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Imunopatogenesis dan Penatalaksanaan

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Steps in Pathogenesis of SLE
1. Genetic factors/immune dysfunction
2. Environmental/endogenous trigger
3. Inflammation
4. Development of Autoimmune
5. Accelerated of Antigen
6. Tissue Damage
7. Clinical Disease
Potential model for autoimmunity
development
Response to
Healthy,
Environmental
No AutoAbs
Exposure

Primordial
Autoimmne
Genetically Response
Susceptible
Individual

Healthy
Cross
Autoimmunity Reaction (s)

Organ/ Epitope
Spreading to
Tissue Pathogenic
Damage AutoAbs

Harley JB, Harley ITW, Guthridge JM and James JA. The curiously suspicious: a role for Epstein-Barr virus in Lupus
Looking for environmental factors
at the right time

Multiple environmental
exposures

Genetically Disease
susceptible
individual
Clinical disease
Early life infectious exposure may Threshold
programme a plastic immune system

Edwards CJ and Cooper C. Early environmental exposure and the development of lupus. Lupus 2006 ; 15 :
814-819.
Autoimmune pathogenesis paradigm. APC, antigen-
presenting cell; MHC, major histocompability complex
EVOLVING
AUTOIMMUNE AUTOIMMUNITY
SPECTRUM OF
*DIATHESIS* WITHOUT DISEASE
AUTOIMMUNE
DISEASE
Genetic Risk Factors :
Autoreactive
- MHC
Lymphocytes
- Other

Tolerance Breakdown Autoimmune Disease


Trigger
- APC stimulation Susceptible End - Lupus
Factor
- Molecular mimicry Organs - Sjrgrens
(Infective
- Cryptic antigen recognition (Skin, joint, - Scleroderma
Ischaemic
- Immune / apoptotic others) - Rheumatoid
latrogenic)
- dysregulation - Polymyositis

Autoreactive Autoreactive
Lymphocytes Lymphocytes

Modulating and Perpetuating Factors acting at multiple levels: e.g. UV radiation, hormones, drugs,
Reeves G.E.M. Update on the immunology, diagnosis and management of systemic lupus erythematosus. Internal Medicine Journal 2004;34:338-347
Therapy

Induction
Maintenance

Prednison Cyclo MPA

Prednison AZT MPA

MPA = Mycophenolic acid


Autoantibodies Precede
Disease by Years

Some AutoAb
before Dx: 80%

ANA: 3 yrs Anti-DNA: 2 yrs Anti-Sm: 1 yr


Anti-Ro/La Anti-PL Anti-RNP

Arbuckle et al NEJM 2003


Gambaran klinis SLE
Limphadenopati Kelelahan
SSP 12-50% 90%
20% Panas lama
Hepotomepali/ 80-82%
Splenomegali BB turun
20% 60%

Sal cerna
SLE Artritis/Artralgia
90%
18%
Kulit
Paru 50-58%
38% Ginjal
Hematologi 50%
Jantung Vaskulitis
50%
48%
Trigger/Eksaserbation
Procainamid
Drugs: Hidralazin UV radiance
Metildopa
CPZ
(320-400 nm)

Abortion Infection
SLE

Pregnancy Surgery
Erythematous Rash
Small Vessel
Vasculitis
Discoid Lupus
Discoid Lupus
Photosensitivity
Oral Ulcers
The 1997 Revised Criteria for
the Classification of SLE
(MD SOAP BRAIN)
1. Malar rash
2. Discoid rash
3. Serositis
a. Pericarditis
b. Pleuritis
4. Oral ulcer
5. Arthritis
6. Photosensitivity
The 1997 Revised Criteria for
the Classification of SLE
7. Blood / Hematologic disorder
a. Hemolytic anemia OR
b. Leukopenia (< 4000/ ml) OR
c. Lymphopenia (<1500/ ml) OR
d. Thrombocytopenia (<100.000)

8. Renal disorder
a. Persistent Proteinuria (>0.5 gr/d)
b. Cellular cast or any tipe

9. ANA
10. Immunologic disorder
a. Anti ds DNA OR
b. Anti Sm OR
c. Antiphospholipid ab
11. Neurological disorder
CURRENT TREATMENT
OF SYSTEMIC LUPUS
ERYTHEMATOSUS
Principles of therapy

