SjögrenSjögren´́s syndromes syndrome

Definition: chronic, slowly progressive Definition: chronic, slowly progressive autoimmune diseaseautoimmune disease

Lymphocytic infiltration of the exocrine Lymphocytic infiltration of the exocrine glands→ xerostomia and dry eyesglands→ xerostomia and dry eyes

Malignant lymphomaMalignant lymphoma Primary and secondary formsPrimary and secondary forms Middle-aged womenMiddle-aged women Prevalence: 0.5-1 %Prevalence: 0.5-1 %

PathogenesisPathogenesis

T cell lymphocytic infiltration of the T cell lymphocytic infiltration of the exocrine glands→ salivary gland exocrine glands→ salivary gland enlargementenlargement

B lymphocyte hyperreactivityB lymphocyte hyperreactivity Monoclonal immunoglobulinsMonoclonal immunoglobulins Anti-Ro/SS-A,anti-La/SS-B AbsAnti-Ro/SS-A,anti-La/SS-B Abs Antibodies to Antibodies to αα-fodrin (salivary gland--fodrin (salivary gland-

specific protein) specific protein)

Clinical manifestationsClinical manifestations Diminished lacrimal and salivary gland functionDiminished lacrimal and salivary gland function Mucosal dryness = xerostomiaMucosal dryness = xerostomia Difficulty in swallowing dry foodDifficulty in swallowing dry food Inrease in dental caries, problems in wearing Inrease in dental caries, problems in wearing

complete denturescomplete dentures Dry, sticky oral mucosaDry, sticky oral mucosa Saliva from the major glands not expressibleSaliva from the major glands not expressible Enlargement of the parotidEnlargement of the parotid

Clinical manifestations 2.Clinical manifestations 2. Diagnotic tests: sialography, scintigraphy, Diagnotic tests: sialography, scintigraphy,

sialometrysialometry Labial minor salivary gland biosy→ focal Labial minor salivary gland biosy→ focal

lymphocytic infiltrateslymphocytic infiltrates Keratoconjunctivitis siccaKeratoconjunctivitis sicca Measurement of tear flow by SchirmerMeasurement of tear flow by Schirmer´́s tests test Decrease in mucous gland secretion of the Decrease in mucous gland secretion of the

upper and lower respiratory treeupper and lower respiratory tree Atrophic gastritisAtrophic gastritis Dry skin and external genitaliaDry skin and external genitalia

Extraglandular manifestationsExtraglandular manifestations Arthralgias/arthritisArthralgias/arthritis RaynaudRaynaud´́s phenomenons phenomenon LympadenopathyLympadenopathy Lung involvementLung involvement VasculitisVasculitis Kidney involvement→ interstitial nephritisKidney involvement→ interstitial nephritis Liver involvementLiver involvement LymphomaLymphoma Anemia, ESR↑Anemia, ESR↑

DiagnosisDiagnosis

1. Ocular symptoms: dry eyes, use of 1. Ocular symptoms: dry eyes, use of arteficial teararteficial tear

2. Oral symptoms: dry mouth, swollen 2. Oral symptoms: dry mouth, swollen salivary glands, frequent liquid drinkingsalivary glands, frequent liquid drinking

3. Ocular signs: positive Shirmer3. Ocular signs: positive Shirmer´́s tests test 4. Histopathology: in minor salivary glands 4. Histopathology: in minor salivary glands

focal lymphocytic sialodenitisfocal lymphocytic sialodenitis

Diagnosis 2.Diagnosis 2. 5. Objective evidence of salivary gland 5. Objective evidence of salivary gland

involvement: parotid sialography, salivary involvement: parotid sialography, salivary scintigraphy, decreased salivary flow (scintigraphy, decreased salivary flow (<<1.5 ml in 1.5 ml in 15 min)15 min)

6. Antibodies in the serum to Ro/SS-A or La/SS-6. Antibodies in the serum to Ro/SS-A or La/SS-B antigens, or bothB antigens, or both

Dg: any 4 of the 6 items, or any 3 of the 4 Dg: any 4 of the 6 items, or any 3 of the 4 objective criteria itemsobjective criteria items

