University of Groningen Primary Sjögren's Syndrome Delli

University of Groningen

Primary Sjögren’s Syndrome Delli, Konstantina

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record

Publication date: 2017

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA): Delli, K. (2017). Primary Sjögren’s Syndrome: towards a new era in diagnosis, treatment and e-patient education. University of Groningen.

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Download date: 02-10-2021 Chapter 2

Xerostomia

Konstantina Delli1, Frederik KL Spijkervet1, Frans GM Kroese2, Hendrika Bootsma2, Arjan Vissink1

1. Department of Oral and Maxillofacial Surgery

2. Department of Rheumatology and Clinical Immunology

University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Edited version of: Monogr Oral Sci. 2014;24:109-25.. 20 radiotherapy canbehighlybeneficialfor techniques patients. duction ofthedosetoandvolume ofirradiated salivaryglands by advanced sive lossofglandularfunctionandadiminishedsalivaryoutput.Inparticular, re- salivary glands, which are to progres leads of located the in head, the periphery - andneckradiotherapy,During head theadministrationtomajor ofhighdoses composition canchange. tion offluidandelectrolytesinsalivaryglandscanbereduced andthesalivary geting neurotransmitters andreceptors. Asaresult, amongstothers theproduc- Certain classes ofdrugscaninduce hyposalivation classes Certain and/or xerostomia by, e.g., tar malignant Bcelllymphoma,mostlymucosaassociatedtissuelymphomas(MALT). glandular epithelialcells.About7.5% ofpatientswithSjögren’s syndrome develop involvesgenesis systemic B-cell hyperactivity and T-cell targeting lymphocytes infiltration oftheexocrine glands,thesalivaryandlacrimalinparticular. Thepatho- Sjögren’s syndrome isachronic systemic characterised autoimmunedisease by syndrome, medicationandradiotherapy andneck. inthehead tions have beenassociatedwithxerostomia. Three are: majorcauses Sjögren’s Xerostomia isthesubjective feeling Several oforal dryness. andcondi- diseases Summary - Introduction standing theeyes’standing appearancecan benormal.Ocularcomplaintsmay include maytoms, dryness result andsoreness, insensationofitching, grittiness, notwith- SS primarilyaffects lacrimalandsalivaryglands. With tothe respect eyes’ symp- Glandular manifestations features Clinical with SLEfulfilthecriteriafor sSS. InRAtheprevalenceages. ofSS isaround 30%and approximately 20% ofpatients 9:1). Themedianageofoccurrence isaround 50 years, althoughitcanariseinall population.Itaffectsin thetotal mainly women (i.e. female tomale ratio equalsto SS withaprevalence isoneofthemost commonrheumaticdiseases, of0.5-1% Epidemiology matosus (SLE),scleroderma andmixed connective tissuedisease. aresue diseases present,- (RA),systemic suchasrheumatoidarthritis lupuserythe Sjögren’ssent, andsecondary syndrome (sSS), incaseadditionalconnective tis- Sjögren’sin primary syndrome (pSS), ispre in case nootherautoimmunedisease Consensus Grouppean (AECG) classificationcriteria[2],SS canbedistinguished lar manifestations, evident inalmostany organ. According totheAmerican-Euro- symptoms, known alsoassiccasymptoms, may beaccompaniedby extraglandu - glands, resulting inxerostomia eyes anddry (keratoconjunctivitis sicca).These infiltration oftheexocrine glands.Itcommonlyaffects thesalivaryandlacrimal andlymphoproliferativetory disorder thatisprincipallycharacterised by chronic by theSwedish ophthalmologistHenrik Sjögren in1930. Itisachronic inflamma- Sjögren’s syndrome (SS), in the form thatitiscurrently defined, was first described Sjögren’s syndrome radiotherapy andneck. ofthehead will focus onthethree Sjögren’s mostcommoncauses: syndrome, medicationand has been associated with transient or persistent xerostomia (Table 1). This chapter in individualshousedlong-termcare facilities. Anumberoffactors may causeor itbetweenestimate 13 and 63% [1]. It is more prominent in women, in elderly and The prevalence ofxerostomia isdifficulttobedeterminedandnumerous studies Greek words “xeros’’ and“stoma” dry (ξηρός),meaning mouth. (στόμα),meaning Xerostomia isthesubjective feeling Thetermisderived oforal dryness. from the 21

Chapter 2 22 tongue, inparticular, fissured becomes often andexhibits atrophy ofthepapillae. andcharacteristicallymucosa istenderanddry forms (Figure finewrinkles 3).The lacking oftheusualpooling inthefloorofmouth.Inadvanced disease, theoral progresses,turised but while the disease foamy,saliva and becomes diminishes candidiasis.IntheonsetofSS,in particular mouthappearstobenormally mois- (Figureincreased cervically especially caries, risk of dental 2), and oral infection, of time, burningsensationofthemouth,discomfort whilewearing dentures, and eating dry difficulty in food (e.g. crackers), problems inspeaking for longperiod to areduced saliva production). Thissymptom associatedwith dysgeusia, isoften Another prominent symptom of SS is xerostomia (sensation mouth related of dry perforation [4]. cations may ulceration, include corneal vascularisation, opacification, and, rarely, Progressive keratitis may result inlossofvisionpatientswithSS. Ocular compli- charge intheeyes, andthesensationofafilmacross thevisual field[3](Figure 1). photosensitivity/photophobia, eye erythema, fatigue, decreased visual acuity, dis- Schirmer’s test. production,tear examined with Figure eye 1:Dry duetodiminished fine wrinkles. fine wrinkles. mucosa, characteristically forming Figure 2:Tender oral anddry dyspareunia [6]. of SS patientswhileinfemale patientswithSS ofthevagina desiccation results in respiratory tracts resulting innon-productive skinaffects Dry cough[5]. about 55% glandular enlargement. ofupperandlower canoccur atmucosalsurfaces Dryness intheparotidmas, inmostcases alsotomore gland,canlead persistent unilateral infection,secondary encouragingswelling. further Thedevelopment oflympho- processof an autoinflammatory of salivaglands and stasis in these can result in tent topersistence innature. Theswelling isgenerally attributed tothepre livary glandsisusuallybilateral, may benon-painfultoslightlytenderandintermit- glands (Figure 4)isacommonphenomenoninpatientswithSS. Swelling ofthesa Enlargement theparotid ofthe salivaryglands,especially andsubmandibular Table 1:Conditionscausingxerostomia Jensenetal.,2010). (modifiedafter Sjögren’s syndrome Musculoskeletal disorders connective tissuediseases Chronic inflammatory &neckradiotherapyHead Xerogenic drugs Neurological disorders Autoimmune liver diseases bowel diseases Chronic inflammatory Endocrine disorders Chronic fatigue syndrome Mixed connective tissuedisease Hypothyroidism mellitus Diabetes Amyloidosis Fibromyalgia Scleroderma Parkinson’s disease Burning mouthsyndrome Holmes-Adie syndrome Alzheimer’s disease composition Changed +/- + + + + + + ? ? ? ? ? ? ? ? Infectious diseases Cancer-associated disturbances Eating disorders disturbances Metabolic HIV/AIDS Bulimia nervosa Hepatitis Cvirus Chemotherapy Anorexia nervosa Malnutrition Sodium retention syndrome Water andsaltimbalance GVHD composition Changed +/- +/- +/- + + + + + ? sence 23

