LUPUS ERITEMATOSUS

SISTEMIK
Dr. SUHAEMI, SpPD, FINASIM

PENDAHULUAN
Lupus Eritematosus Sistemik/LES
merupakan penyakit sistemik evolutif yg
mengenai satu atau beberapa organ
tubuh, ditandai oleh inflamasi luas pada
pembuluh darah dan jaringan ikat, bersifat
episodik yang diselingi oleh periode remisi.
Manifestasi klinis LES sangat bervariasi
dgn perjalanan penyakit yg sulit diduga,
tidak dapat diobati, dan sering berakhir
dengan kematian
2

SLE
Autoimmune disease that affects
multisystems
1.5 million cases of lupus
Prevalence of 17 to 48 per 100,000
population
Women > Men - 9:1 ratio
90% cases are women
African Americans > Whites
Onset usually between ages of 15 and 45
years, but
Can occur in childhood or later in life
3

 Karena gambaran klinisnya

bervariasi dan penampilan awalnya
tidak selalu menunjukkan
keterlibatan multi organ, maka sering
kali gejala awal sudah timbul lama,
bahkan bertahun tahun sebelum
didiagnosis SLE ditegakkan.
Kadang pada waktu SLE ditegakkan,
kelainan ginjal sudah ditemukan
4

INTRODUCTION

Systemic lupus erythematosus (SLE) is a

chronic autoimmune disease that can be fatal;
however, with recent medical advances, fatalities
are becoming increasingly rare.
The immune system attacks the bodys cells and
tissue, resulting in inflammation and tissue damage.
SLE can affect any part of the body, but most often
harms the heart, joints, skin, lungs, blood vessels,
liver, kidneys, and nervous system.
Lupus can occur at any age, and is most common in
women, particularly of non-European descent.

ETIOLOGI

1.
2.
3.
4.

Faktor
Faktor
Faktor
Faktor

GENETIK
ENDOKRIN
OBAT
INFEKSI

Etiophathogenesis = Cellular Level

T-Cell dysfunction
B-Cell activation
Abnormal Cytokine production
Bottom line:(the above factorsand other immune
dysregulation culminates in an) abnormal abundance
ofautoantibodies and reduced reaction to pathogens

T-Cell Dysfunction

Decreased Th1
activity--> normally
regulate other Tcells
o Decreased IL-2,
TNF-alpha, INFgamma
Increased Th2
activity--> normally
regulate B cell
growth
o IL-4,5,6,10

antigen binds
here

B-Cell Activation

Abnormal Cytokine Production

Increased Th2-->
o Increased IL-10--l IL-1,2
(spontaneous in ppl w/
SLE)
o IL-10 --> Th2 cytokines
that activate B cells and
deactivate
macrophages... viscious
cycle...

10

PATOFISIOLOGI
LES timbul sebagai ekspresi klinis suatu mekanisme
sekuensial, yang awalnya merupakan berbagai faktor
etiologi yang masih belum diketahui dengan jelas.
Secara ringkas LES berawal dari ketidak mampuan
sistem imun tubuh untuk mengebnal struktur antigen
diri sehingga terjadi mekanisme autoimun.
Autoantibodi yg terbentuk akan berikatan dgn
autoantigen membentuk kompleks imun yang
mengendap berupa depot dalam jaringan.
Akibatnya akan terjadi aktivasi komplemen sehingga
terjadi reaksi inflamasi yang menimbulkan lesi
ditempat tersebut.
11

Systemic Lupus
Erythematosus:
An Autoimmune Story
12

This time...

