systemisk lupus erythematosus og andre bindevÆvslidelser · systemisk lupus erythematosus og....
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Kristian Stengaard-Pedersen
Reumatologisk afdeling U, Århus Universitetshospital
SYSTEMISK LUPUS ERYTHEMATOSUS OGANDRE BINDEVÆVSLIDELSER
BINDEVÆVSSYGDOMME
BINDEVÆVSSYGDOMME, ANDREPolymyositis, dermatornyositisProgressiv systemisk sklerodermiSjogren's syndromAntifosfolipidsyndrom
VASKULITWegners granulomatoseArteritis temporalisPolymyalgia rheumatica etc.
SYSTEMISK LUPUS ERYTHEMATOSUS (SLE, LED)
BINDEVÆVSSYGDOMME• Fællestræk
Flere organsystemer indvolveretVasculitis er hyppigFasereaktanter ofte forhøjetImmunologiske fund ofte karakteristiske
• ForskelleHvilke organer der rammesKøn og aldersfordelingDe immunologiske fundDen inflammatoriske reaktionsfase(inflammation – fibrose)
EPIDEMIOLOGi
SLE
• 20 – 40 SLE pt. / 100000 i befolkningen
• > 90% er kvinder
• topincidens 20 - 40 år
Prevalence 0.4/1000 inhabitants
Debut 20/40 years
Female:male ratio 9:1
ÅRSAGER TIL SLE KRONISK FORSTYRRELSE I IMMUNFORSVARET
AUTOIMMUNITY
T-CELL TOLERANCE
AUTOIMMUNE DISEASE HOW T-CELL TOLERANCE BREAKS DOWN
Defekt apoptose øget B-lymfocytfunktion
Immunkompleksafhængig inflammation antistofafhængig måldestruktion
strukturel og funktionel cellebeskadigelse
sygdomsmanifestationer
PATOGENESE VED SLEGener, hormoner,
infektioner
hyperimmunoglobulinæmi 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%Raynaud’s 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 ecchymoses
Mucous membranes
MUCOCUTANEOUS LESIONS
Systemic lupus erythematosusPhotosensitivity, butterfly rash
Skin biopsy: immunoglobuline and complement deposition
Systemic lupus erythematosus: skalp alopecia
Systemic erythematosus: bullous lesions, palate
RAYNAUD’S FÆNOMENvarme kulde
Normal
Raynaud’s fænomen
Endarteritis
RAYNAUD’S FÆNOMEN
Raynaud's phenomenon
Systemic lupus erythematosus, livedo reticularis
HUDUNDERSØGELSER
• Anamnese og objektiv undersøgelse
• 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 også og hyppigt livstruende
KNOGLER OG LED
MUSKLER OG SENER
LED, SENER OG MUSKLER
• Artralgier
• Polyartrit, specielt hænder og knæled
• 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
BEVÆGEAPPARATSUNDERSØGELSER• Anamnese, objektiv undersøgelse
• Blodanalyser: fasereaktanter, leukocytter etc.