Chapter 2 24 Table 4:Possible factors predisposing toSS. Table 3:Serologic findingsinSS patients. Table 2:Riskfactors for thedevelopment oflymphoma. Exogenous Endogenous rheumatoid factor acetylcholine receptor 3 anti-muscarinic anti-alpha fodrin anti-La/SSB anti-Ro/SSA Autoantibody Peripheral neuropathy Renal involvement Vasculitis Palpable purpura Persistent lymphadenopathy Persistent enlargement ofparotid gland Clinical 5. 4. 3. 2. 1. Female gender HLA-DR3/DQ-2 Immunologic disturbance

Hepatitis C HIV Retroviruses (e.g. HTLV-10) Coxsackie Epstein Barr Virus infection 50 71-90 30 50 70 (%) patients Frequency inSS Cryoglobulinemia Increase inIgGlevels CD4+ Tlymphocytopenia Reduced levels ofcomplementC4 Monoclonal gammopathy Serological NO NO YES NO NO Specific for SS hepatitis CandHIVinfections canproduce both symptoms andpathological find- sialoadenitiswithformationlymphocytic offoci around theducts[15].Additio bly, theirglandularpersistence insalivaryglandepithelialcellsmay tochronic lead suchasEpsteinBarr,viruses, Coxsackie andretroviruses may be implicated.Possi- of aninfection, possiblyviral orhasanothercause. Several that findingssuggest role. Itis notclarifiedyet whetherthisdisturbanceexists primarilyorisaresult poorly understood. Undoubtedly, adisturbanceoftheimmunesystem plays akey SS isconsidered tobeanautoimmunedisorder, thatis butwithapathogenesis Etiopathogenesis be more insituationswhere suitable misclassificationmay present risks health [14]. loped from registry collectedwithstandardized data measures andare thoughtto for SS, basedmerely onobjective TheACR tests. classificationcriteriawere deve the AmericanCollegeofRheumatology(ACR) proposed new classificationcriteria be carefully re-evaluated [1].Recently, duetotheemergence ofbiologicagents, gic drugsare widelyusedby patientsfor many conditions,theirexclusion should classificationcriteriaandthatsinceanticholiner notcompletely fulfilthese does serological findings.ItmustbeunderlinedthatSS canbepresent inapatientwho keratoconjuctivitis siccaandhyposalvation togetherwithhistopathologicaland combinesubjectivecriteria successfully symptoms, aswell asobjective signsof ria for SS andsince todatethey are themostwidelyacceptedcriteria[2].These A jointstudyoftheAECG presented in2002 therevised AECG classificationcrite- Diagnostic criteria their presence theclinicianfor shouldalert thepossibilityofSS-diagnosis. SSB are notspecificfor SS, sincethey canalsooccurin,e.g., patientswithSLE, been associatedwithextraglandular anti-Ro/SSA [13].Despite disease andanti-La/ Their titers reflect activity, disease while high titers anti-La/SSB of particularly have (Tableautoantibodies 3),whichare present in70% and50%respectively. ofcases, The mostcharacteristicinSS autoantibodies are theanti-Ro/SSA andanti-La/SSB Serological findings increase inIgGlevels, orcryoglobulinemia [7-12] (Table 2). gammopathy, reduced levels ofcomplementC4, sharp CD+4Tlymphocytopenia, monic, shouldraisewhenitiscombinedwithmonoclonal suspicion,especially (Figure 6),renal involvement andperipheral neuropathy, althoughnotpathogno- is analarmingclinicalsign.Thepresence ofpalpablepurpura (Figure 5),vasculitis parotid gland.Theconversion from variable topersistent enlargement ofthegland in developing lymphomas[9].Bcellare mostfrequently locatedinthe is MALT-type [7,8]. SS patientsalsohave an18.8 (CI:9.5-37.3) increased times risk About 7.5% ofpatientswithSS develop malignantBcelllymphoma,48-75% ofwhich Lymphoma development nally, 25 -

Chapter 2 26 Prolonged • hyperactivity andalsoT-cell targeting lymphocytes glandularepithelial cells: The complexity of the pathogenetic pathways in SS involves both systemic B-cell factors, too[16,17]. with theC4nullgenebeingpresent in50% ofSS patientsprobably evincesgenetic of hormonalfactors, whiletheextended haplotypeHLA-DR3/DQ-2 incombination volved (Table 4).Thestrong female preponderance possibleinvolvement implies fromApart exogenous these factors, various endogenousfactors may bealsoin- an exclusion criterion for SS. ings similartothatinSS, butfor thetimebeingpresence infections ofthese is atrophy ofthepapillae. Figure 3:Red, fissured tonguewith classification criteriaofSS aswell asoneofthethree objective ACR criteria[2,4]. sis ofSS anditshistopathologyisconsidered asoneofthefour objective AECG Biopsy oftheminorsalivaryglandslower lipiswidelyused for thediagno- Histopathology Ductal • cells inaffected labialsalivaryglands[18]. positive (70-80%). CD8-positive T-cells constitutearound 10% ofinfiltrating globulinemia inSS patients; SSA andanti-La/SSB RF, antibodies, type2cryoclobulins andhypergamma- epithelial B-cell cells survival are and surrounded B-cell hyperactivity by to thedevelopment ofMALT lymphoma. Figure 4: Enlarged parotid salivarygland due activated leads T-cells, to presence predominantly of anti-Ro/ CD4- tion ofthefacial nerve was observed. loss ofsensibilityandpain. Innoneoftheparotid glandbiopsy adisturb- studies morbidity ofaparotid glandbiopsy compared toalipbiopsy [20,22] withregard to remaining wound isclosedinlayers [21](Figure Several 7). show studies alower out, followed by bluntdissectiontothe parotid glandandanincisionalbiopsy. The tissue istaken from thearea around the lower lobe. ear An1cmincisioniscarried tion criteria. With this technique, alsoperformed parotid underlocalanaesthesia, validated for theAECG classificationcriteria[20], butnotyet for theACR classifica- are usedasan alternative Parotid to minorsalivary gland biopsies. are biopsies collected [19]. Parotid are biopsies increasingly gaining broader and acceptance of approximately 1.5 seven cmismadeandatleast individual labial glandsare The procedure isperformed Alower underlocalanaesthesia. lipmucosaincision Figure 6:Raynaud’s phenomenon. Figure 5:Purpura isacommonextraglandular manifestation inSS patients. 27

