand genital ulcers with inflamed cartilage syndrome.fever, aphthosis. pharyngitis, and adenitis syndrome.and cychc neutropenia.'- The prodromal phase forRAS. recognized by most patients, consists of a btmiingsensation a few days prior to the onset of ulcération, aswell as the perception of stress.'

'AssocBEe Proiessor, UCLA School of Dentistry, Los Angeles, Calrfonna;Psychnneuroiminunology Group. Inc. Los Angeles, CaTrfomia-

i 'r ivate Practice, Dental Gioup of Sherman Oaks. Stierman Oal(s.Catbmia-

teprint requests: Dr Francesco CtiiappelD, CHS 63-090, Los Angeles, CAM095-16es. E-mail: ChiaH>dliedentucia-edu

Another common mucocutaneous immunologie dis-ease, oral lichen planus (OLP), manifests as lesions thatmay form a reticular pattern of sligbtly raised, interlac-ing white keratotie streaks, termed Wiciiham's striae(ie, lacelike keratotie patterns), atrophie reticular ker-atosis and erythema, papules and plaques, erosive at-rophie mucosa v\ith shallow ulcers, or large thln-waliedbullae. Lesions are typically multiple, painful, and bilat-eral. They occur primarily in the buccal aspect of thesoft mucosa and in the sublingual regions. Lesions inthe vestibular aspect of the hps. the hard and softpalates, and the alveolar ridge/gingiva are rare. OLP isgenerally recognized as a chronic inflammatory disor-der, vv'hich afflicts up to 2" a of the popuiation. predomi-nantly peri- or postmenopausal women.' It may resultfrom an abnormal Immune response of unknowncause, in which changes in the antigenicity of cell-sur-face epithelial cells cause them to be recognized as Im-munogenic, in a manner akin to an autoimmune disor-der," The waxing and waning nature of the lesions hasbeen attributed to tbe perception of stress.'^^'

Histopatbologically, RAS Involves Invading inflam-matory (ie. macrophages, neutrophiis) and lymphoidcells (¡e, mainly CD3-(- T cells), and early Intraepithe-lial degeneration in the strattmi splnosum.-*- Elevatedmessenger expression of THl cytokines (eg, IL-2,•Í-1FN) and TNF-a. but not IL-10 are evident in RAS,Glucocortieoids, which alter TH1/TH2 cytokine bal-ance, and thaiidomide. which inhibits TNF-a produc-tion, are common treatment for RAS. Nonspecific

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lesions at the surface epithelium have a central area ofdestruction.'" Active fibrosis occurs at the base andsides of the ulcerated areas, with keratinocytes death.

The histopathoiogy of OLP characteristically showsdegeneration of the basal cell layer, hyperkeratiniza-tion, dense subepithelial lymphocytic infiltrate, exten-sive epithelial basal cell destruction, basement mem-brane branching and duplication, and apoptotic hasalkeratinocytes, which form homogenous globules posi-tive for Annexin, OLP lesions are also Invaded hyCD3-I- T cells, with threefold significant predominanceof CD4-I- lymphocytes over CDS-)- T cells, which lineprimarily the epithelial-mesenchymal interface. Over75% of invading T cells express the memory pheno-type (CD45RO4-) and the ßl integrin, CD29-(-, whichrender them essentially sessile. The authors* data showthat they express markers of activation (ie, a chain ofthe lL-2 receptor, CD25, and CD69), as well as thatcirculafing CD4-t-CD45R0-i- cells in patients with OLPare 66% of the circulating leukocyte population, com-pared to 49% in healthy control subjects (unpublisheddata)," Serum levels of TNF-a and lL-6 are signifi-cantly elevated in patients with OLP. Erosive and bul-lous OLP lesions may predispose to oral carcinomasat an alarming several fold increase over the generalpopulafion, and in a mean time of 3 to 5 years afteronset of 0LP,"i2

The etiology of RAS includes trauma to the mu-cosa, since an intact epithelium constitutes the maindefense against a variety of pathogens, including her-pes simplex virus (HSV), the causative factors for aspectrum of orofacial lesions, including primary her-petic stomatifis, recurrent herpes iabialis, and recur-rent intraoral infections. HSV-associated lesions arereminiscent of RAS, particularly of the two subtypesHSV-1 and HSV-2, the former being associated withherpetic stomatitis. Primary HSV infections are pre-dominantly subclinical with stomatitis and pharyngifis,the cardinal clinical manifestations. Latent viruses (eg,VZV, CMV) have also heen proposed as etiologic fac-tors for RAS. An efiologic role for certain foods is stillunder debate. RAS lesions may reach maximum inci-dence in the postovulatory phase of the menstrualcycle in women, when estrogen levels drop and pro-gesterone levels rise.'-̂ A genetic propensity is clear inthat RAS is more common among patients with theHLA-Cw7 (23% versus 9% in controls) and HLA-B51(23% versus 5% in controls) phenotypes, also com-mon in Bebcet's syndrome.'' Polymorphism for IL-lband IL-6 alíeles may also be predictors of RAS."