• Ledvæskeundersøgelse
• Billeddiagnostiske undersøgelser
- Konventionel røntgen
- 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
LUNGEUNDERSØGELSER
• Anamnese, objektiv undersøgelse
• Lungefunktionsundersøgelse
• Konventional røntgen
• HR-CT-scanning
• BAL, transbronkial biopsi
• Torakoskopisk biopsi
Systemic lupus erythematosus: premature atherosclerosisAngina, myocardial infarction, heart failure
Systemic lupus erythematosus: Libman - Sacks endocarditis
HJERTEUNDERSØGELSER
• Anamnese, objektiv undersøgelse
• Ekg, røntgen 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
NYREUNDERSØGELSER
• Anamnese, objektiv undersøgelse
• S-kreatinin, kreatinin clearance
• Døgnurin-protein, U-sediment
• Blodtryksmåling
• 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
NERVESYSTEMSUNDERSØGELSER
• Anamnese, objektiv undersøgelse
• MR-scanning
• Cerebrospinalvæskeundersøgelser
• Neurofysiologiske undersøgelser
• 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 <58Mucous membrane lesion 27-41
Alopecia <71Raynaud's phenomenon 17-30Purpura 15Urticaria 8
FREQUENCY OF CLINICAL SYMPTOMS IN SLE AT ANY TIME
Symptoms % Symptoms %
● Renal 50 Murmurs 23
Nephrosis 18 ECG changes 34-70
● Gastrointestinal 38 ● Lymphadenopathy 50
● Pulmonary 0.9-98 ● Splenomegaly 10-20
Pleurisy 45 ● Hepatomegaly 25
Effusion 24 ● Central nervous system 25-75
Pneumonia 29 ● Functional most
● Cardiac 46 Psychosis 5-52
Pericarditis 8-48 Convulsions 15-20
BLODPRØVER VED SLE
BLODPRØVER• C-reaktivt protein (blodsænkning)
• Hæmoglobin (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 ANTINUKLEÆRE ANTISTOFFER VED INFLAMMATORISKE REUMATISKE SYGDOMME
Sygdom Hyppighed af ANA (%) Positivitet/titer
SLE 95 stærk/høj*
Medikamentel LE 95 stærk/høj
MCTD 95 stærk/høj
Sklerodermi 90 stærk/høj
Primær SS 80 stærk/høj
PM/DM 40 middel/middelhøj**
RA 50 middel/middelhøj
Juvenil RA 70 middel/middelhøjUgeskrift for læger; 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 Højn-RNP*** MCTD 100 LavSm SLE 15-30 Meget højSSA Primær Sjögren 80-100 LavSSB Primær Sjögren 70-95 LavScl-70 Sklerodermi 20-60 HøjCentromer CREST**** 60-90 Høj
* Antistoffet: GS-ANA** ds-DNA: dobbeltstrenget DNA*** n-RNP: nukleaert ribonukleoprotein**** Undergruppe af sklerodermi med kalcinose, Raynauds fænomen,
esophagusdysmotilitet, sklerodaktyli og teleangiektasier
FOREKOMST AF ANTINUKLEÆRE ANTISTOFFER
Negativ
ANA, hep-2-celler
Positiv
Anti-DNA Anti-ENA Anti-SSB
SLE
Sm Anti-RNP
SLE Sklerodermi, MTC, andre
Sjögren
ANTINUKLEÆRE 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-pulmonary
manifestations (feared by all)
DIAGNOSEN SLE
4 ud af 11 bestemte sygdomstræk og abnormiteter i blodprøver skal være tilstede for at diagnosen kan stillesOftest en speciallægeopgave 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 analgetika
•NSAID
•OH-klorokinfosfat
• Lokale steroider
• SolbeskyttelsesfaktorPlus livs- eller organtruende sygdom
• Glukokortikoider
• Immunodepressiva- Azathioprin, MTX- Cyklofosfamid- Rituximab
Antifosfolipidantistoffer + trombose
- AK behandling- Rituximab
Symptomatisk behandling
• Hypertension
• Infektion
• Nyreinsufficiens
• Raynaud’s fænomen
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, præeklampsi
• Sen abort, tidlig fødsel / lille barn ( APS )
• Kongenit AV blok (anti-SSA / SSB )
• Kongenit SLE
SLE OG GRAVIDITET
• Us. for klinisk og biokemisk sygdomsaktivitet
Ro i >1år før graviditet
• IgM og IgG antikardiolipin ab
beta-2-GP-1 ab, lupus antikoagulans
• anti-SSA / SSB
hæmolyse, penier i blodbilledet,ændring i C3 / C4 og anti-DNA
SLE OG GRAVIDITET
ALTID
• Us. for klinisk og biokemisk sygdomsaktivitet
Ro i >1år før graviditet
• Hyppig kontrol reumatologisk / obstetrisk
Klinisk, 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, Århus Universitetshospital
SYSTEMISK LUPUS ERYTHEMATOSUS OGANDRE BINDEVÆVSLIDELSER
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