Chapter 2 28 4 mm more than50 cells,they are calledfocus. Thepresence ofmore thanonefocus per and are locatedaround infiltratesare thestriatedducts. Whenthese composedof filtrates are composedofbothB-andT-lymphocytes aswell asnon-lymphoidcells ofacini(Figuretion ofsalivaryglandsincombinationwithdestruction 8A).Thein- The mostprominent microscopic finding inSS infiltra lymphocytic - isperiductal Table 5:Treatment ofSS. ing thecourse of thedisease. glands. Repeated from biopsies the same parotid gland offer information concern- phoma, asMALT develop lymphomasoften intheparotid glandandrarely inlabial histopathological results of a parotid biopsy can be indicative of malignant lym- patients andthepossibilitytoinitiatepreventive B-cell-directed therapy [23].The for non-Hodgkinlymphoma(NHL)development, allowing for riskstratiﬁcation of pSS isahighlypredictive diagnosticsalivary biopsies andeasy-to-obtain marker that the detection of suggested GC-like(2011) structures by light microscopy in well-formed lymphoidfollicles orgerminal centersandcolleagues (GC).Theander labial salivaryglands[20] andadditionally canprovide evidence about LELsand The sensitivity and specificityoftheparotid biopsy are comparable withthatof seen. acteristic epimyoepithelial islandsinabackground oflymphoidstroma are usually (LEL) (Figurethelial lesion 8B) can also be present. In major salivary glands, char of SS. Furthermore, ifthemajorglandsare enlarged, progression toalymphoepi- SUPPORTIVE b. a. c. b. a. e. d. c. b. a.

Cevimeline Pilocarpine 2. Systemic Fluoride application Antifungal therapy salivaArtificial MOUTH Blocking thelacrimalpunctum glasses Sealed Immunosuppressives Corticosteroids tears Artificial EYE 1. Local 2 area ofglandulartissueisregarded asapositive criterionfor thediagnosis

e.g. Rontalizumab 4. IFN e.g. Infliximab, Etanercept 3. antiTNF-a e.g. Abatacept 2. InhibitionofcostimulationT-cells e.g. Rituximab 1. B-celldepletion CAUSAL - of debate[26]. The therapeutic approach tothepatients withSS andMALT lymphomaisamatter treatment ofSS [24,25]. treatments targeting theco-stimulationofT-cells have beenalsorecruited inthe perspective, inhibitors of TNF-, INF-, B-celldepletiontherapies, BAFF-inhibitors and thatarecells orcytokines intheimmune response. fundamental Under thisnew During thepasttwo biologicalshave decades, becomeavailable totarget specific patients. is indicatedindentate aweeklycaries, todailyuseoftopicalneutral fluorideapplicationsormouthrinses frequently isneeded totreat oral candidiasis.Duetotheincreased risk ofdental gal therapy, suchas local treatment withnystatin, myconazole or amphotericin B, totreattry xerostomia saliva artificial and/or withmouthrinses, oral gels.Antifun- relief ofxerostomia. Whenstimulation ofsalivarysecretion isuneventful, onecan cal (chewing gum)orsialagoguemedication(pilocarpine, cevimeline) results in whether stimulatingsalivarysecretion by(sugar-free gustatory sweets), mechani- ing thenormaldrainage tothenose. To treat xerostomia, onefirst hastoestimate uncutintheinnermarginthe lachrymal oftheeyelid canalsobehelpfulby block an attempttoprevent evaporation oftearsandtoconserve film.Sealing thetear and localimmunosuppressive may are glasses beused.Sealed alsointroduced in eyes,tears lubricatedry andincaseofkeratoconjuctivitis localcorticosteroids Local treatment for ofeyes dryness andmouthishelpfulinmany Artificial cases. mostly mainlysupportive (Table 5). Evidence-based therapy for SS islimitedandthetreatment ofpatientswithSS is Treatment (http://www.imshealth.com). Table 6:Top 10Therapeuticby Classes U.S. DispensedPrescriptions in2011 6 5 4 3 2 1 10 9 8 7 Ranking Beta BlockersBeta ACE Inhibitors agents Anti-diabetes Narcotic Analgesics Lipid Regulators Antidepressants Anti-epileptics Diuretics Anti-ulcerants Respiratory Agents Drug Class Xerogenic Effect Uncommon YES YES YES YES YES YES YES NO NO 29 -

Chapter 2 30 drugs aswell. while xerostomiathe capacitytoinduceoral dryness, can occurintheabsenceof mouthisprimarilyreversible,induced dry andanincreasing amountofdrugshas mouthincreasesdry withageandthenumberofdrugs taken perday. Alsodrug- tribute to theproblem. itis generally Nonetheless, accepted thatthe prevalence of report. The situation is even more and disorders complicated in diseases that con- form, timeofintake, duration ofuse, druginteraction andreliability ofpatient’s many factors, suchastypeofdrug,numberdrugs,drugcombination,dose, The exact relationship between mouthanddrugsisvariably dry influenced by was mouth(80.5%) dry followed by dysgeusia(47.5%) andstomatitis(33.9%) [27]. quently prescribed drugs in the U.S. revealed that the most common side effect Drugs are mouth.Areview themost common causeofdry ofthe200 mostfre- Drugs removed. parotidsmall amountofsuperficial tissueis sule oftheglandiscarefully openedanda sule isexposed by bluntdissection.Thecap- C. Theskinisincisedandtheparotid cap- tion anesthesia. TheareaA. isanesthetizedwithlocalinfiltra- Figure 7:Incisionalbiopsy oftheparotid gland. layer isclosedwith5-0nylon sutures. sutures (polyglycolic acid),whiletheskin 3-layered closure with4-0gaugeabsorbable D. Theprocedure iscompletedwitha2to theposteriorangleofmandible.near is madejustbelow andbehindtheearlobe B. With aNo15bladesmall1-2cmincision selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors depressants fall intofour different viz.tricyclic classes, antidepressants(TCAs), sants report themfor taking more than2years, and14% for 10years ormore. Anti U.S. Even more isthefact notable thatover 60% ofpatientsprescribed antidepres- Antidepressants were prescribed themostcommondrugcategory in 2011 inthe Antidepressants about xerogenic medicationcanbefound in‘www.drymouth.info’. commonly usedtherapeutic drugs(Table 6)inducexerostomia. More lists detailed [29]. This section will focus the mechanism upon on which describing the most stimulation produces littlesaliva butrichinprotein, givingasensationofdryness mulation produces abundantsaliva oflow protein concentration whilesympathetic the result oftheireffect onneurotransmitters and receptors. Parasympathetic sti weight compoundsorby reducing body’s contentofsaltandwater. This ismainly insalivaryglands,by affectinglytes theproduction ofproteins andhighmolecular byDrugs induceoral dryness interfering with the production of fluid andelectro- Possible mechanisms wasdryness greater inwomen thanmen[28]. the aforementioned butalsoconcludedthatthepresence data, ofdrug-induced related theprevalence mouthandage, ofdry Nederfors etal.notonlyconfirmed mouth increases withthenumberofdrugstaken perday (Figure 10).Inastudythat from theageof18to65respectively (Figure 9).Theprevalence ofdry ample, the intake of 1-2drugs/day/person progressively increases from 24% to87% indicate thattheaverageStudies intake ofdrugsincreases withage. InU.S., for ex Interrelation withageandsex between theserous acini(magnification10x). infiltratelar lymphocytic anddepositionoffat (A) Parotid gland tissue showing a periductu- Figure 8:Microscopic findingsinSS. (Pijpe etal.,2007) infiltratea lymphocytic (magnification 20x) (B) Lymphoepithelial surrounded lesions by 31 -