The etiology of OLP may depend in part upon go-nadal hormones since women are 1.5 to 2.0 timesmore at risk than men. Aging may also play a role inthe onset of OLP since over 95% of OLP cases occur

at ages over 30 years. Men are afflicted at an earlierage tban women (40 to 49 years versus 50 to 59years). The incidence of OLP docs not vary signifi-cantly across ethnic groups, but a genetic propensityfor OLP is suggested by the observation that expres-sion of HLA-Bw57 favors OLP, whereas HLA-Dql ex-pression seems to provide resistance to it The initialtrigger for OLP may include chemically induced cellu-lar trauma, allergens (eg, cinnamon), mechanicaltrauma (eg, Koebner phenomenon), or a putative anti-gen (eg, mercury). Human hepatitis C virus (HCV)may be a predisposing factor for OLP, and comorbid-ity of HCV infection, and OLP is noted in associationwith the HLA-Dr6 alíele, OLP lesions exacerbate withpharmacologie treatments with nonsteroidal anti-in-flammatory drugs, anti-rheumatics, angiotensin-con-verting enzyme inhibitors, anfi-hypertensives, antibi-otics, or ß-blockers.'"

Stress and anxiety may play a significant role in theonset and recurrence of RAS lesions. Findings otheightened anxiety levels, measured with the HospitalAnxiety and Depression scale, and of significantly ele-vated salivary cortisoi by radioimmunoassay, sug-gested stress plays a part In the etiology of RAS. RAScan have profound effects upon quality of life, includ-ing recurrent prolonged burning pain that hamperschewing, talking, and other oral funcfions.^' Pain maybe so dehilitating that pain control is often necessarywith medications or with adherent agents that coat theulcers. Patients with persistent RAS often show ele-vated anxiety (ie, Self-rafing Anxiety Scale), which canengage a psychobiologic response.''^'^

Patients with OLP also experience significant dis-comfort, which can interfere with eating and can lowerquality of life, and OLP may have a psychoneuroen-docrine component,^ The authors' data have con-firmed that the progression from the reticular to the at-rophie, erosive, and bullous forms of the disorder maybe driven by anxiety, psychologic trauma, and turmoil,and significant difterences in psychoimmune interac-tions exist between patients afflicted with nonerosiveOLP lesions compared to those with erosive OLP le-sions, A large proportion (> 50%) of patients withOLP report elevated levels of iife stress prior to theonset of tbe exacerbation of lesions, and score high onthe Hamilton anxiety scale, the Hamilton depressivescale, and the Profile of Moods scale' Their psycho-logic symptoms are, interestingly, not detected by theHospital Anxiety and Depression scale.''^

In brief, research to date suggests a psychosomaticcomponent to the etiology and prognosis of RAS andOLP, These conditions are often referred to as "stress-related" or "stress-associated" ulcérations of the oralmucosa.''* However, the field remains controversial,"primarily because of the complexity of the field of

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Stress research, and because its integration in tbe do-main of oral biology and medicine is still in itsinfancy.*'*

IMPUCATIONS FOR THE CLINIC

To fully appreciate the potential relevance of the fieldof stress research to the management of stress-relatedoral ulcers in the dental clinic emironment. certainsalient issues must be mentioned. For instance, it isimportant that the treating clinician realizes the pa-dent's owTi perspective on stress.

