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Kristian Stengaard-Pedersen Reumatologisk afdeling U, Århus Universitetshospital SYSTEMISK LUPUS ERYTHEMATOSUS OG ANDRE BINDEVÆVSLIDELSER

SYSTEMISK LUPUS ERYTHEMATOSUS OG ANDRE BINDEVÆVSLIDELSER · SYSTEMISK LUPUS ERYTHEMATOSUS OG. ANDRE BINDEVÆVSLIDELSER. ... heart failure. Systemic lupus erythematosus: Libman

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Text of SYSTEMISK LUPUS ERYTHEMATOSUS OG ANDRE BINDEVÆVSLIDELSER · SYSTEMISK LUPUS ERYTHEMATOSUS OG....

  • Kristian Stengaard-Pedersen

    Reumatologisk afdeling U, rhus Universitetshospital

    SYSTEMISK LUPUS ERYTHEMATOSUS OGANDRE BINDEVVSLIDELSER

  • BINDEVVSSYGDOMME

    BINDEVVSSYGDOMME, ANDREPolymyositis, dermatornyositisProgressiv systemisk sklerodermiSjogren's syndromAntifosfolipidsyndrom

    VASKULITWegners granulomatoseArteritis temporalisPolymyalgia rheumatica etc.

    SYSTEMISK LUPUS ERYTHEMATOSUS (SLE, LED)

  • BINDEVVSSYGDOMME Fllestrk

    Flere organsystemer indvolveretVasculitis er hyppigFasereaktanter ofte forhjetImmunologiske fund ofte karakteristiske

    ForskelleHvilke organer der rammesKn og aldersfordelingDe immunologiske fundDen inflammatoriske reaktionsfase(inflammation fibrose)

  • EPIDEMIOLOGi

    SLE

    20 40 SLE pt. / 100000 i befolkningen

    > 90% er kvinder

    topincidens 20 - 40 r

  • Prevalence 0.4/1000 inhabitants

    Debut 20/40 years

    Female:male ratio 9:1

  • RSAGER TIL SLE KRONISK FORSTYRRELSE I IMMUNFORSVARET

  • AUTOIMMUNITY

  • T-CELL TOLERANCE

  • AUTOIMMUNE DISEASE HOW T-CELL TOLERANCE BREAKS DOWN

  • Defekt apoptose get B-lymfocytfunktion

    Immunkompleksafhngig inflammation antistofafhngig mldestruktion

    strukturel og funktionel cellebeskadigelse

    sygdomsmanifestationer

    PATOGENESE VED SLEGener, hormoner,

    infektioner

    hyperimmunoglobulinmi og

    autoantistoffer

  • IMMUNE COMPLEX ACTIVATION OF INFLAMMATION

  • AUTOIMMUNE DISEASES DEFINITIONS

    AutoimmunityImmunoglobulin antibodies and /or T-lymphocyte receptors against self-antigens

    Autoimmune diseasesTissue damage caused by autoimmunity

  • CLINICAL FEATURES ON PRESENTATION IN SLE

    Arthritis or arthralgia 55%

    Skin involvement 20%

    Nephritis 5%

    Fever 5%

    Other 15%

  • ORGANINVOLVEMENT IN SLE

    Joints 90%Skin- rashes- discoid lesions- alopecia

    70%30%40%

    Pleuropericardium 60%Kidney 50%Raynauds 20%Mucous membranes 15%

    CNS (psychosis/convulsions) 15%

  • HUDSYGDOM VED SLE

  • Photosensitivity Vascular lesion Acute, erythematous,

    edematous Periungual erythema

    Subacute Livedo reticularisAnnular/polycyclic TeleangiectasiaPsoriasiform Raynaud's phenomenonDiscoid VasculitisLupus profundus/panniculitis Urtecaria purpuraNeonatal LE Atrophie blance