Chapter 2 32 rience dry mouth. The main categories ofrespiratory mouth.Themaincategories rience dry agentsassociatedtodry reportedSmidt etal.(2011) that27% respiratory ofpatients taking agentsexpe- Respiratory agents [32,33]. drugscomplainoforalthese dryness similar actions and sideeffects. thatabout 1-13% suggest Reports of patientsusing located inthevascular smoothmuscle. BothACE inhibitors andAIIRAspresent (AIIRAs) actby blockingthebinding ofangiotensinIItothereceptors conversion ofangiotensinItoII.AngiotensinIIreceptor antagonists ACE inhibitors are widely usedfor thetreatment of hypertension. They inhibitthe Angiotensin converting inhibitors enzyme (ACE inhibitors) persistent withamoderate tosevere intensityin57% ofthem[31]. among patientswhoreceived morphineduetocancerpain.Thesymptom was ate acuteandchronic pain.Glare etal.reported aprevalence of95% mouth ofdry some synthetic derivatives are classifiedasNAsandare principallyusedtoallevi- ing pathway by bindingtoopioidreceptors. aswell Morphineanditsanalogues as Narcotic (NAs)ingeneral analgesics reduce neuronal excitability inthepaincarry Narcotic analgesics of patientsonSSRIs [30]. SSRIs mouth occurred that dry in28% TCAs ofpatients taking incomparison to 7% [30]. Wilson et al. showed of the adverse in a meta-analysis effects of TCAs versus pacity of TCAs is high,and28% TCAs of patientstaking may develop oral dryness (MAOIs) and atypical antidepressants. It has beenshown thatthe xerogenic ca- Figure 9:Prescription druguseinU.S., 2001-2004 (modifiedafter: Sreenby andVissink, 2010). Percentage 100 10 20 30 40 50 60 70 80 90 0 Under 18 18-44 Age (years) 44-64 64 and older 3 ormore drugs At least 1drug - rates inpatientstreated withomeprazole, acommonproton-pump inhibitor[41]. pylori [40]. Teare and co-workers reported subnormal parotid or wholesaliva flow 41% ofpatientsreceiving H2-receptor for antagonist eradication ofHelicobacter anti-ulcerants are H2-blockers andproton-pump inhibitors.mouthisfound Dry in Anti-ulcerants are ofthetreatment usedaspart ofulcers. Thetwo of basic types Anti-ulcerants Three are• antihistamines antihistamines commonlyused,viz.bromphenira- • • mouth are [34]: Figure 10:Prevalence mouth(modifiedafter: ofdrugsanddry Sreenby andVissink, 2010). Prevalence of dry mouth (%) [38,39]. aswelldecongestants asbreathing through mouth mouthcancausedry mine, clopheniramine andcarbinoxamine. Theirfrequent combinationwith in0.4-11%the capacitytoinduceoral dryness ofpatients[38,39]. relieves demonstrated nasalobstruction.Studies thatpseudoepinephrinehas phenylephrine results intheshrinkingofnasalmucousmembranesand the mucousmembrane oftherespiratory tract by pseudoepinephrineand cough andcoldpreparations Stimulationofα-andß-adrenergic receptors in receiving itcomplainfor xerostomia [36,37]. versus 1.6% relative to placebo; p < 0.05) [35], while overall 6-13% of patients event inpatientsontiotropium (ananti-muscarinicagent)was mouth(9.3% dry drugs for obstructive airway diseaseThemostcommonlyreported adverse 20 30 40 50 60 70 80 10 Number ofdrugstakenperday 1 2 3 4 5 6 7 Nederfors 1996 1989 Screenby etal. 33

Chapter 2 34 acid, clonazepam, zonisamide effect hasbeenattributedtocarbamazepine, oxcarbazepine, gabapentin, valproic [43] oreven phenytoin-induced pseudo-Sjögren’s syndrome [44]. Mildxerogenic also sporadic reports oftransient ‘sicca syndrome’ treatment duringphenobarbital pregabalin, evidentadosageof150mg/day whichbecomes after [42]. There are tive theadministration mouthafter of dose-dependentpatternintheonsetofdry the brainseizure thatcauses activity. According toZaccara etal.there isaselec- Anti-epileptics are aclassofdrugsthatprevent rapid, repetitive, stimulationof Anti-epileptics 16%, respectively [33]. thiazide,sparingdiureticsmouth inpatientstaking loopandpotassium in3, 8and ics experience mouth [34]. dry Hebbab et al. distinguished the frequency of dry composition ofsaliva. According toSmidtetal.,17.8% diuret ofpatientstaking - output andbloodpressure. Furthermore, diuretics affect theflow andelectrolyte crease inthevolume ofextracellular water andaconsequentreduction incardiac Diuretics increase theformation andextraction ofurine. Asaresult, there isade- Diuretics In most cases, radiationIn mostcases, damage tosalivaryglandtissueresults inprogressive loss uptake ofthisagenttoo. thyroidmage tosalivaryglandtissue as,besides glands,salivaryglandshave high of thyroid cancerwithradioactive iodinetreatment canalsoresult inradiation da tothemajorsalivaryglands.Ithasbementionedthat ablationtherapydoses with surgery and/or chemotherapy andtypicallyinvolves administration ofhigh andneckcancer.with head Itcanbe usedas a singlemodalityorin combination Radiotherapy plays role afundamental inthetreatment ofthemajoritypatients Radiotherapy aged duringtheirtreatment with xerogenic drugs. malic acid duringdaytime duringnight,shouldbe encour and gel type substitutes withastimulatingadditive saliva,substitutes usage ofartificial inparticular suchas of thetherapy. Inorder patients,usageofsalivarystimulantsor these tosupport nent andsalivaryglandfunctionwillreturn topro-treatment levels theend after sible, patientsshouldbereassured thisconditionisnotperma- that in mostcases similar therapeutic properties canusuallyrelieve thesymptoms. Ifthisisnotpos- drugs orminimizingtheirexposure tothem. Substitution ofadifferent agentwith Drug inducedxerostomia canbeprevented or diminishedby avoiding xerogenic Management of drug-inducedxerostomia , lamotrigine, andtopiramate (www.drymouth.info ). - 2. 2. ducts); of theparotid gland where thestemcellsresided (probably themainexcretory oftheparotideas glandfrom radiationmeanwhile injury guaranteeing thoseareas apoptosis [56]. Currently, research focuses onvery selective ar blockingcertain radiation-inducedearly salivaryglanddysfunctionresulted from p53-dependent radiation after therapyapoptotic cellsearly [55], whereas Avila etal.found that versial findings. Paardenkooper et al. did not observe a dose related increase in study oftherole radiotherapy after of apoptotic celldeath cameupwithcontro - cing acinarcells, but ducts,althoughdeprived of function,remain [54]. intact The glands respond acutely[51,53]. tothelossofsaliva leads produ Radiationinjury theradiation,and compositionofsalivaafter indicatingthatsalivary occurshortly to belateresponding tissue(>60 days) However, [52]. inquantity thechanges salivary glandshave aslow turnover rate (60-120 days), they would beexpected ofcellsthatattempttodivide. orsenescence Basedonthefactdeath thatcellsof 1. DNA-damage caused by radiation impairs proper cell division, resulting in cell eral have theories beenproposed, amongstothers: The mechanismofacutesalivarydamageisnotfullyunderstood andtodatesev [51]. mucous submandibularglandsare probably equallysensitive toionizingradiation [48-50]. More recent revealed, studies however, thattheserous parotid andsero- cins andproteins. Laterecovery ofmoderate ispossibleincases radiation mode decline intheserous, watery contentofthesaliva, compared tothedeclineofmu- of xerostomia ischaracterized by thickandstickysaliva, asaresult ofthefaster are typicallydelivered, by thesalivaryoutputdeclines 60-90%. Theacutephase One week theonsetofconventional after radiotherapy treatment, when5-10 Gy Pathophysiology xerostomia, butalsotoxerostomia from otherorigins. ways correlate withsalivaryflow rates;thisnotonlycountstoradiation-induced [46,47]. It must be noted that the subjective symptom of xerostomia not al- does reduced saliva flow andaltered saliva compositionmay inradiation lead caries inoralThe shift microflora towards cariogenicbacteriaincombinationwiththe andatrophic,mucosa canbecomedry tofrequent leading ulceration andinjury. andofingested of insufficientlubricationmucosalsurfaces food [45]. Theoral impairmentoforalness, functions(speech, chewing, andswallowing) because of glandularfunctionanddiminishedsalivaryoutput.Patients complainoforal dry stu asanalternativegested explanation for thisphenomenon[57,58]. Nevertheless, The dies showdies nocell lossduringthefirst days irradiation after [51,59-61]. leakage ofgranules andsubsequentlysisofacinarcellshave beensug - 35 - - -