1. Remission
2. Organ/ Renal
Survival
3. Patient Survival
4. Complication/
Comorbid
5. Quality of Life
(Cost)
Introduction
Anti-inflammatory drugs
Cortocosteroids
Anti-malarials
Cytotoxic, or immunosuppressive, drugd
Investigational (research) drugs:
Hormone modifications
More selective immunosuppressive
Biologic agents
Klippel John H, et.all. Medications. Lupus Fondation of Amerika
Anti Inflammatory Drugs
Anti-inflammatory medication are the most
commonly used drugs for lupus treatment,
particularly for symptoms such as:
o Fever
o Arthritis, or
o Pleurisy
Improvement in symptoms is generally noted
within several days of beginning treatment
In the majority of people with lupus, anti-
inflammatory drugs are the only medication
that is ever required to control their lupus
Types of anti malarials

Hydroxychloroquine (Plaquenil)
Chloroquine (aralen)
Quinacrine (atabrine)

Gluck O, Anti-Malarials in The Treatment of Lupus, Lupus Foundation of America. 2001


Anti - malarials are:
Muscle and joint pain
Inflammation of the lining of
the heart (pericarditis)
Inflammation of the lining of
the lung (pleuritis)
Other symptoms of lupus such
as fatigue and fever

Gluck O, Anti-Malarials in The Treatment of Lupus, Lupus Foundation of America. 2001


Anti malarials
Other side effects can include:
Hair loss
Dry skin
Loss of appetite
Abdominal bloating
Upset stomach
Stomach cramps
Nausea, vomiting and
diarrhea

Gluck O, Anti-Malarials in The Treatment of Lupus, Lupus Foundation of America. 2001


Corticosteroid
Corticosteroids are extremely effective anti-
inflammatory agents and can be very helpful in
treating
Treatment with steroids should always be kept
at the lowest possible effective dose and should
never be stopped suddenly
The hope is that effective alternative therapies
will soon be developed which will not be as toxic
as steroids
The history of most therapies shows, however,
that those which are extremely effective often are
associated with side effects. This is certainly the
case with steroids
Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
Important Anti-Inflammatory and
Immunosuppresive Effects of Glucocorticoids
Anti-inflammatory Effects
1. Inhibition of blood vessel dilatation and
permeability
2. Inhibition of neutrophil and monocyte
migration to periphery
3. Inhibition of synthesis of inflammatory
mediators such as eicosanoids by
downregulating phospholipase A2 and COX-2
4. Downregulation of destructive enzymes
5. Alteration of cytokine balance in favor of
anti-inflammatory cytokines whereas
proinflammatory cytokines are suppressed

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition,
Lippincot Williams & Wilkins 2007
Which Medication are Right for My Lupus

1. The type and severity of lupus


symptoms
2. The persons response to treatment
3. Risks of drug side effects

Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
Immunosuppressive effects
1. Lymphopenia
2. Inhibition of signal transduction events critical
for T-cell activation
3. Inhibition of IL2 synthesis and signaling
4. Downregulation of cell surface molecules
important for full T-cell activation and function
5. Inhibition of antigen-presenting cell function.
Depletion of plasmacytoid dendritic cells and
production of interferon-alpha
6. Deviation of immune responses towards a Th2-
type cytokine formation
7. Induction of T-cell apoptosis
Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
Williams & Wilkins 2007
Prednisone
It may be givens as often as four times each day,
as frequently as once every other day, or at any
frequency

Dose Miligrams
Low Less than 10 mg daily
Moderate 11 to 40 mg daily
High 41 to 100 mg daily

Occasionally, very large doses of steroids may be


given for a short period of time. This treatment,
referred to as pulse steroids
Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
Prednisone
Prednisone is an extremely effective drug may be
necessary to control active lupus
Those individuals with organ-threatening diseases
(i.e., heart, lung, kidney, liver) usually need
steroids in order to prevent loss of function in the
organ.
People who tolerate steroids poorly or do not
respond optimally often benefit from the addition
of steroid-sparing of immune suppressive drugs

Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
1 gr/IV 3 hari berturut-turut

Oliguria akut (RF)