The perception of stress can be interpreted by thepatient in a \'ariet>' of ways and can be assessed andverified by simple in-practice methods by the inter-ested professional, and with weU-characterized simpleinstruments readily available for this purpose. For ex-ample, patients can make a distinction bet«'een posi-tive ("eustress." "good" stress) and negative chaiienges("distress." "bad" stress); or they may distinguish be-tween major stressful life events (eg, divorce, final ex-aminations), and minor daily hassles (eg. someone•stole"" theii parking spot "causing" them to be late tothe dental appointment and to arrive frazzled). Inmost cases, the patient wiil perceive some sort of psy-choemotional stress consequentially to the perceivedlack, or loss of fit within the surrounding environment(ie. person/environment fit).'^ '*

However conceptualized, psychoemotional stress isconsistently associated with psychologic manifesta-tions, including anxietj'. irritabiiitj' and anger, sad anddepressed moods, tension, and fatigue, and «ith cer-tain bodily manifestations, including perspiration,blushing or blanching of the face, increased heart beator decreased blood pressure, and intestinal crampsand discomfort The clinician may observe these signsof stress, and query the patient as to their nature, du-ration, chronicity. and severity'. Vocalization and theprocess of bringing out into consciousness the trou-bling issues, and the realization that a caring indi\id-ual is lending a concerned ear. can often assuage thepatient's concerns, tension, anxiety, and stress.'-*"'

Tlie clinician should also be aware of the underly-ing physiology of stress reactions, which involves thenervous system, hormonal system, as well as the im-mune system. Stress alters the regulation of both thesimpathetic and the parasympathetic branches of theautonomie nervous system, with consequential alter-ations in hjipothalamic control of the endocrine re-sponse controlled by the pituitarj' gland. Autonomieictivation and the elevation of hormones, includingthose produced by the hypothalamic-pituitarj'-adrenaiixis. play pivotal roles in regulating immune surveil-ance mechanisms, including the production of cy-

tokines that control the inflammatory process as wellas events responsible for healing.^-"*

The renowned French physiologist of the 1800s,Claude Bernard, first asserted that defense of the inter-nal milieu {le milieu intérieur) is a fundamental featureof physiologic regulation in mammalian systems^^;hence, the term homeostasis was coined. By the early1930s. Cannon proposed that organisms engage in adynamic process of adjustment of the physiologic bal-ance of the internal miheu in response to changing en-vironmentai conditions; thus. Selye established thecardinal points of the "Generalized Stress Response"in his demonstration of concerted physiologic re-sponses to stressful challenges. Selye also proposed theterm heterostasis to describe the situation where thedemands upon the organism exceed its inherent physi-ologic limiting capacity'.-" Three decades later, Sterüngand Eyer '̂ introduced the concept of "allostasis'" to de-scribe the events that involve whole-brain andwhole-body regulation, rather than simple local feed-back. They argued that, whereas homeostatic regula-tion may include more than local circuits, allostaticregulation emphasizes the role of the central and pe-ripheral nervous systems in the maintenance of inter-nal balance and viability amidst changing circum-stances, diverse environments, and stressful challenges.

Thus, the stressed dental patient is one whose psy-chobiologic balance is significantly altered. The cKni-cian must realize that allostasis (or allostatic regula-tion) in the stressed patient encompasses a range ofbehavioral and physiologic functions that direct theadaptive function of regulating homeostatic systems toa given stress (ie. aUostatic state). The cumulative loadof the allostatic state is referred to as the allostaticload, and the pathologic side effects of failed attemptsat adaptation are recognized as the allostatic overload.In brief, allostasis means achiering stability' throughchange of state. It pertains to regulator '̂ systems thathave variable set points, that are characterized by indi-viduai differences, that are associated with anticipa-tory behavioral and physiologic responses, and thatare vulnerable to physiologic overload and the break-down of regulatory capacities."-^'

This realization should alert the clinician to threefundamental issues: (1) the consequences of stressupon patients are not uniform, and the psychopatho-logic and physiopathologic impact of stress may besignificantly greater in some patients than others; (2)the impact of stress is d^Tiamic and multi-faceted, suchthat the same patient may exhibit a varietjf of manifes-tations of the psychoneuroendocrine-immune stressresponse with varying degrees of severity at differentvisits; (3) the outcome of stress can be ambivalent inthe sense that patients may position themselves alongthe spectrum of allostatic regulation, somewhere

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between the allostatic state (toward regaining physio-logic halance), and the allostatic overload (towardphysiologic collapse, with associated potential onset ofvaried pathologies).

Indeed, two distinct states of allostatic overloadhave heen recognized. In type 1 allostatic overload,stress responses arc directed at self-preservation bytneans of developing and establishing temporary orpermanent adaptation skills. Patients in this mode di-rect their energy to survive the perturbation in the bestcondition possible, and to normalize their normai lifecycle,̂ ^ Major life events, and, to some extent at least,the accumulation of minor daily hassles are examplesof situations that may engender a type 1 allostaticoverload situation.