Chapter 2 distribution tothetumorand therefore provides bettersparing ofthesurrounding as itallows amore accurate distributionofspecificradiation dosageand IMRT iscurrently recommended asa standard approach cancer, inhead-and-neck be significantlyworse bilateral after compared tounilateral treatment. crease theprevalence andseverity of xerostomia, xerostomia hasbeenshown to the completion of radiotherapyafter [62]. Albeit 3-D-CRT has the potential to de- glands result lossofsalivaryglandfunction post-radiotherapy inless upto2years is evidence thatreduced radiotherapy by dosages 3-D-CRT tocontralateral parotid radiation canbeshapedexactly beams tothecontouroftreatment area. There is achieved by creating athree dimensional imageofthetumor, sothatmultiple 3-D-CRT to deliver is designed an exact dose of irradiation to a target volume. This most commonlyapplied. radiotherapy (3-D-CRT) andIntensitymodulatedradiotherapy (IMRT) are currently advanced are techniques shown inFigure 11, ofwhich3-dimensionalconformal Prevalence ratesofxerostomia radiotherapy after withconventional andmore Advanced radiation delivery techniques beneficial for patients. incombination withsalivaryprotectorsniques and/or stimulators canbehighly Reducing thevolume ofirradiated salivaryglandsby advanced radiotherapy tech- Management 36 Vissink etal.,2010). ventional radiotherapy (RT) andparotid sparingintensity-modulated RT (IMRT) (modifiedafter: Figure 11 : Stimulatedparotid andsubmandibular/sublingual (SM/SL) saliva flow ratecon- after Salivary flow rate (% of pretreatment) 100 120 20 40 60 80 0 Time afterstartofradiotherapy(weeks) 0 5 13 26 39 52 IMRT SM /SLglands, conventional RT SM /SLglands, conventional RT Parotid glands, IMRT Parotid glands, cancer patients[79]. of tumorprotection. whether itissafe Thus,thedebatecontinues, touseitin ing, hypotension). Furthermore amifostine mightalsohave theundesirable effect venous administration is accompanied by several side effects (e.g. nausea, vomit- rently delivered withradiation, patientscontinue toexperience xerostomia. Intra- free radicals [78]. Althoughsalivaryflow ispreserved whenamifostine isconcur Direct radioprotection canbeachieved by theuseofamifostine, ascavenger of Amifostine flow andreduce patient-rated xerostomia [77]. administration ofpilocarpineduringradiotherapy canconsiderably spare parotid the dosedistributioninparotid glandsandwhenparotid doseexceeds 40 Gy, is analternative choice [75,76]. Thebeneficialeffect ofpilocarpineisdependedon term post-irradiation treatment, administration ofpilocarpine during radiotherapy In order toprotect salivaryglandsduringradiotherapy andto eliminate thelong- The results ofpost-irradiationwhenpatientsstopusingit. pilocarpinedisappear shown tohave agreater resistance toirradiation [74]. inthepalate, theones whichhaveof theminorsalivaryglands,especially been tion oftheresidual functionofthemajorsalivaryglandsaswell asthestimulation quired before maximumeffect isvisible. Thepossiblemechanisminvolves stimula- pine [72,73]. Adoseof5mgt.i.d. isrecommended, andupto4weeks mightbere- with post-radiotherapy xerostomia canbenefitfrom theadministration ofpilocar acting asanagonistatmuscarinicreceptors. Onethird totwo thirds ofpatients Restoration of lubrication Pilocarpine Agents for prevention of xerostomia orrestoration of lubrication patientstreatedas inthehead-and-neck withbilateral neckirradiation [71]. with tumors[67,68] locatedinthepharynx andtheparanasal[69,70] sinuses aswell that thedosetocriticalorgans canbesignificantlyreduced, inpatients especially aswelltissues asthelatesideeffects are minimized. The existing literature shows dose distribution,compared withphotonradiotherapy. Thus,thedosetonormal used photons.Thephysical andradiobiological properties ofprotons allow abetter apy A rather new technique that is yet sparsely applied in the clinic is However, approximately 40%mouth[66]. ofpatientsstillcomplaindry results in a significant decrease of xerostomia (both patient- and observer-rated). rates andthereduction ofxerostomia [63-65].IMRT compared to2D-radiotherapy dibular andminor),itcancontributetothemaintenanceofadequatesaliva flow Sinceitreducestissues. thedosetosalivaryglands(parotid, sublingual,subman- . This technique uses charged. Thistechniqueuses (e.g., particles protons) ofthecurrently instead Pilocarpine isacholinergic parasympathomimetic agent, proton radiother 37 - -

