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The modern diagnostic &therapeutic approach forSjögren’s SyndromeR. Manthorpe,Malmö University HospitalSweden

History• First reported 1888 by Johann Mikulicz• Named by Henrik Sjögren(Swedish ophthalmologist)• Described the ocular symptoms and signs inhis thesis from 1933. First recognised worldwide after the second world war.Prof.Manthorpe Sept. 2002 Slide no. 2

Key issues• Chronic autoimmune disorder• All organs may be involved• Wide spectrum of severity• No medical cure - thereforeseveral local treatment modalitiesand few oral preparations.Prof.Manthorpe Sept. 2002 Slide no. 3

Key issues• Can start at any age - even in childhood• Peak incidence: fourth and fifth decades• Female-to-male ratio 9:1• Epidemiological investigations suggest thedisease to be the most common chronicinflammatory disorder with a frequencyaround 2% in the age group 50-70 years old.Prof.Manthorpe Sept. 2002 Slide no. 4

Etiology and pathomechanisms• Mostly unknown• Genes involved. Clear overrepresentation ofHLA-DR2 & -DR3• Virus. Never proven• Hormones - may be involved. At present aDHEA clinical trial will startProf.Manthorpe Sept. 2002 Slide no. 5

Etiology and pathomechanisms (2)• Often a focal lymphocytic infiltration.• Poor correlation between focus scoreand functional test results fromlachrymal and salivary glands.Prof.Manthorpe Sept. 2002 Slide no. 6

SS is divided into two parts• Secondary SS -where another CTD can be verified• Primary SS -where no other CTD is involvedProf.Manthorpe Sept. 2002 Slide no. 7

ExocrineNonexocrinepSSSurfaceInternal organMonoclonalB-lymphocyteInflammatoryvascularNoninflammatoryvascularMediatorinducedAutoimmuneendocrineEyeNasalL-TPh-OSkinG-TVaginaMusclesJointsPancreasGastrointestinalKidneysMalignantlymphomaLungsPseudolymphomaBenignlymphomaHepatobiliaryMouthHematologiccytopeniaSkinRaynaud´sphenomenonSerosaeThyroiditisCNSPNS inclANSFatigueFever

Ocular symptoms = KCS• Irritation, chronic• Gritty & sandy sensation• Ocular photosensitivity. Some patients even waresunglasses indoor (NB: SLE patients have skinphotosensitivity)• Often reject car driving night-time• Hate to enter rooms with tobacco or other pollution -unless they are smokers themselves!• Blurred vision• Very seldom loss of sightProf.Manthorpe Sept. 2002 Slide no. 9

Ocular symptoms = KCS (2)• Genuine SS patients do NOT complaint ofdry eyes as there are no free nerve endingswhich can detect dryness in cornea.• Cornea otherwise the most innervatedorgan.Prof.Manthorpe Sept. 2002 Slide no. 10

Manifestations: OcularProf.Manthorpe Sept. 2002 Slide no. 11

Oral symptomsRemember that medication may influenceoral symptoms and signs• Dry Mouth due to oral mucosal dryness• Difficulties to chew without adding water• Dysphagia• Hoarse voice• Difficulties to speak more than a few minutes• Wake up several times during night due to oral dryness.Solved by drinking little water. (Patients with otherdisorder, e.g. diabetes, wake up for urinating and willthen need additional water!)Prof.Manthorpe Sept. 2002 Slide no. 12

Oral symptoms• Caries - usually at atypical places and may besevere and costly• Swelling - often intermittent - of big exocrineglands• NHML often starts in the oral cavityProf.Manthorpe Sept. 2002 Slide no. 13

Sjögren manifestations: OralProf.Manthorpe Sept. 2002 Slide no. 14

Sjögren’s syndromeCervical dental cariesProf.Manthorpe Sept. 2002 Slide no. 15

Sjögren’s syndrome - Dry lobulatedtongue & angular cheilitisProf.Manthorpe Sept. 2002 Slide no. 16

Sjögren’s syndrome andautoimmune blood disorders• Among a group of patients with primary Sjögrengren’ssyndrome there is an increased incidence of: ITP,PRCA, autoimmune leukopenia, idiopatic CD4+ -T-lymphocytopenia, myelofibrosis and other fibroticconditions• NHML, has previously been described to have arelative risk of 44. In practical terms approx. . 5 % ofpatients with primary SS will later on develop thisconditionProf.Manthorpe Sept. 2002 Slide no. 17