House is
wrong...
13

Systemic Lupus Erythematosus

A chronic inflammatory systemic
autoimmune disease of unknown
etiology characterized by polyclonal
B-cell activation and abnormal
autoantibodies

14

MANIFESTASI KLINIS
Gejala yang timbul merupakan manifestasi aktivitas
autoantibodi dan /atau depot kompleks imun dgn
vaskulitis.
Semua organ tubuh dapat terserang pada suatu saat,
atau pada tahap evolusi penyakit yang berbeda.
Pada awal perjalanan penyakit, gejala klinis yang muncul
sangat terbatas hingga diagnosis sulit ditegakkan.
Pada perjalanan penyakit selanjutnya gejala klinis
tersebut akan lebih kerap ditemukan.
Bila gejala tsb muncul berulang atau disertai gejala lain
sehingga menjadi lengkap, maka diagnosis dapat lebih
mudah ditegakkan

15

Gambaran klinis LES

Limphadenopati
Limphadenopati
12-50%
12-50%
SSP
SSP
20%
20%
Hepotomepali/
Hepotomepali/
Splenomegali
Splenomegali
20%
20%
Sal cerna
18%
18%

Kelelahan
Kelelahan
90%
90%
Panas
Panas lama
lama
80-82%
80-82%
BB
BB turun
60%
60%
Artritis/Artralgia
Artritis/Artralgia
90%
90%
Kulit
Kulit
50-58%
50-58%

LES

Paru
Paru
38%
38%
Hematologi
Hematologi
50%
50%

Jantung
Jantung
48%

Vaskulitis
Vaskulitis

Ginjal
Ginjal
50%

16

SYMPTOMS
SYMPTOMS

PERCENTAGE (%)

Achy joints / arthralgia

95

Fever of more than 100 degrees F / 38 degrees C

90

Arthritis / swollen joints

90

Prolonged or extreme fatigue

81

Skin Rashes

74

Anemia

71

Kidney Involvement

50

Pain in the chest on deep breathing / pleurisy

45

Butterfly-shaped rash across the cheeks and nose

42

Sun or light sensitivity / photosensitivity

30

Hair loss

27

Abnormal blood clotting problems

20

Fingers turning white and/or blue in the cold

17

Mouth or nose ulcers

17

12

Systemic Lupus Erythematosus

butterfly rash

Skin rashes
Finger turns blue
18

Immunogenetics
Increased Risk for SLE in:
HLA-DR2 (anti-DNA Abs)
HLA-DR3 (anti-Ro Abs)
Null alleles at C2 and C4 loci
SLE may be transmitted in an
autosomal dominant pattern (family
studies)

19

Not MHC Related

SLE Genetic C1q deficiency (rare but highest

Susceptibility risk)
Chromosome 1 region 1q41-43
MHC Related

HLA-DR1, 2, 3, 4
Alleles of HLA-DRB1, IRF5,
and STAT4
C2 - C4 deficiency
TNF- polymorphisms

(PARP), region 1q23 (FcRIIA,

FcRIIIA)
IL-10, IL-6 and MBL
polymorphisms
Chromosome 8.p23.1: reduced
expression of BLK and increased
expression of C8orf13 (B cell
tyrosine kinase), chromosome
16p11.22: integrin genes IGAMITGAX
B cell gene BANK1
X chromosome-linked gene IRAK1

20

DIAGNOSIS
Criterion

Definition

Malar Rash Rash over the cheeks

Discoid Rash Red raised patches
Photosensitivit Reaction to sunlight, resulting in the
y development of or increase in skin rash
Oral Ulcers Ulcers in the nose or mouth, usually
painless
Arthritis Nonerosive arthritis involving two or more
peripheral joints (arthritis in which the
bones around the joints do not become
destroyed)
Serositis Pleuritis or pericarditis (inflammation of
the lining of the lung or heart)
Renal Excessive protein in the urine (greater
Disorder than 0.5 gm/day or 3+ on
21 test sticks)
and/or cellular casts (abnormal elements

DIAGNOSIS
Criterion

Definition

Neurologic Seizures (convulsions) and/or psychosis

Disorder in the absence of drugs or metabolic
disturbances which are known to cause
such effects
Hematologic Hemolytic anemia , leukopenia ,
Disorder lymphopenia or thrombocytopenia. The
leukopenia and lymphopenia must be
detected on two or more occasions. The
thrombocytopenia must be detected in
the absence of drugs known to induce it.
Antinuclear Positive test for antinuclear antibodies
Antibody (ANA) in the absence of drugs known to
induce it.
Immunologic Positive anti-double stranded anti-DNA
Disorder test, positive anti-Sm test, positive
Adapted from: Tan, E.M., et. al. The 1982 Revised Criteria for the Classification
of SLE. Arth Rheum 25:
22
antiphospholipid antibody
such as
1271-1277.