Chapter 2 more durable cure for hyposalivation [87]. a basisfor development ofastemcell-basedtherapy for xerostomia toprovide a cent identificationofsalivaryglandstemandprogenitor cellpopulationsprovides ment therapy may beagoodoptiontotreat radiation-induced hyposalivation. Re- cells, resulting from radiation-inducedStemcellreplace stem cellsterilization. - address thesource oftheproblem: alackoffunctionalsaliva-producing acinar tion, buttheireffects are transient. atbest donot Such managementtechniques ameliorateofhyposaliva lubricants andsialogogues theconsequences Artificial - Adult salivaryglandstemcells low level, gel-like salivaare substitutes preferred [86]. arecellulose basedsalivaDuringnightandwhendailyactivities substitutes. ata they have superiorrheologicandwetting properties compared tocarboxymethyl - [85]. are substitutes Mucin-andxanthamgum-containing usallypreferred because aresubstitutes basedoncarboxymethylcellulose [83], mucin[84] orxanthamgum of theaforementioned studiedsaliva agents.Themostcommonlyappliedandbest secretion there isinsufficientorincases isacontra-indication intheadministration Symptomatic approach ofxerostomia isattemptedwhenstimulation ofresidual Oral lubricantsandsaliva substitutes stem cellsthatsurvived thetreatment. administration ofKGF mostlikely acceleratesexpansion ofthepoolprogenitor/ survivalandproliferationand enhances ofsalivaryacinarcells[82]. Postirradiation KGF canbeadministered priororduringradiotherapy. KGF suppresses apoptosis Keratinocyte growth factor (KGF) for humanclinicaltrials. tecting salivaryglands,butnottumortissue[81]. Thustempolcouldbeconsidered has been proven to significantly reduce salivary gland hypofunction [80], by pro- oxide activityandscavenging dismutase free radicals. Inamousemodel,tempol Tempol nitroxide, isstable providing radioprotection possiblyby mimickingsuper Tempol 38 symptom andconditionstheresulting ofawidevariety ofdiseases complaints and to a dramatic decrease in the quality of life. Xerostomia is also a common very to sensationan of abundance oralof oral unpleasant dryness, complaints when it is routinely found abundant in the oral cavity, to the its diminution leads in thefunctionandprojection ofthehumanbody. Althoughnotmuchappreciated forAlthough notessential themaintenanceoflife, saliva plays role afundamental Epilogue - plaints are hard totreat tothepatients’ satisfaction. thatthereindisputable ismore tobedoneasstillxerostomia anditsrelated com- achieved sofar intheinvestigation ofitsmechanismsandtreatment options,it is may pointthephysician totheunderlyingdisease.Whilemuchprogress hasbeen 39

Chapter 2 40 2. Vitali C Iowa Wiley-Blackwell, 2010. levolent symptom: aclinicalguide. 1stedition. 1. Sreenby LM,Vissink A: mouth.Thema- Dry References proliferative and predictive disease classifica- HM. 10. IoannidisJP, Vassiliou VA, Moutsopoulos tern Med2005;165:2337-2344. Arch ameta-analysis. toimmune diseases: In- HM. Theriskoflymphomadevelopment inau- 9. Voulgarelis E, Zintzaras M,Moutsopoulos 1998;28:80-87. Sjögren’s syndrome. Rheum SeminArthritis dictors oflymphomadevelopment inprimary 8. Sutcliffe N,InancM,Speight P, etal.Pre Ann RheumDis2006;65:796-803. cancer incidenceandlymphomapredictors. Sjögren‘smary syndrome: study on a cohort al. 7. Henriksson G, E, Theander Ljungberg O, et Pathol Med2001;301-306. manifestations inSjögren’s syndrome. JOral Frequency andpredictive value oftheclinical 6. Al-HashimiI,KhuderS, HaghighatN,etal. ease. Ann RheumDis1995;5861-5864. drome ismainlyrelated tothesmallairway dis- al. Lung involvement Sjögren’s inprimary syn- 5. Papiris SA, et Maniati M, Constantopoulos, pp 1291-1298. Adult Medicine, 4th ed. Baltimore Mosby ,1997, sirer JP, Greene H,Leds: Current Therapy in 4. Anaya JM,Talal N:Sjögren’s syndrome. Kas- Med 2004;164:1275-1284. drome.More Author Information Arch Intern festations andEarlyDiagnosisofSjögren Syn- 3. KassanSS, MoutsopoulosHM:ClinicalMani - Group. AnnRheumDis2002;61:554-558. posed by theAmerican-European Consensus a revised version oftheEuropean criteriapro- Classification criteriafor Sjögren’s syndrome: Lymphoma inpri- andothermalignancies Long-term and lympho- riskofmortality , Bombardieri S , Jonsson R , etal. - rotid glandbiopsy compared withlabialbi- 20. PijpeJ, KalkWW, van der Wal etal.Pa JE, Oral Pathol 1974;37:217-229. Oralsalivary glandbiopsies. Surg Oral Med histopathology ofSjögren’s syndrome inlabial 19. Greenspan JS, Talal DanielsTE, N,etal.The Med Interne(Paris) 1998;149:17-24. Immunopathology ofSjögren’s syndrome. Ann 18. Tapinos NI,Polihronis M,Tzioufas AG, etal. 565. therapy. CurrOpinRheumatol2005;17:558- implications for managementand disease Sjögren’s ofprimary pathogenesis syndrome: 17. DörnerT. LipskyPE, HansenA, Immuno - 1995;25:117-133. of Sjögren’s syndrome. Rheum SeminArthritis 16. Rheum 2004;50:2897-902. Sjögren’stion inprimary syndrome. Arthritis poulos HM.Evidence for coxsackievirus infec- 15. Triantafyllopoulou Tapinos A, N, Moutso- 2012;64:475-487. Care Arthritis ResAlliance cohort. (Hoboken) Sjögren’s InternationalCollaborative Clinical data-driven, expert consensusapproach inthe sification criteriafor Sjögren’s syndrome: a al. 14. ShiboskiSC, et ShiboskiCH,Criswell L, 87. Sjögren’s syndrome. J Autoimmun 1993;6:379- SSA, but not anti-La/SSB in primary antibodies Predominance of IgG1subclassanti-Ro/ 13. Maran R,etal. DueymesM,Pennec YL, 2005;366:321-331. 12. Fox RI.Sjögren’s syndrome. Lancet study. Rheum2004;50:1262-1269. Arthritis Sjögren’s syndrome: aprospective cohort inprimary ofdeath andcauses Mortality ManthorpeR,11. JacobssonLT. E, Theander Rheum 2002;46:741-747. Sjögren’stion ofprimary syndrome. Arthritis Price EJ American CollegeofRheumatologyclas- , Venables PJ . The etiopathogenesis . Theetiopathogenesis - dry mouth. Oraldry Dis2003;9:165-176. 29. ScullyC. Drugeffects onsalivaryglands: Dent Oral Epidemiol1997;25:211-216. to age, sex andpharmacotherapy. Community mouth inanadultSwedish population--relation al. 28. Nederfors T, Isaksson R, H,et Mörnstad Care Dentist1994;14:96-102. the mostfrequently prescribed drugs.Spec 27. SmithRG, AP. Burtner Oral side-effects of 208. tive clinicalstudy. JRheumatol 2011;38:2198- lymphoma inSjogren’s syndrome: aretrospec- ment ofmucosa-associatedlymphoidtissue 26. Pollard RP, PijpeJ, BootsmaH,etal.Treat Biol Ther2011;11:1381-1394. Opin approach point?Expert or justastarting with anti-CD20 therapy (rituximab).Afeasible al. 25. Meiners PM,VissinkKallenberg A, CG, et results. Rheum2003;49:585-593 Arthritis by theoromucosal route: combinedphaseIII low-dose human interferon alfa administered Treatment Sjögren’s ofprimary syndrome with 24. CumminsMJ, KammerGM,etal. Papas A, 2011;70:1363-1368. Sjögren‘smary syndrome. AnnRheumDis development ofmalignantlymphomainpri- isapossible predictorgland biopsies for the al. et Vasaitis23. BaecklundE, E, Theander L, 1988;15:621-9. disease, sialosisandlymphoma.JRheumatol and confirmationofsarcoidosis, Sjögren’s incisional parotid inthedetection biopsies spective studycomparingincisionallabialto KS, Hartman 22. MarxRE, Rethman KV. Apro- rotid biopsy. JOral Surg 1975;33:328. 21. Kraaijenhagen HA: Letter: Technique for pa- 2007;46:335-341. Sjögren’s’s syndrome. Rheumatology(Oxford) opsy in the diagnosis of patients with primary Prevalence of perceived symptoms ofdry Treatment Sjögren’s of primary syndrome Lymphoid organisation in labialsalivary - ephedrine. Drugs2001;61:2231-42. 39. Wellington B. Cetirizine/pseudo K,Jarvis - allergic rhinitis.AmJTher1998;5:245-251. rine combinationsversus placeboinseasonal versus twice-daily loratadine-pseudoephed- Comparative efficacy andsafety ofonce-daily 38. KaiserHB, Banov CH,Berkowitz RR, etal. 2004;3:247-268. in patientswithCOPD. Treat Respir Med A review of its useasmaintenancetherapy 37. Keam SJ, Keating GM.Tiotropium bromide. (Bayl Univ MedCent)2004;17:366-373. chronic obstructive disease.Proc pulmonary daily inhaledanticholinergic medicationfor 36. DurhamMC. Tiotropium (Spiriva): aonce- 2000;118:1294-1302.Chest ticenter trial. The US Tiotropium Study Group. with tiotropium COPD: instable a13-week mul- The spirometric efficacy ofonce-dailydosing 35. R, Casaburi BriggsDDJr, DonohueJF, etal. 2011;39:276-288. er people. CommunityDentOral Epidemiol andmedicationsinasampleofold- diseases labial and whole salivary flow rates, systemic sociations between oral andoculardryness, 34. SmidtD, Torpet B,etal.As- Nauntofte LA, Oral Dis2010;16:769-773. oral manifestations of cardiovascular drugs. 33. DR, HabbabKM,Moles Porter SR. Potential of ACE inhibitors. MinervaMed1998;89:91-97. intensivepital monitoringofadverse reactions 32. Mangrella M, Motola G, Russo F, et al. 2006;23:229-235. for chronic cancer pain. Am J Hosp Palliat Care common symptoms duringrepeated dosing effects of morphine: a prospective survey of 31. Glare P, Walsh D, SheehanD. Theadverse Psychiatry 2004;19:754-762. pressed IntJGeriatr patients:ameta-analysis. tors andtricyclic antidepressants inolderde- effects ofselective serotonin reuptake inhibi- 30. Wilson K,Mottram P. Acomparisonofside Hos- 41