Lupus serebral dengan koma
Krisis lupus (acute serious SLE)
High-Dose Corticosteroid
Therapy
1. Severe lupus nephritis
2. CNS lupus with severe
manifestations
3. Autoimmune thrombocytopenia
(<30000/mm3)
4. Autoimunehemolytic anemia
5. Acute pneumonitis
Side Effect From Steroids Use
1. Changes in appearance
Acne
Development of a round or moon-shaped face
Weight gain due to increased appetite
A redistribution of fat, leading to a swollen face
and abdomen, but thin arms and legs
2. Psychologyical problems
Iritability
Agitation
Euphoria or depression
Insomnia
Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
Side Effect From Steroids Use

4. An increase in susceptibility to infection may


occur with high doses of steroids
5. Prednisone may aggravate:
Diabetes
Glaucoma
High blood pressure
6. Prednisone often increases levels of:
Cholesterol
Triglycerides
7. Steroids also can suppress growth in children
Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
Side Effect From Long-term
Use of Steroids

Avascular necrosis of bone


Osteoporosis or thinning of the bones
Cataracts
Premature arteriosclerosis

Katz R.S. Steroids In The Treatment of Lupus. Lupus Foundation of America, 2001
Retinal damage that is caused
by Plaquenil is sometimes
reversible if it is detected early.
However, damage due to the
use of chloroquine (Aralen) is
irreversible

Gluck O, Anti-Malarials in The Treatment of Lupus, Lupus Foundation of America. 2001


When Should My Doctor Prescribe
Immunosuppressive Drugs?
These drugs are generally reserved for
people with more serious manifestations of
lupus, such as lupus nephritis or neurologic
disease, in whom treatment with
corticosteroids has failed

It is very important that cytotoxic drugs


only be given by physicians who are
experienced with the use of these
medications
Katz. R.S. Immune Suppressants and Related Drugs Used for Lupus
Cytotoxic (Immunosuppressive drugs)

Azathioprine (brand name: Imuran)


Cyclophosphamide (brand name:
Cytoxan)
Methotrexate (brand name: Rheumatrex)
Cyclosporin (brand name: Sandimmune,
Neoral)

Katz. R.S. Immune Suppressants and Related Drugs Used for Lupus
IMURAN
Prolong life
Preserve kidney function
Reduce disease symptoms
Reduce damage to vital organs, such
as the kidney and lungs
Sometimes even serve to put the
disease info remission

Katz. R.S. Immune Suppressants and Related Drugs Used for Lupus
Cytoxan (Cyclophosphamide)
An increasing risk of developing malignancies, including
leukimia and bladder cancer, with long-term Cytoxan
use
Temporary or permanent sterility in both women and
men
Leading to damage of a developing fetus if a woman gets
pregnant while being treated with the drug
Bleeding from the bladder-this usually can be prevented
by drinking large amounts of water
Causing a prediposition to develop shingles
Hair loss
Like Imuran, causing a prediposition to develop unusual
infections, particularly when given in combination with
high doses of steroids
Katz. R.S. Immune Suppressants and Related Drugs Used for Lupus
Immunosuppressive Side Effects
The drugs have a major effect on cells produced by the
bone marrow, including:
o White blood cells
o Red blood cells
o Platelets
Thus, people treated with cytotoxic drugs must have
regular complete blood counts (CBCs) to make certain
that levels of these cells do not become too low
In addition, cytotoxic drugs reduce a persons ability to
fight off infections
Those receiving cytotoxic drugs are more likely to
contract viral infections such as shingles (herpes zoster)
Katz. R.S. Immune Suppressants and Related Drugs Used for Lupus
Possible Risk Cytotoxic Drugs
The immune system may be suppressed too
much, which causes an increased susceptibility
to infection, particularly shingles (a painful,
blistering skin condition) and pneumonia
The bone marrow can be suppressed as well,
which results in reduction in red blood cells,
white blood cells, or clot-forming platelets
Suppression of hair cell growth may lead to
overall lost of hair
The cytotoxic effects on gonadal cells can lead
sterility
New Treatment in SLE
(cell surface molecules)
Treatment Mode of action Status
Anti CD20 (Rituximab) B cell depletion Phase II/III trial in
patients SLE is
ongoing
Anti CD22 Modulation of B cell Safe in phase I. Phase
(Epratuzumab) signaling II it is on going