    Alopecia Chilblain lupus

    Bullous lesions Steroid-induced ecchymosesMucous membranes

    MUCOCUTANEOUS LESIONS

  • Systemic lupus erythematosusPhotosensitivity, butterfly rash

  • Skin biopsy: immunoglobuline and complement deposition

  • Systemic lupus erythematosus: skalp alopecia

  • Systemic erythematosus: bullous lesions, palate

  • RAYNAUDS FNOMENvarme kulde

    Normal

    Raynauds fnomen

    Endarteritis

  • RAYNAUDS FNOMEN

  • Raynaud's phenomenon

  • Systemic lupus erythematosus, livedo reticularis

  • HUDUNDERSGELSER

    Anamnese og objektiv undersgelse

    Stansebiopsi

    - Histologisk

    - Immunfluorescens

  • Systemic lupus erythematosus: vasculitis

  • Systemic lupus erythematosus: vasculitis

  • Systemic lupus erythematosus: vasculitis, digital gangrene

  • Systemic lupus erythematosus: vasculitis

  • Systemic lupus erythematosus: vasculitis

  • Systemic lupus erythematosus: vasculitis

  • Vasculitis of vasa vasorum Sensory neuropathy Mononeuritis muliplex

    Systemic lupus erythematosus

  • Vasculitis ved SLE

    Huden afficeres hyppigst

    Cor, lunger, CNS / perifere nerver mv.afficeres ogs og hyppigt livstruende

  • KNOGLER OG LED

  • MUSKLER OG SENER

  • LED, SENER OG MUSKLER

    Artralgier Polyartrit, specielt hnder og knled Osteonekrose Tendosynovit Myalgier / myosit

  • SLE RA

    Arthralgia Common Common Arthritis Common Deforming

    Symmetry Yes Yes

    Joints involved PIP>MCP >wrist>knee MCP>wrist >knee

    Synovial hypertrophy Rare CommonSynovial membrane abnormality Minimal Proliferative

    Synovial fluid Transudate Exudate Subcutaneous nodules Rare 35% Erosions Very Rare Common

    Morning stiffness Minutes HoursMyalgia Common CommonMyositis Rare UncommonOsteoporosis Variable CommonAvascular necrosis 5-50% UncommonDeforming arthritis Uncommon CommonSwan neck 10% CommonUlnar deviation 5% Common

    MUSKULOSKELETAL MANIFESTATIONS IN SLE

  • Systemic lupus erythematosus: arthritis

  • Systemic lupus erythematosus: Charcot's artropathy

  • Systemic lupus erythematosus: knee pain / avascular necrosis

  • Systemic lupus erythematosus: shoulder pain / avascular necrosis

  • Systemic lupus erythematosus: hip pain / avascular necrosis, scintigraphy

  • BEVGEAPPARATSUNDERSGELSER Anamnese, objektiv undersgelse Blodanalyser: fasereaktanter, leukocytter etc. Ledvskeundersgelse Billeddiagnostiske undersgelser

    - Konventionel rntgen- Ultralydscanning- MR-scanning- Scintigrafi

  • SYGDOM I INDVENDIGE ORGANER VED SLE

  • LUNGER OG HJERTE Pleuritis Lungefibrose Pulmonal hypertension Pericarditis Mitralklapsygdom / vegetationer Myokardieinfarkt Hjerteinsufficiens

  • Systemic lupus erythematosus: pleuritis and pericarditis

  • Systemic lupus erythematosus: pulmonary vasculitis

  • Systemic lupus erythematous: vasculitis

    Histology Immunofluorescens

  • LUNGEUNDERSGELSER

    Anamnese, objektiv undersgelse Lungefunktionsundersgelse Konventional rntgen HR-CT-scanning BAL, transbronkial biopsi Torakoskopisk biopsi

  • Systemic lupus erythematosus: premature atherosclerosisAngina, myocardial infarction, heart failure

  • Systemic lupus erythematosus: Libman - Sacks endocarditis

  • HJERTEUNDERSGELSER

    Anamnese, objektiv undersgelse Ekg, rntgen af thorax Ekkokardiografi

  • NYRESYGDOM VED SLE

  • SYSTEMIC LUPUS ERYTHEMATOSUS: RENAL HISTOLOGY Normal light microscopy, but immunoglobulin

    or complement protein deposits present

    Mesangial lupus nephritis

    Mild focal glomerulonephritis

    Diffuse proliferative glomerulonephritis

    Membranous glomerulonephritis

    Interstitial and tubular nephritis

  • Systemic lupus erythematosus: mesangial glomerulonephritis

  • Systemic lupus erythematosus: focal glomerulonephritis

  • Systemic lupus erythematosus: focal glomerulonephritis

  • Systemic lupus erythematosus: immunoglobulin and complement deposition

  • Systemic lupus erythematosus: electron micrograph of glomerulonephritis

  • NYREUNDERSGELSER

    Anamnese, objektiv undersgelse S-kreatinin, kreatinin clearance Dgnurin-protein, U-sediment Blodtryksmling Nyrebiopsi

  • SLE SYGDOM I HJERNE, RYGMARV OG PERIFERE NERVER

  • CNS LUPUS Central nervous system

    EpilepsyHemiparesisCranial nerve lesionsBrain stem/cord lesionsAseptic meningitisTransverse myelitis

    Peripheral nervous systemPeripheral neuropathiesMyasthenia gravisMononeuritis multiplex

    PsychiatricDisorders of mental function

    - organic- non-organic

  • Systemic lupus erythematosus: MRI of the brain White matter lesions: microinfarcts or vasculitis