Sjögren’s syndrome and serology• Hyper-IgGIgG-emiawhich secondarily give rise to anidiopatic ESR• Hyper-IgAIgA-emiaand/or hyper-IgMIgM-emiausually lackclinical relevance• Paraproteins, , usually develops before clinical NHML• Cryoglobulins - seems most common in southernEurope• Slight/moderate elevations of hepatic enzymes• Acidosis, usually seen in connection with RTAProf.Manthorpe Sept. 2002 Slide no. 18

Manifestations: General• Fatigue - most troublesome symptom. Usuallyeven worse than oral and ocular complaint• Sleep disorder - average extra rest/sleepingtime - 2h/ 24h• Depression• Nocturnal polydipsia• Nocturnal myoclonusProf.Manthorpe Sept. 2002 Slide no. 19

Modern terminology for organinvolvement• Exocrine and non-exocrine organmanifestations• Corresponds to articular and extra-articular organ involvement in RAProf.Manthorpe Sept. 2002 Slide no. 20

Diagnostic tools: KCS• Slit lamp examination• BUT✻ positive if: ≤ 10 sec.• Schirmer-1 test with closed eyes for 5 min✻ positive if: ≤ 5 mm/5 min• Rose bengal or lissamine green stainingtest✻ positive if: score ≥ 4• Hypertonic tears osmolarityProf.Manthorpe Sept. 2002 Slide no. 21

Salivary tests - functional tests• UWSUnstimulated whole sialometry measuredfor 15 min* positive if: ≤ 1.5 ml/15 min• SWSStimulated whole sialometry measured for5 min* positive if: ≤ 3.5 ml/5 minProf.Manthorpe Sept. 2002 Slide no. 22

Diagnostic tools: salivary tests -stationary tests• Sialography - for “Grapepunctate”changes• Ultrasound for homogeneity - hypoechoicareas• MRI - nonhomogenous structures• Lower lip biopsy for “focus score” in smallsalivary glandsProf.Manthorpe Sept. 2002 Slide no. 23

Why so many classificationsystems?• Etiology of SS not known• Pathophysiological mechanismsunknown• No single test specific enough• Various medical specialities involvedProf.Manthorpe Sept. 2002 Slide no. 24

Recent important observations• Epidemiology studies:✻ Most common systemic rheumatic disease• Smokers:✻ less lower lip focus score✻ less circulating anti-SSA/SSBantibodies✻ smoking effects are dose dependent✻ might be observed even years after last cigarette• Focus score and anti-SSA/SSBantibodiesare dependent variablesProf.Manthorpe Sept. 2002 Slide no. 25

Number of different classificationsystems in 2002?1427968593Prof.Manthorpe Sept. 2002 Slide no. 26

New criteria for diagnosingSjögren's syndrome:A step forward? - or ….US-EU Consensus 2002Japanese III 1999Copenhagen 1975/6Japanese II1997EU II 1996EU I 1993Japanese I 1984Greek 1986California 1986Prof.Manthorpe Sept. 2002 Slide no. 27

Copenhagen criteria, 1975/76What are they?Lachrymal gland functionSalivary gland function• At least two abnormal objective test resultsfrom both organs• Normal values for tests should be knownProf.Manthorpe Sept. 2002 Slide no. 28

Pitfalls• Prognosis is good from standpoint ofmortality• Poor morbidity and medical pitfalls includefailure to diagnose• Low QoL• Too few NHML cases to change lifespansignificantlyProf.Manthorpe Sept. 2002 Slide no. 29

Crux• Diagnosis of SS remains problematic due tolack of Sjögrencentres• Symptoms are common and non-specific• Undiagnosed or misdiagnosed for the first 7-9years (few months - >50 years)• Lack of agreement upon diagnostic criteriaProf.Manthorpe Sept. 2002 Slide no. 30

Treatment: Goals• Provide symptomatic relief• Provide relief by prescribing drugs for local andsystemic treatment• Increase QoL• Increase disease knowledge for patient and family• Orientate about patient associations• Orientate about money in return if great expensesat dentist• Orientate about drugs in pipelines at medicalcompaniesProf.Manthorpe Sept. 2002 Slide no. 31