1982 ACR (Revised 1997) SLE Classification

Criteria
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

Malar (butterfly) rash

Discoid lesions
Photosensitivity
Oral ulcers
Non-deforming arthritis (non-erosive for the most part)
Serositis: pleuropericarditis, aseptic peritonitis
Renal: persistent proteinuria 0.5 g/d or 3+ or cellular casts
Neurologic disorders: seizures, psychosis
Heme: hemolytic anemia; leukopenia, thrombocytopenia
Immune: anti-DNA, or anti-Sm, or APS (ACA IgG, IgM), or lupus
anticoagulant (standard) or false + RPR
11. Positive FANA (fluorescent antinuclear antibody)
Definite SLE = 4 or more positive criteria
23

Lupus Diagnostic Criteria (need 4)

1. Malar Rash: Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

2. Discoid rash: Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic
scarring may occur in older lesions

3. Photosensitivity: Skin rash as a result of unusual reaction to sunlight, by patient history or physician
observation

4. Oral ulcers: Oral or nasopharyngeal ulceration, usually painless, observed by physician

From http://www.rheumatology.org/publications/classification/SLE/1997UpdateOf1982RevisedCriteriaClassificationSLE.asp?aud=pat

24

Gambar Rash berbentuk KUPU KUPUseperti

kupu-kupu pada penderita SLE

25

26

27

SLE photosensitiv
erythema

28

Malar
rash

29

SLE discoid brelvltozs

30

31

Arthritis (with swelling)

32

33
Joint involvement in lupus mimics rheumatoid arthritis
(RA) but milder

SLE arthritis

Korriglhat deformits
Jaccoud arthropathia:
szalaglazasg,
hypermobilits
34

Arthritis (Jaccouds)

35

Photosensit
ivity

36

 Malar rash: This is

a "butterflyshaped" red rash
over the cheeks
below the eyes
and across the
bridge of the nose.
It may be a flat or
a raised rash.
The rashes are
made worse by
sun exposure.

37

SLE-Clinical and Laboratory Features

Musculoskeletal 90%
Skin 80%
Renal 50%
CNS 15%
Severe thrombocytopenia
Positive ANA
95+%

5-10%

Also, cardiopulmonary involvement, thrombotic

tendency (APS), and premature or
accelerated atherosclerosis!

38

SLE Pathogenetic Mechanisms

Immune complex-mediated damage: glomerulonephritis
Direct autoantibody-induced damage: thrombocytopenia
and hemolytic anemia
Antiphospholipid antibody-induced thrombosis
Complement-mediated inflammation: CNS lupus (C3a),
hypoxemia, and also anti-phospholipid mediated fetal
loss
Either failure of or abnormal response to normal
39
apoptosis

Immune-complex Injury in
SLE

DNA + Anti-DNA = DNA - Anti-DNA

complex
C3

C4
Tissue Injury

SLE:

Anti-DNA,

C3, C4
40

SLE THE USE OF

POSITIVE ANAS
A positive ANA alone is not enough to diagnose SLE!
Are there other autoantibodies present, e.g., anti-DNA, antiSm, anti-Ro?

What are the patients clinical features that suggest lupus?

Photosensitivity, serositis, thrombocytopenia, proteinuria,
skin rashes?

An ANA should only be ordered if the clinical picture

warrants
it!