  • Systemic lupus erythematosus: MRI of the brain

    T1-weigthed, cerebral vasculitis T2-weigthed, cerebral vasculitis

  • NERVESYSTEMSUNDERSGELSER

    Anamnese, objektiv undersgelse MR-scanning Cerebrospinalvskeundersgelser Neurofysiologiske undersgelser N. suralisbiopsi

  • Acute episodes Chronic morbidity

    Glomerulonephritis End-stage renal disease, dialysis, transplantation

    Vasculitis Atherosclerosis, venous syndromes, pulmonary emboli

    Arthritis Osteonecrosis

    Cerebritis Neuropsychiatric dysfunction

    Pneumonitis Shrinking lung syndrome

    LATE COMPLICATIONS OF SLE

  • FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME

    Symptoms Percentage Fatigue 80-100

    Fever >80Weight loss >60

    Arthritis, arthralgia 95 Skin >80

    Butterfly rash >50Photosensitivity

  • FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME

    Symptoms % Symptoms %

    Renal 50 Murmurs 23Nephrosis 18 ECG changes 34-70

    Gastrointestinal 38 Lymphadenopathy 50 Pulmonary 0.9-98 Splenomegaly 10-20

    Pleurisy 45 Hepatomegaly 25Effusion 24 Central nervous system 25-75Pneumonia 29 Functional most

    Cardiac 46 Psychosis 5-52Pericarditis 8-48 Convulsions 15-20

  • BLODPRVER VED SLE

  • BLODPRVER C-reaktivt protein (blodsnkning) Hmoglobin (blodprocent) Antistoffer

    IgG, ANA, anti-DNA

    Komplement C3 og C4 Erytrocytter, leukocytter, trombocytter S-kreatinin, kreatinin clearance (nyrefunktion) Urin for protein og blod

  • FOREKOMST OG REAKTIVITET AF ANTINUKLERE ANTISTOFFER VED INFLAMMATORISKE REUMATISKE SYGDOMME

    Sygdom Hyppighed af ANA (%) Positivitet/titer

    SLE 95 strk/hj*

    Medikamentel LE 95 strk/hj

    MCTD 95 strk/hj

    Sklerodermi 90 strk/hj

    Primr SS 80 strk/hj

    PM/DM 40 middel/middelhj**

    RA 50 middel/middelhj

    Juvenil RA 70 middel/middelhjUgeskrift for lger; 2002:610-14, Allan Wiik*) 1.280

    **) 320-640

  • Antigen Sygdom Sensitivitet SpecificitetKerneantigen i RA 50-75 ModeratGranulocytter og monocytter* Feltys syndrom -100 ModeratHistoner Med. SLE 90 Lavds-dna** SLE 50-60 Hjn-RNP*** MCTD 100 LavSm SLE 15-30 Meget hjSSA Primr Sjgren 80-100 LavSSB Primr Sjgren 70-95 LavScl-70 Sklerodermi 20-60 HjCentromer CREST**** 60-90 Hj

    * Antistoffet: GS-ANA** ds-DNA: dobbeltstrenget DNA*** n-RNP: nukleaert ribonukleoprotein**** Undergruppe af sklerodermi med kalcinose, Raynauds fnomen,

    esophagusdysmotilitet, sklerodaktyli og teleangiektasier

    FOREKOMST AF ANTINUKLERE ANTISTOFFER

  • Negativ

    ANA, hep-2-celler

    Positiv

    Anti-DNA Anti-ENA Anti-SSB

    SLE

    Sm Anti-RNP

    SLE Sklerodermi, MTC, andre

    Sjgren

    ANTINUKLERE CELLER

  • AUTOANTIBODY-DISEASE ASSOCIATIONS:SLE AND DRUG-INDUCED LUPUSAntigen SLE Drug-induced LE

    Native DNA 40% No

    Denatured DNA 70% 75-80%

    Histones 70% >95%

    SM Antigen 30% No

    Nuclear RNP 30% No

    Ribosomal RNP 10%

    SS-A/RO 35% No

    SS.B/La 15% No

  • CLINICAL MANIFESTATIONSSUMMARY

    Fatigue, artralgia / arthritis, rash (all) Lympho-, neutro-,trombocytopenia

    complement low, anti-DNA high (all)

    Renal-, CNS-, Cardio-pulmonarymanifestations (feared by all)

  • DIAGNOSEN SLE

    4 ud af 11 bestemte sygdomstrk og abnormiteter i blodprver skal vre tilstede for at diagnosen kan stillesOftest en speciallgeopgave at stille diagnosen