Treatment• Local and systemic• Organ specific andNon-organ specificProf.Manthorpe Sept. 2002 Slide no. 32

Ocular - local• Several artificial tearsIn Sweden around 22. To some are addedpreservatives which sometimes give rise totoxic-allergic reactions. Why add preservatives?Should one preserve the eyes or the artificialtears?• Artificial gels/ ointmentsfor use during night timeProf.Manthorpe Sept. 2002 Slide no. 33

Oral - local• Several artificial saliva preparations. . Are statisticalbetter than Placebo when tested for 1-2 weeks. Aftermonths of therapy nearly every patient is only usingwater which they carry with them in small bottleswherever they go.• Sugar free gum - probably the best for localtreatment, if they can be used• Chewing on inert substances• Using special cream at the oral mucosa duringnight-time. Rather popular.Prof.Manthorpe Sept. 2002 Slide no. 34

Other exocrine glands -mainly in skin, nose, pulmonary system andvagina. Local treatment• Several creams for the skin - all with 4-5 % carbamide• Try to avoid glucocorticosteroid (GCS) cream unlessskin disorders usually are treated this way.• Oil solution for the nose• Inhalations with bronchodilators and weak GCSsolutions• Vagitories consisting of polycarbofile which can bindwater 60 times of its own weight• Local estrogens can help the postmenopausal patientbut are of no value in the premenopausal patientProf.Manthorpe Sept. 2002 Slide no. 35

Non-exocrine organmanifestations - local treatmentE.g. arthralgia in hands, moderate Raynaud• Creme consisting of non-steroidals• NSAID’s or Cox-2 inhibitors• Creme with glycerol• Vasodilatation - CalciumantagonistProf.Manthorpe Sept. 2002 Slide no. 36

Exocrine glands -systemic therapy• Bromhexine in daily dose of at least 16mg tid.Efficacy in 20-25%• Acetylcystein• Pilopcarpin - specially for oral and laryngeal drysymptoms• Cevimeline - only available in Japan and US• Other systemic secretagogues are not betterthan placeboProf.Manthorpe Sept. 2002 Slide no. 37

Non-exocrine organ manifestationssystemic therapy• NSAID’s, , acetaminophen, salicylates formusculoskeletal pain• Hydroxychloroquine, , mainly for arthralgia & skineruptions and hyper-IgGIgG-emia. . A US-favoritebut acontrolled db investigation for 2 years in NL could notdemonstrate clinical significant changes• GCS, Cyclosporin A, Azathioprine and MTX have notshown any efficacy superior to placebo. Single or incombination they are only to be recommended incase of severe organ - life-threatening - involvementProf.Manthorpe Sept. 2002 Slide no. 38

Salagen ® -Tablets• Pilocarpine hydrochloride. Tablet 5 mg✻ 84 tablets / package• Naturally occuring plant alcaloid✻ pilocarpus jaborandi• Parasympathomimetic• Cholinergic agonist M2-M3• Causes smooth muscle contraction• Produces subjective and objective benefitsProf.Manthorpe Sept. 2002 Slide no. 39

Salagen ® -Tablets• Pilot study Fox et al.(1986)✻ Single-centercenter, , double-blind, placebo-controlled✻ Cross-over✻ N=6 female patients with sicca syndrome andsialadenitis✻ Observation period: 4 days✻ 5 mg pilocarpine or placebo per day✻ Saliva production, saliva composition, safetyparametersProf.Manthorpe Sept. 2002 Slide no. 40

Salagen ® -TabletsSaliva flow (mL/min gland)0.32520150.110050SalagenPlacebo0306090120150180210240Time after drug (min)270300330360Fox et al., 1986Unstimulated parotid saliva flowProf.Manthorpe Sept. 2002 Slide no. 41

Salagen ® -TabletsSaliva flow (mL/min gland)0.30.13025201510050SalagenPlacebo0306090120150Time after drug (min)Unstimulated submandibular and/or sublingual saliva flow180210240270300330360Fox et al., 1986Prof.Manthorpe Sept. 2002 Slide no. 42

Salagen ® -Tablets• Dose escalation clinical trial Papas et al. (1997)✻ Multi-centercenter, , double-blind, placebo-controlled✻ N=256 SS-patients✻ Observation period: 12 weeks✻ Dosing:✦ BL - week 6 placebo or 5mg pilocarpine QID✦ week 7 to week 12:+ placebo to placebo QID+ 5 mg pilocarpine to 7.5 mg pilocarpine QID✻ Subjective and objective testsProf.Manthorpe Sept. 2002 Slide no. 43