In type 2 allostatic overload, the stressful challengeis often perceived as excessive and continued, andthus drives allostasis constantly. As a result, an escaperesponse is not found, and the physiopathologic re-sponse can become chronic in nature (eg, hypercorti-solemia, glucoccrticoid resistance), with consequentialerosion in health and immune surveillance mecha-nisms.^' A significant accumulation of daily hassles,which may result in the perception of social defeat,and situations of social submissiveness exemplify theconsequences of type 2 allostatic overload, as demon-strated in the authors' experimental work.'"

In order for clinicians to more effectively treat pa-tients with RAS or OLP, it is important that future re-search test the similarities and the differences betweenRAS and OLP psychophysiopathology. RAS appears tobe associated with acute stressful events immediatelypreceding the onset of the lesion, and interventionsaimed at reducing stress (ie, increasing the uncon-scious or conscious perception of person/environmentfit} hasten the resolution of the lesions. RAS may per-tain to a type 1 atlostatic overload response. Stress-management interventions (eg, relaxation, imagery,meditation), which may benefit the patients by provid-ing tools and methods for self-preservation and adapta-tion to stressful challenges, have in fact been reportedto reduce RAS recurrence.'•̂ •̂ •'•̂ '

RAS lesions may be associated with the initial stageof stress, that which could be called "deregulation ofhomeostasis." RAS lesions always drain to the proximallymph nodes, indicating a local immune activation andsurveillance process. By contrast, OLP lesions are notassociated with lymphadenopathy, and seem to behavein a manner more similar to an autoimmune disease ofa chronic nature. The temporal pattern of exacerbationof the lesions suggest that OLP may be more closely as-sociated with the type 2 process of the allostatic over-load. This proposition suggests that the fundamentalpsychobioiogic or antigenic stressful challenge in OLPis persistent and chronic in nature. Such a stimulus that

persists, despite behavioral, autonomie, neuroen-docrine, and immune responses that should serve to re-duce it, provides long-term activation of a commonstress response network that directs sustained auto-nomie, neuroendocrine, and immune involvement,^One outcome of this sustained state of allostatic activa-tion may be attaining a novel state of balance, at whichpoint psychoneuroendocrine-immune equilibrium is re-instated, and thus, OLP lesions are contained. Anotheroutcome of this precarious state of physiologic balartcemay be the collapse of aliostatic regulation consequen-tial to a psychologic, neuroendocrine, or antigenic trig-ger, and renewed allostatic overload. Hence, the OLPlesions exacerbate. That is to say, OLP may pertain to amore severe form of type 1 allostatic overload, whichcould be termed type lb, because it's not immediatelyidentical to type 2, but has the potential to evolve intothis second type (cf, predisposition of more aggressiveOLP lesions for oral carcinoma).

If this discriminative hypothesis is true, then RASand OLP stand at the two opposite ends of the allosta-tis load spectrum: the one, RAS, being associated withthe initial deregulation in physiologic response follow-ing stress (a typical type 1 allostatic overload), and theother, OLP, with an atypical type 1 process of ailosta-tic overload, which would be labeled type lb because itis not as immediately detrimental to survival as type 2.This information should be suggestive and useful toclinicians treating patients with RAS or OLP hecauseit could alert them of the systemic physiopathologicresponse individual patients undergo, and it could sug-gest appropriate aitxiliary psychobiologic interventions(eg, counseling, biofeedback), wbich could beneficiallysupplement the recommended dental treatment.

From the perspective of in-practice research, it maybe hypothesized that patients with RAS and patientswith OLP ought to respond very differently to an ex-perimental stress, such as the nonadrenergic cold pres-sor test. The test examines the nature, extent, andtime-line of tolerance to pain, and the neuroendo-crine-immune response, and involves insertion of thepatient's nondominant hand in ice water, recording thelength of immersion time, and collection of whoiesaliva for hormonal and cytokine assays by an outsidelaboratory, if desired. It is a controlled and well-estab-lished stressful pain stimulus, that is simple, fast, andeasy to perform, without need for expensive equipmentor training, whose experimental validity and reliabilityts widely recognized. The fundamental physiologicmechanism underlying the test involves response totemperature in the form of blood flow of both superfi-cial and deep tissues of the hand, and the consequen-tial perception of pain,'It is an adequate model to studypam reactivity by inducing cold-induced vasospasmsthat are common in syndromes of chronic pain.^'s

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Clinicians could augment the clinical informationabout their patients having RAS or OLP with dataabout their allostatic load response by means of thissimple test administered by the dental assisting staff ateach visit. With minimal expense or risk, clinicianscould obtain new information about the systemic stateof health of tbe patients, for tbeir ultimate benefit

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