TreatmentTreatment Symptomatic reliefSymptomatic relief Arteficial tears: Liquifilm, 0.5% Methylcellulose, Arteficial tears: Liquifilm, 0.5% Methylcellulose,

Hypo TearsHypo Tears Antidepressants, diuretics should be avoided→ Antidepressants, diuretics should be avoided→

decrease salivary and lacrimal secretiondecrease salivary and lacrimal secretion Xerostomia: fluidXerostomia: fluid Pilocarpine 5mg 3x daily→ stimulate secretionsPilocarpine 5mg 3x daily→ stimulate secretions

Systemic SclerosisSystemic Sclerosis

SclerodermaScleroderma

DefinitionDefinition

Chronic systemic disorderChronic systemic disorder Unknown etiologyUnknown etiology Thickening of the skin = sclerodermaThickening of the skin = scleroderma Involvement of multiple internal organsInvolvement of multiple internal organs Early stage: inflammationEarly stage: inflammation Later stage: fibrosisLater stage: fibrosis

Conditions associated with Conditions associated with scleroderma-like indurationscleroderma-like induration

Limited cutaneous SScLimited cutaneous SSc Diffuse cutaneous SScDiffuse cutaneous SSc Morphea (localized)Morphea (localized) Overlap syndromes: MCTD, SSc/PMOverlap syndromes: MCTD, SSc/PM ScleromyxedemaScleromyxedema Paraneoplastic syndromeParaneoplastic syndrome Vinyl chloride-induced SScVinyl chloride-induced SSc Pentazocine-induces SScPentazocine-induces SSc

Limited cutaneous SScLimited cutaneous SSc Skin: limited to fingers, distal to elbows, face, Skin: limited to fingers, distal to elbows, face,

slow progressionslow progression RaynaudRaynaud´́s phenomenon: precedes skin s phenomenon: precedes skin

involvementinvolvement Pulmonary fibrosis:moderatePulmonary fibrosis:moderate Pulmonary arterial hypertension:frequentPulmonary arterial hypertension:frequent Scleroderma renal crisis: very rareScleroderma renal crisis: very rare Calcinosis cutis: frequent, prominentCalcinosis cutis: frequent, prominent Autoantibodies: AnticentromereAutoantibodies: Anticentromere

Diffuse cutaneous SScDiffuse cutaneous SSc

Skin:diffuse, fingers, extremities, face, Skin:diffuse, fingers, extremities, face, trunk, rapid progressiontrunk, rapid progression

RaynaudRaynaud´́s phenomenons phenomenon Pulmonary fibrosis: frequent, early, severePulmonary fibrosis: frequent, early, severe Scleroderms renal crisis: occurss in 15%Scleroderms renal crisis: occurss in 15% Calcinosis cutis: mildCalcinosis cutis: mild Autoantibodies: Antitopoisomerase = Autoantibodies: Antitopoisomerase =

Scl-70Scl-70

CREST syndromeCREST syndrome

Calcinosis cutisCalcinosis cutis RaynaudRaynaud´́s phenomenons phenomenon Esophageal dysmotilityEsophageal dysmotility SclerodactylySclerodactyly TelangiectasiaTelangiectasia

EpidemiologyEpidemiology

Incidence: 9-19 cases/million/yearIncidence: 9-19 cases/million/year Female predominanceFemale predominance Greatest in the childbearing yearsGreatest in the childbearing years Onset: range of 30-50 yearsOnset: range of 30-50 years

PathogenesisPathogenesis

Vascular injuryVascular injury Cellular and humoral immunityCellular and humoral immunity Progressive visceral and vascular fibrosis Progressive visceral and vascular fibrosis

in multiple organsin multiple organs

Vasculopathy and FibrosisVasculopathy and Fibrosis RaynaudRaynaud´́s phenomenon: altered blood---s phenomenon: altered blood---

flow response to coldflow response to cold Endothelial cell injuryEndothelial cell injury Fibrosis affects multiple organsFibrosis affects multiple organs Fibroblasts proliferateFibroblasts proliferate Scar formation via producing collagenScar formation via producing collagen TGFTGFββ Circulating autoantibodiesCirculating autoantibodies