SalagenPlaceboResponders (%)706050403020100GlobalimprovementDecreasedseverityImprovedoral comfortAbility toswallowDecr. use ofsaliva subst.Ability tosleepSalagen ® -TabletsEfficacy on dry mouthProf.Manthorpe Sept. 2002 Slide no. 44Decreasedwater to speak*p< 0.0488 *p< 0.0001 *p< 0.0002*p< 0.0001 *p< 0.0001 *p< 0.0001 *p< 0.0001Papas et al., 1997

SalagenPlaceboResponders (%)6050403020100Salagen ® -TabletsEfficacy on keratoconjunctivtis sicca symptomsProf.Manthorpe Sept. 2002 Slide no. 45GlobalimprovementComfortLightsensitivityItchingTiredness.RednessForeign bodysensationReduceduse of AT*p< 0.0001*p< 0.0018*p< 0.05*p< 0.0006*p< 0.0199*p< 0.0042*p< 0.016*p< 0.007Sherrer et al., 1997

Salagen ® -Tablets• Fixed dose clinical trialVivino et al. (1999)✻ Multi-centercenter, , double-blind, placebo-controlled✻ N=373 SS-patients✻ Observation period: 12 weeks✻ Randomized to placebo, 2.5 mg or 5 mg, 4 times/day✻ Subjective and objective tests✻ Baseline, week 6 and week 12 efficacy assessments✻ Safety assessments throughout the studyProf.Manthorpe Sept. 2002 Slide no. 46

Salagen ® -Tablets7060*p< 0.001*p< 0.009SalagenPlaceboGlobal improvement (%)50403020100Dry mouth “Dry” eyes Vivino et al., 1999Efficacy in dry mouth and “dry” eyesProf.Manthorpe Sept. 2002 Slide no. 47

Salagen ® -TabletsUrinary frequencyDizzinessRhinitisNauseaFlu syndromeHeadacheSweating*p< 0.01SalagenPlacebo*p< 0.001%0 5 10 15 20 25 30 35 40 45 50Safety profileVivino et al., 1999Prof.Manthorpe Sept. 2002 Slide no. 48

Salagen ® -Tablets• Pilot studyRhodus et al. (1998)✻ Single-centercenter, , open✻ N=12 female SS-patients✻ Observation period: 1 year✻ Candida albicans culturesProf.Manthorpe Sept. 2002 Slide no. 49

Salagen ® -Tablets% %807060755040302025100BL1 yearRhodus et al., 1998Subjects with positive cultures of Candida albicansProf.Manthorpe Sept. 2002 Slide no. 50

Salagen ® -Tablets• Effect on BUT and rose bengalFonseca et al. (1999)✻ 20 patients with primary SS✻ Observation period 5 months✻ 5 mg pilocarpine TIDProf.Manthorpe Sept. 2002 Slide no. 51

Salagen ® -Tablets6056Improvement (%)50403020100Break-up Time44Rose bengalFonseca et al., 1999Effect on BUT and rose bengal stainingProf.Manthorpe Sept. 2002 Slide no. 52

• Dosage:Salagen ® -Tablets✻ 5 mg four times daily✻ Dosage can be increased to a maximum of 30 mgdaily✻ Lethal dose: 100 mg• Response time:✻ Effect measurable after intake of first tablet✻ However, symptomatic relief take 6 to 12 weeks• Maintenance:✻ Salagen-Tablets have to be use regularly to maintaineffectProf.Manthorpe Sept. 2002 Slide no. 53

Salagen ® -Tablets• Conclusion✻ Salagen ® stimulates the exocrine glands to producenatural tears and saliva✻ Salagen ® stimulates the glands throughout the day✻ Salagen ® stimulates tear, saliva, vaginal fluids, skinglands at the same time✻ Salagen ® reduces the use of artificial tears and saliva✻ Salagen ® offers innovative therapeutic advantage✻ Best potential systemic treatment for prevention oflong-term local complicationsProf.Manthorpe Sept. 2002 Slide no. 54

Prof.Manthorpe Sept. 2002 Slide no. 55

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