  • SLE: 1982 CLASSIFICATION CRITERIA*Malar rash

    Renal disorder

    Neurologic disorder

    Hematologic disorder

    Immunologic disorder

    Antinuclear antibody

    Discoid rash

    Photosensitivity

    Oral ulcers

    Arthritis

    SerositisACR *Must have four criteria simultaneously or serially

  • SYSTEMIC LUPUS ERYTHEMATOSUS1982 CLASSIFICATION CRITERIA DEFINITIONS(continued)

    Oral or nasopharyngeal ulcers

    Usually painless

    Arthritis Non-erosive, inflammatory in two or more peripheral joints

    Serositis Pleuritis or pericarditis

  • SYSTEMIC LUPUS ERYTHEMATOSUS1982 CLASSIFICATION CRITERIA DEFINITIONS(continued)

    Renal disorder Persistent proteinuria or cellular casts

    Neurologic disorder Seizures of psychosis

    Hematologic disorder

    Hemolytic anemia,Leukopenia (>4,000/mm3)Lymphopenia (>1,500/mm3),or thrombocytopenia (>100,00/mm3)

  • SYSTEMIC LUPUS ERYTHEMATOSUS1982 CLASSIFICATION CRITERIA DEFINITIONS(continued)

    Immunologic disorderantibodies to aca or ds-DNA or SM or false positive serologic test for syphillis

    Antinuclear antibody test Positive

  • ANTI-PHOSPHOLIPID ANTIBODY TESTS

    Lupus anticoagulant: prolonged PTT or PT not corrected by adding normal plasma

    Anti-cardiolipin antibody by ELISA

    VDRL positive, FTA-ABS negative

  • BEHANDLING AF SLE

    Ingen livs- eller organtruende sygdom

    Simple analgetikaNSAIDOH-klorokinfosfat Lokale steroider SolbeskyttelsesfaktorPlus livs- eller organtruende sygdom

    Glukokortikoider Immunodepressiva

    - Azathioprin, MTX- Cyklofosfamid- Rituximab

    Antifosfolipidantistoffer + trombose

    - AK behandling- Rituximab

    Symptomatisk behandling

    Hypertension Infektion Nyreinsufficiens Raynauds fnomen

  • NO LIFE OR ORGAN THREATENING DISEASE ACTIVITY

    Tabl. chloroquine phosphate 250 mg daily

    NSAID, simple analgesics

    Local steroids, chemical sun protection

  • TREATMENT OF SLE - LIFE-THREATENING DISEASE ACTIVITY

    Indications: Vasculitis, glomerulonephritis

    Treatment: Glucocorticoids, cyclophosphamide

    Tabl. prednisolone 1-2 mg / kg / daily

    and / or

    methylprednisolone i.v. 1000 mg daily times three every fourth week

    and

    reduce dose after few weeks, maintenance dose tabl. prednisone 7,5 15 mg daily

    Tabl. Cyclophosphamide 1-2 mg / kilo daily

    or

    cyclophosphamide i.v. 1000 mg / m2 body surface every four week for 6 12 months

    Azathioprine 1 2 mg / kg / daily or methotrexate 1o 25 mg once weekly can after 6 12 months substitute cyclophosphamide

  • GRAVIDITET VED SLE

  • SLE OG GRAVIDITET

    SLE-aktivitet, preklampsi Sen abort, tidlig fdsel / lille barn ( APS ) Kongenit AV blok (anti-SSA / SSB )

    Kongenit SLE

  • SLE OG GRAVIDITET

    Us. for klinisk og biokemisk sygdomsaktivitetRo i >1r fr graviditet

    IgM og IgG antikardiolipin abbeta-2-GP-1 ab, lupus antikoagulans

    anti-SSA / SSBhmolyse, penier i blodbilledet,ndring i C3 / C4 og anti-DNA

  • SLE OG GRAVIDITET

    ALTID

    Us. for klinisk og biokemisk sygdomsaktivitetRo i >1r fr graviditet

    Hyppig kontrol reumatologisk / obstetriskKlinisk, biokemisk, UL

  • LUPUS-LIKE SYNDROMS: DRUGS IMPLICATED IN INDUCTION

    Common Rare

    Procainamide Beta-blockers

    Hydralazine D-penicillamineIsoniazidQuinidinePropylthiouracilHydantoinsTrimethadioneChlorpromazine

  • LUPUS-LIKE SYNDROMS: DRUGS IMPLICATED IN INDUCTION (continued)

    Ambiguous or single case reportsAllopurinol MethysergideChlorprothixene MethylthiouracilEstrogen/progestin PhenylbutazoneEthylphenacemide PrimidoneGold salts PropafenoneGriseofulvin ReserpineMethyldopa Streptomycin

    Tetracycline

  • Kristian Stengaard-Pedersen

    Reumatologisk afdeling U, rhus Universitetshospital

    SYSTEMISK LUPUS ERYTHEMATOSUS OGANDRE BINDEVVSLIDELSER

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