Anti CD40L Blocks T-B cell cross


talk

CTLA4 Ig Block co-stimulation Effective in mice


(abcatacept) of T cells
Usual Regimens of Systemic Glucocorticoid Therapy in SLE*
GC Regimen Representative Indications
Pulse GC (PGC): 250 mg Life or organ-threatening complications
PDNeq /d x 1-5 days. Typically 0.5- (i.e.,RPGN, myelopathy, severe acute
1 g MP/d IV x 1-3 d, monthly as confusional state, alveolar hemorrhage,
indicated. Usually with oral GC (30- vasculitis, optic neuritis)**
60 mg PDNeq/d) HDGC-refactory Disease
DPGN or severe FPGN

Very High Dose GC (VHDGC): > 100 Life or organ-threatening complications (as
mg PD Neq/d, IV/PO (Start with for PGC)**
divided doses)
DPGN or severe FPGN (for less than 6-8
High Dose GC (HDGC): >30 mg and weeks)
100 mg PDNeq/d, IV/PO Thrombocytopenia/hemolytic anemia
Acute lupus pneumonitis; Lupus crisis

Moderate Dose GC (MDGC): Moderate SLE flares (i.e., myositis, severe


> 7.5 mg and 30 mg PDNeq/d, IV pleurisy, opthalmoplegia [except optic
or PO neuritis], thrombocytopenia)
With PGC, or CY/AZA for severe disease

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
Williams & Wilkins 2007
Usual Regimens of Systemic Glucocorticoid
Therapy in SLE*
GC Regimen Representative Indications
Low Dose GC (MDGC): Arthritis, mild constitutional
7.5 mg PDNeq/d, PO symptoms (unresponsive to
analgesics/NSAID/AM).
Generalized LN
Maintenance therapy
Alternate Day GC (ADGC) Membranous nephritis with
nephrotic syndrome (120 mg
PDNeq)
During tapering GC dose
Maintenance therapy (i.e., 15
mg PDNeq for GN)

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition,
Lippincot Williams & Wilkins 2007
Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy Maintenance Therapy

Proliferative nephritis Low-dose corticosteroids (i.e.


Mild prednisolone 0.125 mg/kg/day)
High-dose corticosteroids (i.e. Consider further gradual
0.5-1 mg/kg/day) tapering at the end of each year
If no remission within 3 months,
of remission
treat as moderately severe
Moderate MMF (2g/day) (or AZA) with If in remission after first 6-
corticoids as above. If no 12 months, MMF may be tapered
remission after first 6 months, to 1.5g/day for 6-12 months
advance to next therapy and then to 1 g/day
Pulse CY alone or in combination Consider further tapering at
with pulse corticosteroids for first the end of each year in
6 months (total 7 pulses) remission, or
In white patients, low-dose IVCY AZA, or
(6 fortnightly pulses at fixed dose Quarterly pulses of CY
of 500 mg each) might also be
considered
Background corticosteroids 0.5
mg/kg/day for 4 weeks, then taper

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Recommended Therapy for Lupus Nephritis

Disease Induction Therapy Maintenance


severity Therapy
Severe Monthly pulses of CY in Quarterly pulses
combination with pulse of CY for at least
corticosteroids for 6-12 1 year beyond
months remission, or
If no response, consider AZA, or
MMF (2-3 g/day) or MMF
rituximab

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic


approaches for lupus nephritis: what therapy and for whom?, Nature publishing group, 2005
Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy Maintenance Therapy
Membranous
nephropathy
Mild High-dose Low-dose
corticosteroids alone corticosteroids
or in combination with alone or with AZA
Moderate- AZA Low-dose
severe Bimonthly pulse CY ( 6 corticosteroids
pulses) alone or in alone or with
combination with MP AZA, or
Ciclosporine A (3-5 AZA
mg/kg/day) alone or
with AZA
High-dose
corticosteroids with
MMF
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Management LUPUS
Chan et all: MMF 2 gr/ day 6 month
Taper : 1 gr / day
Ginzler : MMF 3 gr /day
Contreas : MMF 1,5 2 gr / day
(max 2 gr)
6 month 0,25 05 gr.
(Pisoni Cn, Karim Y, Cuadrado MJ. Lupus
2005, 14, s9 s11.)
Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathioprine
PRD was started at 0,8 mg /Kg BW/day
p.o. and tapered to reach 10 mg / day at
approximately six months and then taper
then maintained
Complete remission :
- Urinary protein exertion < 0,3 gr / 24
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction
therapy. Lupus 2005. 14, s27-s32
Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathioprine
PRD was started at 0,8 mg /Kg BW/day
p.o. and tapered to reach 10 mg / day at
approximately six months and then taper
then maintained
Complete remission :
- Urinary protein exertion < 0,3 gr / 24
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction
therapy. Lupus 2005. 14, s27-s32
Clinical Monitoring2
ESR, CRP
ANA
95% positive screening test for SLE
3 - 5% negative
5 - 25% population positive
Clinical Monitoring4
Anti DNA antibodies
- ~ active SLE
- Monitoring patients response to theraphy
- Associated organ disease activity renal
disease
- Complement levels: C3C4, CH50
Mode of action of
immunosuppressive drugs