PathologyPathology Obliterative vasculopathy of small arteries Obliterative vasculopathy of small arteries

and arterioles→luminal narrowingand arterioles→luminal narrowing Fibrosis in the skin and internal organsFibrosis in the skin and internal organs Progressive replacement of normal tissue Progressive replacement of normal tissue

architecturearchitecture Skin: collagen fiber accumulationSkin: collagen fiber accumulation Lungs: interstitial fibrosis and vascular Lungs: interstitial fibrosis and vascular

damage, nonspecific interstitial damage, nonspecific interstitial pneumonitis, pulmonary hypertensonpneumonitis, pulmonary hypertenson

Pathology 2Pathology 2 Gastrointestinal tract: from the mouth to the Gastrointestinal tract: from the mouth to the

rectum, lower esophagus, small bowel rectum, lower esophagus, small bowel obstruction, gastroesophageal reflux, obstruction, gastroesophageal reflux, premalignant Barretpremalignant Barret´́s metaplasias metaplasia

Kidneys: chronic renal ischemia, renal crisisKidneys: chronic renal ischemia, renal crisis Heart: myocardial fibrosisHeart: myocardial fibrosis Other organs: synovitis, fibrosis of tendon Other organs: synovitis, fibrosis of tendon

sheats, inflammatory myositis, fibrosis of the sheats, inflammatory myositis, fibrosis of the thyroid gland, fibrosis of the salivary glandsthyroid gland, fibrosis of the salivary glands

Clinical featuresClinical features

SSc can affect every organSSc can affect every organ Great deal of variability in its clinical Great deal of variability in its clinical

expression from one patient to the nextexpression from one patient to the next dcSSc = diffuse cutaneous SScdcSSc = diffuse cutaneous SSc lcSSC = limited cutaneous SSclcSSC = limited cutaneous SSc SSc sine sclerodermaSSc sine scleroderma Digital necrosis: sharply demarcated Digital necrosis: sharply demarcated

necrosis of the fingertipnecrosis of the fingertip

Clinical features 2Clinical features 2 Sclerodactily: skin induration and fixed flexion Sclerodactily: skin induration and fixed flexion

contractures at the proximal and distal interphalangeal contractures at the proximal and distal interphalangeal jointsjoints

RaynaudRaynaud´́s phenomenons phenomenon Soft tissue swelling, intense pruritusSoft tissue swelling, intense pruritus Skin on the fingers, hands, distal limbs, and face Skin on the fingers, hands, distal limbs, and face

affected firstaffected first ArthralgiasArthralgias Decline in sweating capacityDecline in sweating capacity Telangiectasia, calcinosisTelangiectasia, calcinosis The course of the SSc indolentThe course of the SSc indolent Overlap syndromesOverlap syndromes

RaynaudRaynaud´́s Phenomenons Phenomenon Episodic vasoconstriction inthe fingers and toesEpisodic vasoconstriction inthe fingers and toes Tip of the nose and earlobesTip of the nose and earlobes Cold exposureCold exposure pallor→cyanosis→erythema rewarming of the pallor→cyanosis→erythema rewarming of the

fingers, fingers, vasoconstriction→ischemia→reperfusionvasoconstriction→ischemia→reperfusion

Normal population: 3-5%, womenNormal population: 3-5%, women Primary and/or secondaryPrimary and/or secondary Nailbed cutaneous capillaries viewed Nailbed cutaneous capillaries viewed

stereoscopic microscopestereoscopic microscope

Skin featuresSkin features Skin thickening from distal to proximalSkin thickening from distal to proximal Dermal sclerosis due to collagen accumulationDermal sclerosis due to collagen accumulation Hair loss, decreased sweating, dry skinHair loss, decreased sweating, dry skin Face: loss of wrinkles, expressionless facies, Face: loss of wrinkles, expressionless facies,

microstomiamicrostomia Skin ulcerationSkin ulceration Resorption of the terminal phalangesResorption of the terminal phalanges Calcium deposits ulcerate through the skinCalcium deposits ulcerate through the skin