About 6-10% of people in the general

41
population are ANA (+)

SLE Cardiac Disease

Pericarditis
Inflammatory fluid
Rarely tamponade
Myocarditis
Coronary vasculitis Rare
Libmann-Sachs endocarditis
Premature or accelerated atherosclerotic
disease
42

Causes of Cardiovascular Complications in

Lupus

Procoagulant State
(multifactorial, APS)

Strokes

Premature or Accelerated
Atherosclerosis

PVD

MIs

43

CV System
Pericarditis 6-45% of patients: low likelihood of tamponade or constrictive type.
<10% with myocarditis
Libman-Sacks endocarditis
1-4 mm vegetations of accumulations of immune complexes and mononuclear cells on mitral,
tricuspid or aortic valves
Risk of thromboembolism or secondary infective endocarditis (abx prophy)

Aortic insufficiency is the most common valvular abnormality.

Heart disease
Contributes to bimodal pattern of mortality from lupus
A study from U of Pittsburgh comparing rates of MI to that of Framingham Offspring Study data
showed that risk of MI was 50x higher in woman with lupus ages 35-44 and 2.5-4x higher in older
age groups
Autopsy data shows CAD in 40% of SLE patients as opposed to only 2% of age matched controls.
Atherosclerotic plaque burden (via carotid intima media thickness measurements and by coronary
calcium scores) is higher in patients with SLE than in controls
Lupus dyslipoproteinemia is low HDL, high TG, normal or only slightly elevated LDL, increased
lipoprotein(a): this appears to correlate with disease activity
Means of prevention focus on risk factor management and inflammation control, but no clear
guidelines are available as of yet.

44

SLE Heme Manifestations

Autoimmune hemolytic anemia (AHA)
Autoimmune thrombocytopenia, ITP-like
Leukopenia
Pancytopenia
Lymphopenia
Anti-phospholipid antibodies False
positive
RPRs (neg FTA)
Lymphadenopathy
Rarely, aplastic anemia (from anti-stem
cell antibodies)
45

CNS Lupus
Seizures - Epilepsy
Strokes with hemiparesis
Coma (lupus cerebritis)
Cranial nerve and peripheral neuropathies
Brain stem/cord lesions
Aseptic meningitis
Transverse myelitis
Psychiatric: memory loss, cognitive
changes
Myasthenia gravis, multiple-sclerosis like

46

Lungs and Pleura

Over 30% will have pleuritis or an
effusion over the course of their
disease
Fluid is exudative, normal glucose, high
protein, WBC <10,000 (neutrophilic or
lymphocytic), decreased complement

Can have pneumonitis, pulmonary

hemorrhage (rare but often fatal), PE,
pulmonary HTN
Pulmonary HTN more likely to be
47
associated with Raynauds

Anti-Phospholipid Antibody Syndrome (APS)

Clinical and Laboratory Features
Recurrent arterial and/or venous thrombosis (thrombophilia)
Recurrent fetal loss (usually late miscarriages)
Thrombocytopenia, autoimmune hemolytic anemia (AHA)
Livedo reticularis
But also: heart valve vegetations, chorea, transverse
myelitis, multiple sclerosis-like syndrome, cognitive
dysfunction, AVN
Labs: positive antiphospholipid (APL) Abs, and/or (+) lupus
anticoagulant (LAC), and/or (+) anti-2-glycoprotein 1 (anti2GPI) antibodies

There is no consensus yet as to what clinical and lab features

should be included or excluded in the definition of APS!
48

SLE: Therapeutic Approaches

NSAIDS: but be careful with ibuprofen-other NSAIDS and aseptic meningitis
Corticosteroids, including IV pulse Rx
Hydroxychloroquine (Plaquenil): controls and prevents SLE, anticoagulant,