Click to
view
Halloran PF. N Engl J Med 2004; 351; 2715-2729 reference
Prognosis in SLE

I. Disease manifestation

II. Disease activity

III. Specific organ damage

IV. Functional status


Management SLE
( NANANG SUKMANA)

SUPPORT

CARE TREATMENT

MONITORING
Thank You
Sinar matahari
Kelelahan

Diet
Cuaca
Penatalaksanaan
Umum

Merokok
Kontrasepsi oral Stres dan
trauma fisik
Pengobatan muskuloskeletal
pada LES

Artritis Terdinitis Myositis Artralga/


myalgia

NSAID + + - (+)
Anti malaria + + - -
Steroid (+) (+) + -
Imunosupresan - - (+) -
Analgesik - - - +
Clinical Monitoring1
Hematologic abnormalities (Cytopenia)
Anemia
Leukopenia
Lymphocytopenia
Thrombocytopenia

Active SLE
Secondary to drug
Sepsis associated with SLE
4 / 11 ARA 3 / 11
WHO LLD

LES

Kerusakan
Organ

Vaskulitis Ginjal Hematologi Jantung Paru SSP


60-100 mg/hari Anemia hemolitik Efusi Metilpred
(Hari-minggu) 1-1,5 mg/kgbb/hari 15-40 mg/hari 2 mg/kg/hari
60-80mg 100-120 mg + drainage 3-5 hari
(4-6 minggu / 8-12 minggu) L.pneumonitis oral pred
Trombositopeni 1-1,5 mg/kg/hari 48-80 mg/hari
1-2 mg/kgbb/hari (4-6 minggu) 5-7 hari
60-80 mg/hari
(4 minggu)
Looking for environmental factors
at the right time

Multiple environmental
exposures

Genetically Disease
susceptible
individual
Clinical disease
Early life infectious exposure may Threshold
programme a plastic immune system

Edwards CJ and Cooper C. Early environmental exposure and the development of lupus. Lupus 2006 ; 15 :
814-819.
Autoimmune pathogenesis paradigm. APC, antigen-
presenting cell; MHC, major histocompability complex
EVOLVING
AUTOIMMUNE AUTOIMMUNITY
SPECTRUM OF
*DIATHESIS* WITHOUT DISEASE
AUTOIMMUNE
DISEASE
Genetic Risk Factors :
Autoreactive
- MHC
Lymphocytes
- Other

Tolerance Breakdown Autoimmune Disease


Trigger
- APC stimulation Susceptible End - Lupus
Factor
- Molecular mimicry Organs - Sjrgrens
(Infective
- Cryptic antigen recognition (Skin, joint, - Scleroderma
Ischaemic
- Immune / apoptotic others) - Rheumatoid
latrogenic)
- dysregulation - Polymyositis

Autoreactive Autoreactive
Lymphocytes Lymphocytes

Modulating and Perpetuating Factors acting at multiple levels: e.g. UV radiation, hormones, drugs,
Reeves G.E.M. Update on the immunology, diagnosis and management of systemic lupus erythematosus. Internal Medicine Journal 2004;34:338-347
Therapy

Induction
Maintenance

Prednison Cyclo MPA

Prednison AZT MPA

MPA = Mycophenolic acid


Potential model for autoimmunity
development
Response to
Healthy,
Environmental
No AutoAbs
Exposure

Primordial
Autoimmne
Genetically Response
Susceptible
Individual

Healthy
Cross
Autoimmunity Reaction (s)

Organ/ Epitope
Spreading to
Tissue Pathogenic
Damage AutoAbs

Harley JB, Harley ITW, Guthridge JM and James JA. The curiously suspicious: a role for Epstein-Barr virus in Lupus
Looking for environmental factors
at the right time