Pulmonary featuresPulmonary features Exertional dyspnea, chronic dry coughExertional dyspnea, chronic dry cough Crackles at the lung basesCrackles at the lung bases Reductions in forced vital capacityReductions in forced vital capacity ILD = interstitial lung disease HRCT, pulmonary fibrosisILD = interstitial lung disease HRCT, pulmonary fibrosis Restrictive lung diseaseRestrictive lung disease Nonspecific interstitial pneumonitisNonspecific interstitial pneumonitis PAH = pulmonary arterial hypertension: pulmonary arterial PAH = pulmonary arterial hypertension: pulmonary arterial

pressure pressure >>25 mm Hg determined by right heart 25 mm Hg determined by right heart catheterizatiocatheterizatio

Right heart failure, tachypnea, prominent pulmonic S2 Right heart failure, tachypnea, prominent pulmonic S2 heart sound, elevated jugular venous pressure, edemaheart sound, elevated jugular venous pressure, edema

Doppler echocardiographyDoppler echocardiography BNP = brain natriuretic peptide↑BNP = brain natriuretic peptide↑

Gastrointestinal involvementGastrointestinal involvement Abnormal motility of the esophagus, stomach, Abnormal motility of the esophagus, stomach,

small and large intestinessmall and large intestines GERD: heartburn, regurgitation, dysphagiaGERD: heartburn, regurgitation, dysphagia Distal two-thirds of the esophagusDistal two-thirds of the esophagus BarretBarret´́s esophagus→adenocarcinomas esophagus→adenocarcinoma EndoscopyEndoscopy Gastroparesis, gastric ectasia, watermelon Gastroparesis, gastric ectasia, watermelon

stomachstomach Malabsorption, malnutrition, intestinal Malabsorption, malnutrition, intestinal

pseudoobstructionpseudoobstruction

Renal involvementRenal involvement

Hypertension, proteinuria, microscopic Hypertension, proteinuria, microscopic hematuriahematuria

SSc renal crisisSSc renal crisis Abrupt onset of malignant hypertensionAbrupt onset of malignant hypertension Rapidly progrssive oliguric renal failureRapidly progrssive oliguric renal failure Creatinine↑Creatinine↑

Cardiac involvementCardiac involvement

Myocardial fibrosis and pericardial Myocardial fibrosis and pericardial effusion and conduction defects and effusion and conduction defects and arrhythmiasarrhythmias

Heart failureHeart failure Echocardiography: left ventricular diastolic Echocardiography: left ventricular diastolic

dysfunctiondysfunction

Laboratory featuresLaboratory features

Anemia ← chronic inflammationAnemia ← chronic inflammation Iron deficiency anemia → GI bleedingIron deficiency anemia → GI bleeding ESR normalESR normal Scl-70 Ab = topoisomerase-IScl-70 Ab = topoisomerase-I Anticentromere AbAnticentromere Ab

Diagnosis of SScDiagnosis of SSc

Clinical pictureClinical picture Skin induration+ typical visceral organ Skin induration+ typical visceral organ

manifestationsmanifestations Rarely: full-thickness biopsy of the skinRarely: full-thickness biopsy of the skin Digital tip pitting scars+ HRCT pulmonary Digital tip pitting scars+ HRCT pulmonary

fibrosis in the lower lobesfibrosis in the lower lobes

Treatment of SScTreatment of SSc Disease-modifying treatments: Disease-modifying treatments:

Cyclophosphamide in interstitial lung disease Cyclophosphamide in interstitial lung disease and in skin induration 6-12 months, steroids?, and in skin induration 6-12 months, steroids?, Methotrexate, D-penicillamine→antifibrotic agent Methotrexate, D-penicillamine→antifibrotic agent in skin indurationin skin induration

RaynaudRaynaud´́s: dree warmly, calcium channel s: dree warmly, calcium channel blockers, ARBs (angiotensin II receptor blockers, ARBs (angiotensin II receptor blockers) Losartan, iv. prostaglandins, low-dose blockers) Losartan, iv. prostaglandins, low-dose aspirinaspirin