Chapter 2 50. D’Hondtetal.Pa ShipJA, EisbruchA, E, radiotherapy. RadiatRes 1983;95:392-398. man. II.Response ofthe salivaryglandsduring response relationships for in normaltissues 49. Quantitative radiation dose- MossmanKL. BiolMed1978;157:50-53.Soc Exp sensitivity of the human parotid gland. Proc 48. Trodahl Shannon IL, JN,Starcke EN.Radio- Rev Oral Biol Med2003;14:199-212. andneckradiotherapy.sequelae ofhead Crit 47. VissinkJansmaJ, A, Spijkervet FK,etal.Oral 2003;11:207-225. glands in cancer therapy. Support Care Cancer Xerostomia andhypofunction ofthesalivary 46. JensenSB,Pedersen AM,Reibel J, etal. Oncol BiolPhys 2010;78:983-989. andbarriers. IntJRadiat patients: successes tion andxerostomia cancer inhead-and-neck cal managementofsalivaryglandhypofunc- 45. VissinkMitchellJB,BaumBJ, A, etal.Clini- matol 1996;35:1033-1034. duced pseudo-Sjögren’s syndrome. BrJRheu- 44. Chakravarty K,al-Jafari MS. Phenytoin-in- treatment.bital JNeurol Sci2011;300:164. Transient “sicca syndrome” duringphenobar 42 43. controlled trials.Epilepsia2011;52:826-36. tic review ofrandomized andmeta-analysis adverse event profile ofpregabalin: asystema 42. Zaccara G, Gangemi P, Perucca P, et al. The terol 1995;30:216-218. Omeprazole mouth.ScandJGastroen anddry - 41. Teare JP, SpeddingC, MW, Whitehead etal. terol Hepatol2001;13:915-919. A randomized controlled trial. Eur J Gastroen- bacter pylori inIranian pepticulcerpatients. dine for 1or 2 weeks) on eradication of Helico- sub-citrate for 2weeks orwithadditionalraniti - (amoxycillin, metronidazole, colloidalbismuth al. 40. Kaviani MJ, R, Malekzadeh Vahedi H,et Various durations ofastandard regimen Marino D , Malandrini A , Rocchi R , etal. - - lingual glands.RadiatRes 1990;124:259–265. effects on rat parotid andsubmandibular/sub- al. Afunctionalandchemicalstudy ofradiation 59. Vissink‘s-Gravenmade A, EJ, et Ligeon EE, diat Res 1997;147:468–475. The role ofredox-active iron andcopper. Ra- ation-induced damagetothesalivaryglands: 58. Y, NaglerRM,Marmary Fox PC, etal.Irradi - Cell Pathol 1984;45:443–460. the rat submandibulargland. Virchows Arch diosensitivity oftheductularandacinarcell of the and deferringhistochemical studies ra - 57. AbokK,BrunkU, JungB,etal.Morphologic Oncol BiolPhys 2009;73:523–529. from p53-dependentapoptosis.IntJRadiat tion-induced salivaryglanddysfunctionresults 56. Avila GrundmannO, JL, Burd R, etal.Radia- 1998;73:641–648. rat salivaryglandfunction.IntJRadiatBiol sis isnotthecauseofacuteimpairement of RP,Coppes et al.Radiationinducedapopto- 55. Paardenkooper GMRM,Zeilstra LJW, Int JRadiatOncolBiolPhys 2005;62:1187-1194. mechanism ofsalivaryglandradiosensitivity. 54. Konings AW, RP, Coppes VissinkOnthe A. Oncol 2001;61:271-274. flow duringhighdoseradiotherapy. Radiother Parotid andsubmandibular/sublingual salivary 53. BurlageFR, RP, Coppes H,etal. Meertens 2002. pp42-51. sic clinicalradiology. 3rd ed.Arnold,London, fects In:SteelGG, innormaltissues. editor. Ba- 52. Stewart FA, Van der Kogel AJ. Volume ef 1063. receptor 2001;85:1055– agonists.BrJCancer parotid glandby adrenergic andmuscarinic Early tolatesparingofradiation damagetothe 51. RP, Coppes Zeilstra LJW, KampingaHH,etal. one-year results. JDentRes 1997;76:807-813. patients receiving bilateral radiation therapy: rotid andneckcancer sparingstudyinhead - sity-modulated proton therapy versus helical 68. Pierelli Fiorino A, C, Widesott L, etal.Inten- ther Oncol2006;80:263–267. the treatment andneck tumors. ofhead Radio- sity modulatedphotonandproton therapy for 67. Steneker M,LomaxSchneiderU. A, Inten- Biol Phys 2009;74:1–8. dardized follow-up program. IntJRadiatOncol randomized prospective- study using astan health-related qualityoflife: results ofanon- radiation-induced morbidity andimproves al. Intensity- modulatedradiotherapy reduces 66. Vergeer MR, PA, Doornaert Rietveld DH,et Int JRadiatOncolBiolPhys 2008;72:373–382. sparing by intensitymodulatedradiotherapy. bular salivary glands and implications for their al. Dose-effect relationship for thesubmandi 65. Murdoch-Kinch CA, KimHM,Vineberg KAet Radiat OncolBiolPhys 2001;51:938–946 diotherapy region. in the head-and-neck Int J inparotidof changes ra glandfunctionafter - al. Quantitative dose-volume response analysis 64. RoesinkBattermannJJ, JM,MoerlandMA, et 1999;45:577–587. and neckcancer. IntJRadiatOncolBiolPhys and intensity-modulated irradiation ofhead in parotid salivaryglandsfollowing conformal et al.Dose, volume andfunctionrelationships 63. Ten EisbruchA, Haken RK,HyungjinMK, 2010;18:1039-1060. pact onqualityoflife. SupportCare Cancer cer therapies:prevalence, severity andim- function andxerostomia inducedby can- A systematic review ofsalivaryglandhypo- 62. JensenSB,Pedersen AM,Vissinketal. A, Radiat Biol2000;76:419–429. gland anditsrelation toglandfunction.IntJ diation inducedcelllossinrat submandibular 61. Zeilstra LJ, Vissink Konings A, AWT, et al. Ra- Oral Pathol Med1991;20:449–456. and functionofrat submandibularglands.J et al.Acute irradiation effects onmorphology 60. VissinkKalicharan D, A, ’s-Gravenmade EJ, port Oncol2006;4:252-258.port andneckcancerpatients.JSupstudy inhead - results ofRTOG 97-09, aphaseIIIrandomized Effect ofpilocarpineduring radiation therapy: 76. Scarantino C, LeVeque F, Swann RS, etal. Biol Phys 2002;54:9-13. for cancer. head-and-neck IntJRadiatOncol carpine in patients undergoing radiotherapy Phase III placebo-controlled trial of oral pilo- 75. Warde P, O’Sullivan B,AslanidisJ, etal.A 549. Oral Pathol Oral RadiolEndod1998;86:541– ment withoral pilocarpine. Oral Surg Oral Med Radiation-induced hyposalivation and its treat- 74. Niedermeier W, Matthaeus C, Meyer C, et al. Clin Oncol1993;11:1124-1131. xerostomia and neckcancer patients. J in head pilocarpine for treatment ofradiation-induced placebo-controlled, dose-titration studyoforal al. 73. LeVeque FG, M,Potter Montgomery D, et Engl JMed1993;329:390-395. mia and in neck patients cancer.with head N Oral pilocarpinefor post-irradiation xerosto- 72. JohnsonJT, Ferretti GA, WJ, Nethery etal. carcinoma. RadiotherOncol2008;88:S77–S78. and PhotonTherapy incomplex oropharyngeal Scanned IntensityModulatedProton Therapy parative treatment planningstudybetween 71. van de Water T, Lomax T, Bijl HP, et al. Com- col 2003; 66:11–18. protons intheparanasal sinus.RadiotherOn- modulation inradiotherapy: photonsversus 70. Lomax AJ, GoiteinM,Adams J. Intensity 2001;61:287–297. andnecktumours.head RadiotherOncol and proton therapy for treatment ofadvanced therapy, intensitymodulated photon therapy ment planningcomparisonof3Dconformal 69. Fogliata Lomaxetal.Atreat Cozzi L, A, - Oncol BiolPhys 2008; 72:589–596. comparison andNTCP evaluation. IntJRadiat tomotherapy cancer: innasopharynx planning A multicenter, randomized, double-blind, 43