Multiple environmental
exposures

Genetically Disease
susceptible
individual
Clinical disease
Early life infectious exposure may Threshold
programme a plastic immune system

Edwards CJ and Cooper C. Early environmental exposure and the development of lupus. Lupus 2006 ; 15 :
814-819.
Neuropsychiatric syndromes
associated with SLE
Central nervous system Peripheral nervous system

Aseptic meningitis Guillain-Barr syndrome (acute


Cerebrovascular disease inflammatory
Demyelinating syndrome polyradiculoneuropathy)
Headache Autonomic disorder
Movement disorders (chorea) Mononeuropathy (single/multiplex)
Myelopathy Myasthenia gravis
Seizures and Seizure Cranial neuropathy
disorders Plexopathy
Acute confusional state Polyneuropathy
Anxiety disorder
Cognitive dysfunction
Mood disorders
Psychosis
Lau Sing Chak, Atlas of Lupus Erythematosus 2007
Management Principles Other
Immunosupression Used in The Treatment
of SLE Patients
Avoid possible disease triggers
Prevent atherosclerosis
Prevent osteoporosis
Prevent infections
Prevent progression
Prevent clots in patient with antiphospholipid
antibodies (not on warfarin)
Treat fatigue
Use of GC During Stress
Patients on chronic GC therapy should be given
supplemental GC during the stress of surgery or
moderate severe illness
Minor Stress
25 mg of hydrocortisone (or its equivalent) should
be given daily for 1-3 days during minor sheers
Moderate/Severe Stress
50-75 mg hydrocortisone for 1-3 days
Severe Stress
100-150 mg for hydrocortisone
Specific Toxicities
Cyclophosphamide may cause:
Hair loss
Bladder complications
Sterility
Azathioprine may cause:
An allergic type of hepatitis
Pancreatitis
Methotrexate may cause:
Lier damage, including cirrhosis
Serious lung toxicity
Cyclosporine:
Commonly produce hypertension
May lead to kidney damage
Katz. R.S. Immune Suppressants and Related Drugs Used for Lupus
People with lupus often require
other drugs for:

Diuretics for fluid retention


Anti-hypertensive drugs for increased
blood pressure
Anti convulsants for seizure disorders
Antibiotics for infections
Drugs for osteoporosis
Drugs implicated in the development of DILE
Definite Probable Possible Recent case
reports
Hydralazine Sulphasalazine Antibiotics Infliximab
Procainamide Anticonvulsants Non-steroidal Etanercept
anti
inflammatory
agents
Isoniazid Anti-thyroid Antihypertensi Interleukin-2
ves
Methyldopa Statins Lithium Zafirlukast
Quinidine Terbinafine Interferons Clobazam
Minocycline Penicillamine Gold salts Tocainide
Chlorpromazine Fluoroucacil agents Lisinopril
Hydrochlorthiazide Bupropion
Vasoo S. Drug-induced lupus: anm update. Lupus 2006 ; 15 :757-761.
Mode of action of
immunosuppressive drugs

Click to
view
Halloran PF. N Engl J Med 2004; 351; 2715-2729 reference
Global measures of disease
activity
LACC (Lupus Activity Criteria Count)
SLAM (The systemic Lupus Activity Measure)
clinical features
BILAG (The british Isles Lupus Activity Group)
intent to treat approach
SLEDAI (The systemic Lupus Disease Activity Index)
- prognostic studies severity (Toronto 1985) / clinical &
laboratory
ECLAM (European Consensus Lupus Activity
Measurement) ~ SLEDAI
Global measures of damage
SLE

SLICC (The systemic Lupus


International Collaborative Clinics)
damage index
New Treatments for systemic lupus
erythematosus
B-cell anergy
LJP 394: abetimus
B-cell depletion
Anti-CD20: rituximab
Anti-CD22: epratuzumab

Other techniques
Immunoadsorption
AntiC5a
T cell vaccination
chain transfection
Peptide therapies: edratide targeting antiDNA
idiotypes
DCruz P David, Khamashta A Munther, Hughes RV Graham, Systemic lupus erythematosus,
Lancet 2007; 369:587-96
L : Leukopenia, anemia,
thrombocytopenia
U : Urine abnormality as
proteinuria
Imunopatogenesis dan Penatalaksanaan