cardioprotective
Cytotoxics: cyclophosphamide (Cytoxan), MTX, mycophenolate mophetil
(CellCept), azathioprine (Imuran)
IVIG: short-lived correction of thrombocytopenia*
Plasmapheresis: not well documented. Used for CAPS
Experimental: LJP394 (B cell tolerogen for anti-DNA Abs), CTLA4Ig
(abatacept), anti-C5 (? efficacy), anti-T and B cell targets (CD40-CD40L,
rituximab (Rituxan), anti-BLYS Rx (lymphostat-B, belimumab), MEDI545, an anti-IFN monoclonal antibody (MedImmune, Inc.), kinase
inhibitors, prolactin inhibitors, etc
Experimental combination Rx: Cytoxan + CTLA4Ig, other combos, etc
Bone marrow approaches: ablative therapy and stem cell transplant
*Gonzalez EB, Truslow W, Miller SB. Intravenous immunoglobulin (IVIG) offers short-term limited benefit in lupus
thrombocytopenia. Arthritis & Rheumatism 36: S228, 1993

49

The FDA approved Drugs for Lupus

Corticosteriods - including prednisone, prednisolone,
methylprednisolone, and hydrocortisone

Antimalarial - (e.g. hydroxychloroquine) - used as an antiinflammatory drug

Anti inflammatory - e.g. Aspirin, Acetaminophen, NSAID

(Ibuprofen) - used to treat pain and swelling associated
with inflammation

50

Corticosteriods

-Also known as glucocortocoids, cortisone, or just steroids

- Synthetic drugs designed to mimic the actions of the body's

naturally occuring hormones specifically cortisol

- Cortisol helps regulate blood pressure and the immune system,

and it is the bodys most potent anti-inflammatory hormone

- Corticosteroids help to reduce swelling, tenderness and pain

associated with inflamation

- Works by lessening immune system response

-Prednisone is the most popular corticosteroiid prescribed to SLE

patients

- Side effect include changes in appearance and mood and increased

risk of osteoporosis
51

Anti Malarial Drugs

Used in conjunction with steroids

Help to reduce inflammation and thrombosis

Lessen the symptoms of SLE by:

- reducing the production of auto antibodies
- protecting against UV radiation
- improve skin lesions

Two most common types of Antimalarials used for treating SLE:

-Hydrochloroquine
-Chloroquine

Side Effects are usually mild such as upset stomach

52

Mechanism for Hydroxychloroquine

Hydroxychloroquine reduces inflammation by blocking the
activation of the Toll-like Receptors on Plasmacytoid
Dendritic Cells.

Toll-like Receptors are responsible for the maturation of

dendritic cells by promoting the production of Interferon.
Inhibiting the dendritic cells via decreased TLR signaling
helps to reduce the inflammatory cells

53

Anti Inflammatory
- Used to treat inflammation and pain

- Most common treatment form lupus patients (the only

medication needed to control the disease for many)

- Inexpensive and available OTC

- Minimal side effects

- Can cause GI tract irritation

- Examples include Aspirin, Acetaminophen, and Nonsteroidal anti inflammatory drugs (NSAID) such as
Ibuprofen
54

Immunosuppressives
-Used to control inflammation and an overactive immune system

-Usually used after treatment with corticoidsteroids is ineffective

- Common immunosuppressives used in treating lupus include:

-Cylcophosphoamide
-Shown to improve kidney and lung disease
-Methotrexate
-One of the best known treatments for rheumatoid arthritis
-Azathioprine
-Helps to lower steroid dosage and improve liver and
kidney disease
-Obviously there are serious side effects such as reduced ability
to fight off infection
55

Monoclonal Antibody Therapy

Monoclonal antibodies target specific molecules known to
contribute to SLE
Examples:
-Anti-Interleukin 6
-Targets IL-6 which is known to cause inflammation
-Anti TNF therapy
- Helps treat arthritis which occurs in lupus *find mech
- However it has also been shown to cause drug-induced
lupus *find mech
-Anti-Interleukin 10
- Targets IL-10 which is important for activation of B-cells
56