Chapter 2 44 1996;39:57–69. with Sjögren’s syndrome. Rheum Arthritis polymer-based salivainpatients substitutes Vissink etal.Treatment A, ofxerostomia with 85. Van derReijden WA, Van derKwaak H, 1974;3:435–439. saliva onsevere xerostomia. IntJOral Surg AK. Theeffects artificial ofmucin-containing 84. s-Gravenmade EJ, Roukema DA, Panders nol Otol1972;51:422–428. bei derradiogenenRi- Sialadenitis. ZLaryngol chel zurTherapie derHyposalien insbesondere 83. Matzker J, Schreiber J. Synthetischer Spei- munhistologie. Pathologe 1989;10:165–170. len-Sialadenitis. undIm- Stadieneinteilung 82. Dreyer JO, Sakuma Y, Seifert G. DieStrah- Resmodel. ClinCancer 2005;11:7564–7568. following andneck irradiation head in a mouse netics oftempolfor prevention ofxerostomia 81. CotrimAP, SowersLodde BM,etal.Ki- AL, 2007;13:4928–4933. netic resonance Res imaging. ClinCancer panying ofTempol tissueassessment by mag- glands versus tumorby Tempol withaccom- Differential radiation protection of salivary 80. CotrimAP, Hyodo F, MatsumotoKetal. Oncol. 2000;18:3339–3334 dioprotector andneckcancer. inhead JClin Phase IIIrandomized trialofamifostine asara- 79. Brizel DM,Wasserman TH,Henke M,etal. 990. trial. IntJRadiatOncolBiolPhys 2005;63:985– low-up of a prospective, randomized, phase III therapy for cancer: head-and-neck 2year fol- stomia, tumorcontrol, radio andsurvivalafter - Influence ofintravenous amifostine onxero- 78. Int JRadiatOncolBiolPhys 2008;70:14-22. blind, randomized, placebo-controlled study. pilocarpineduringradiotherapy:tant adouble- al. 77. BurlageFR, Roesink JM,KampingaHH,et Protection of salivary function by concomi- Wasserman TH, Brizel DM, Henke M,etal. 2012;31:613-619. potential therapy for xerostomia. Stem Cells review: Adult salivaryglandstemcellsanda 87. PringleS, Van OsR, RP. Coppes Concise Int1998;29:383-8.Quintessence suffe tute inreducing oral complaintsofpatients Efficacy ofa synthetic polymersaliva substi- 86. Regelink G, VissinkReintsema A, H,etal. ring from irradiation-induced xerostomia. 45

Chapter 2

Chapter 3

Diagnosis