Treatment of GI complicationsTreatment of GI complications

PPI (prootn pump inhibitors)PPI (prootn pump inhibitors) H2 blockersH2 blockers

Treatment of pulmonary arterial Treatment of pulmonary arterial hypertensionhypertension

Endothelin-1 receptor antagonist orally: Endothelin-1 receptor antagonist orally: BosentanBosentan

Oxygen supplementtaionOxygen supplementtaion Sildenafil:inhibitor of phosphodiesterase Sildenafil:inhibitor of phosphodiesterase

type 5type 5 Prostcyclin analogues iv.: Epoprostenol, Prostcyclin analogues iv.: Epoprostenol,

IloprostIloprost Lung transplantationLung transplantation

Treatment of renal crisisTreatment of renal crisis

Medical emergencyMedical emergency ACE inhibitorsACE inhibitors Short-term dialysisShort-term dialysis Kidney transplantationKidney transplantation

Skin careSkin care

Hydrophilic ointments and bath oilsHydrophilic ointments and bath oils

Course and prognosis of SScCourse and prognosis of SSc

Difficult to predictDifficult to predict Skin regression possibleSkin regression possible 5-year survival: 70-90%5-year survival: 70-90% 10-year survival: 55-75%10-year survival: 55-75%

Polymyositis (PM) and Polymyositis (PM) and Dermatomyositis (DM)Dermatomyositis (DM)

Clinical features of PM/DMClinical features of PM/DM Prevalence: 1 in 100,000Prevalence: 1 in 100,000 Progressive and symmetric muscle weaknessProgressive and symmetric muscle weakness Difficulty in getting up from a chair, climbing Difficulty in getting up from a chair, climbing

steps, lifting objects, combing hairsteps, lifting objects, combing hair Facial and ocular muscles unaffectedFacial and ocular muscles unaffected Dysphagia, difficulty in holdingup the headDysphagia, difficulty in holdingup the head Rarely: respiratory muscles affectedRarely: respiratory muscles affected Severe weakness,muscle wastingSevere weakness,muscle wasting

PolymyositisPolymyositis

Age at onset: Age at onset: >>18 yr18 yr Association with systemic autoimmun Association with systemic autoimmun

diseasesdiseases Drugs: D-penicillamine, AZT Drugs: D-penicillamine, AZT

(zidovudine)→ inflammatory myopathy(zidovudine)→ inflammatory myopathy

DermatomyositisDermatomyositis Skin rash: heliotrop rash: a blue-purple Skin rash: heliotrop rash: a blue-purple

discoloration on the upper eye-lids with discoloration on the upper eye-lids with edema, Gottronedema, Gottron´́s sign: erythematous flat-s sign: erythematous flat-toppd papules over the knuckles, toppd papules over the knuckles, periungual telangiectases,periungual telangiectases,

Muscle weaknessMuscle weakness Age at onset: adulthood and childhoodAge at onset: adulthood and childhood Overlap syndromes: SSc, MCTDOverlap syndromes: SSc, MCTD Malignancy: 15% of casesMalignancy: 15% of cases

Extramuscular manifestationsExtramuscular manifestations

Fever, weight loss, arthralgia, RaynaudFever, weight loss, arthralgia, Raynaud´́ss Joint contracturesJoint contractures Dysphagia and GI symptomsDysphagia and GI symptoms Cardiac disturbances: AV conduction Cardiac disturbances: AV conduction

defects, tachyarrythmias, DCM, defects, tachyarrythmias, DCM, congestive heart failurecongestive heart failure

Pulmonary dysfunctionPulmonary dysfunction

Association with malignanciesAssociation with malignancies

Ovarian cancerOvarian cancer Breast cancerBreast cancer MelanomaMelanoma Colon cancerColon cancer NHLNHL