Current Research

Because SLE is a complex

disease and involves many
factors, research for SLE has
taken on many direction

57

Autoantibodies
ANA: against targets in the nucleus, but only those which have intrinsic
immunological activity: i.e.. They can activate the innate immune system
via Toll-like receptors
Anti DS-DNA in particular recognizes DNA in complex with nucleosome
components (histone-derived peptides in particular)
Can correlate with nephritis
Immune complexes with anti-DNA ab/DNA can increase the expression of IFN- via plamacytoid
dendritic cells

Anti-Sm: detects ribonucleoproteins involved in processing of mRNA; doesnt

track with disease, specific for lupus
SSA/Ro and SSB/La: detect ribonucleoproteins, associated with SICCA
syndrome and photosensitivity
Anti NMDA to subunits NR2a and NR2b may be associated with
neuropsychiatric symptoms
Antiphospholipid antibodies are ab against phospholipid-binding proteins
or phospholipids that are prothrombogenic. Ex: lupus anticoagulant,
anticardiolipin, and anti beta2-glycoprotein I
58

Mechanism Summary
Defects in clearance of apoptotic cells
can lead to exposure of intracellular
immunogenic components which can
be taken up by DC and presented to
autoreactive B cells (made this way
during random somatic hypermutation).
In the right genetic environment, these
B cells may become activated to
produce autoantibodies.
Polymorphisms or mutations in genes
in numerous steps of B-cell regulation or
IFN-responsiveness can predispose to SLE (FcRIIa, IRF5,
STAT4, BLK)
59

Why are autoantibodies so

bad?
Renal disease
IgA, IgM, IgG and complement deposition in the mesangium and
subendothelial and subepithelial of the GBM that results in
complement activation and recruitment of inflammatory cells
that result in tissue destruction.
Cross reactivity of anti-DS DNA antibodies with -actinin may
also result in a direct focusing of complement activation

Skin disease
Inflammation and breakdown of the dermal-epidermal junction.
UV exposure can worsen because it promotes apoptosis in the
skin resulting in autoantibody binding and tissue injury via
complement activation or inflammatory cell activation
Anti-Ro antibodies are associated with skin flares

60

Why are autoantibodies so

bad?
In the CNS, vasculitis is rare
Anti-NMDA receptor antibodies may contribute to
cerebral lupus phenotypes
See more microinfarcts and degeneration or
proliferative changes in blood vessels, thought to be
related to IC deposition

Antiphospholipid abs may contribute to

thrombotic events anywhere in the body
aPLs bind to endothelial cells, monocytes, neutrophils
and platelets causing inflammation and procoagulant
release
This process is dependent on complement activation
61

Renal:

A) Proteinuria (>500 mg/24hrs)

B) Cellular casts

62

 The anti-nuclear antibody test (ANA) to determine if

autoantibodies to cell nuclei are present in the blood.
The anti-DNA antibody test to determine if there are
antibodies to the genetic material in the cell .
The anti-Sm antibody test to determine if there are antibodies
to Sm, which is a ribonucleoprotein found in the cell nucleus .
Tests to examine the total level of serum (blood) complement
(a group of proteins which can be consumed in immune
reactions), and specific levels of complement proteins C3 and
C4.

Blood tests in the diagnosis of SLE

63

Anti-nuclear antibodies
(ANA)
Rim

Nucleolar

Diffuse

Speckled
64

LE Cell
The LE cell is a
neutrophil that has
engulfed the antibodycoated nucleus of
another neutrophil.
LE cells may appear in
rosettes where there
are several neutrophils
vying for an individual
complement covered
protein.

65

Renal (Kidney) Manifestations

50-70% of all lupus

patients experience
renal developments.
Most Dangerous:
Glomerulonephritis
where at least 50% of
the glomeruli have
cellular proliferation
Glomeruli capillary
beds in the kidney
that filter the blood.

Renal Failure because

of Glomerulonephritis
is the leading cause of
death among lupus
patients.

Normal

66

Glomerulonephritis

Summary
Lupus = Autoimmunity
Systemic and affects connective tissue

Caused by malfunctions of:

T-cells
B-cells
Complement System
Signal Transduction

Can be lethal or not

Unique to each individual
67

68