PathogenesisPathogenesis

Autoimmune etiologyAutoimmune etiology 20% of patients: autoantibodies20% of patients: autoantibodies anti-Jo-1 Ab: directed against the histidyl-anti-Jo-1 Ab: directed against the histidyl-

transfer RNA synthetasetransfer RNA synthetase Endomysial inflammatory infiltrates, Endomysial inflammatory infiltrates,

muscle-fiber necrosismuscle-fiber necrosis

Differential diagnosisDifferential diagnosis Chronic progressive muscle weakness: amyotrophic Chronic progressive muscle weakness: amyotrophic

lateral sclerosis, spinal muscular atrophies, muscular lateral sclerosis, spinal muscular atrophies, muscular dystrophies,mitochondrial diseases, endocrine dystrophies,mitochondrial diseases, endocrine myopathies, neoplasm, myasthenia gravismyopathies, neoplasm, myasthenia gravis

Acute muscle weakness: Guillain-BarrAcute muscle weakness: Guillain-Barréé syndrome, syndrome, transverse myelitis, poliomyelitis, parasitic polymyositis, transverse myelitis, poliomyelitis, parasitic polymyositis, suppurative pyomyositis, chronic alcoholicssuppurative pyomyositis, chronic alcoholics

Necrotizing myositis: cancer, viral infectionNecrotizing myositis: cancer, viral infection Drug-induced myopathies: d-penicillamine, Drug-induced myopathies: d-penicillamine,

procainamide, statins, fibrates, cyclosporine, steroidsprocainamide, statins, fibrates, cyclosporine, steroids Weakness due to muscle pain and muscle tenderness: Weakness due to muscle pain and muscle tenderness:

polymyalgia rheumatica, fibromyalgia, chronic fatigue polymyalgia rheumatica, fibromyalgia, chronic fatigue syndromesyndrome

DiagnosisDiagnosis

Serum muscle enzymes: CK↑ 50-fold, Serum muscle enzymes: CK↑ 50-fold, LDH, SGOT, SGPT, aldolase↑LDH, SGOT, SGPT, aldolase↑

Needle EMG (electromyography): Needle EMG (electromyography): myopathic potentialsmyopathic potentials

Muscle biopsy: definitive test, inflammation Muscle biopsy: definitive test, inflammation + muscle fiber necrosis detected+ muscle fiber necrosis detected

Treatment of PM and DMTreatment of PM and DM

Goal: improve muscle strengthGoal: improve muscle strength Oral Prednisone: 1 mg/kg per day, Oral Prednisone: 1 mg/kg per day,

response after 3 months, steroid response after 3 months, steroid myopathy, steroid resistancymyopathy, steroid resistancy

Azathioprine: 3 mg/kgdailyAzathioprine: 3 mg/kgdaily Methotrexate orally: 7.5 mg/week→25 mg Methotrexate orally: 7.5 mg/week→25 mg

weeklyweekly Mycophenolate mofetil: 2.5 mf/dayMycophenolate mofetil: 2.5 mf/day

Treatment of PM and DM 2Treatment of PM and DM 2

Rituximab= monoclonal anti-CD20 in DMRituximab= monoclonal anti-CD20 in DM CyclosporineCyclosporine Cyclophosphamide: 0.5-1 g iv. monthly for Cyclophosphamide: 0.5-1 g iv. monthly for

6 months6 months Tacrolimus in PMTacrolimus in PM IVIG (intravenous immunoglobulin)IVIG (intravenous immunoglobulin) PlasmapheresisPlasmapheresis

PrognosisPrognosis

5-year survival rate: 95%5-year survival rate: 95% 10-year survival rate: 84%10-year survival rate: 84% Dysphagia, respiratory difficulties, cancerDysphagia, respiratory difficulties, cancer DM responds better to therapy than PMDM responds better to therapy than PM Relapses at any timeRelapses at any time

MCTDMCTD

Mixed Connective Tissue DiseaseMixed Connective Tissue Disease

MCTDMCTD Features of PSS, SLE, PM, RAFeatures of PSS, SLE, PM, RA Autoantibodies to U1-RNPAutoantibodies to U1-RNP RaynaudRaynaud´́s phenomenon + puffy fingers + s phenomenon + puffy fingers +

myalgia + arthralgia/erosive polyarthritismyalgia + arthralgia/erosive polyarthritis ESR↑ESR↑ HypergammaglobulinemiaHypergammaglobulinemia Steroids → good responseSteroids → good response Long-term prognosis: betterLong-term prognosis: better