Nanang Sukmana
Subbagian Alergi - Imunologi Klinik
Bag. Ilmu Penyakit Dalam FKUI / RSCM - Jakarta
Anti-DNA antibodies
dsDNA antibodies are associated with systemic lupus and nephritis,
but not subacute cutaneous lupus or discoid lupus.
Frequency of serological positivity in SLE
Autoantibody % Positive at any Possible clinical association
target stage of disease (see text)
(any assay)
dsDNA 30-70 Nephritis, disease activity
Sm 20-40 Rarely seen outside SLE
RNP 40-60 MCTD/overlap features
Ribosomal P0, 10-15 Sjorgrens/skin invovement/congenital
P1, P2 heart block
Histone 5-10 Neuropsychiatric SLE, disease activity
ACA 30 Drug induced SLE, idiopathic SLE,
disease activity
40-50 Risk of thrombotic complications/fetal
loss/ITP

Egner William. The Use of Laboratory tests in the diagnosis of SLE. J Clin Pathol 2000;53:424-432
Common antinuclear antibody (ANA) HEp-2
patterns and their clinical use in SLE

Pattern Autoantibody association Clinical association

Homogenous dsDNA, ssDNA, SLE, AICAH, and


histories, nucleosomes, many non-
Ku pathological ANAs
Rim/peripheral dsDNA, laminin, nuclear SLE/AICAH
pore
Speckled (coarse) RNP/Sm SLE/MCTD

Speckled (fine) may Ro/La (also cytoplasmic) SLE/SCLE/scleroder


be missed on IIF ma
owing to variable Ro
expression on tissue
Speckled Centromere A,B,C Primary Raynauds,
(centromere) kinetechore proteins scleroderma, SLE
Egner William. The Use of Laboratory tests in the diagnosis of SLE. J Clin Pathol 2000;53:424-432
Mechanism
of Sedimentation Immune Complex
Factors associated with development
of systemic lupus erythematosus
Sunlight
Drugs: > described in association with drug induced
lupus
Epstein-Barr virus
Abnormalities of apoptosis
Abnormal signal transduction: tc II like receptors
Cytokine patterns: interferon signature; decreased
interleukin 2 from T cells
Genes: CRP and serum amyloid P genes, FcyR
receptors, programmed cell death
Occupational exposure: silica, pesticides, mercury

DCruz P David, Khamashta A Munther, Hughes RV Graham, Systemic lupus erythematosus, Lancet 2007;
369:587-96
LES MEDICATION
Anti malaria
Hydrockcycloroquin
Cloroquin

Cortikosteroide
Prednisone
Metilprednosolone

Immunosupresif
Azathioprine
MMF
Cyclophospamide

Plasmapheresis
Usual Regimens of Systemic Glucocorticoid Therapy in SLE*
GC Regimen Representative Indications
Pulse GC (PGC): 250 mg Life or organ-threatening complications
PDNeq /d x 1-5 days. Typically 0.5- (i.e.,RPGN, myelopathy, severe acute
1 g MP/d IV x 1-3 d, monthly as confusional state, alveolar hemorrhage,
indicated. Usually with oral GC (30- vasculitis, optic neuritis)**
60 mg PDNeq/d) HDGC-refactory Disease
DPGN or severe FPGN

Very High Dose GC (VHDGC): > 100 Life or organ-threatening complications (as
mg PD Neq/d, IV/PO (Start with for PGC)**
divided doses)
DPGN or severe FPGN (for less than 6-8
High Dose GC (HDGC): >30 mg and weeks)
100 mg PDNeq/d, IV/PO Thrombocytopenia/hemolytic anemia
Acute lupus pneumonitis; Lupus crisis

Moderate Dose GC (MDGC): Moderate SLE flares (i.e., myositis, severe


> 7.5 mg and 30 mg PDNeq/d, IV pleurisy, opthalmoplegia [except optic
or PO neuritis], thrombocytopenia)
With PGC, or CY/AZA for severe disease

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
Williams & Wilkins 2007
Usual Regimens of Systemic Glucocorticoid
Therapy in SLE*
GC Regimen Representative Indications
Low Dose GC (MDGC): Arthritis, mild constitutional
7.5 mg PDNeq/d, PO symptoms (unresponsive to
analgesics/NSAID/AM).
Generalized LN
Maintenance therapy
Alternate Day GC (ADGC) Membranous nephritis with
nephrotic syndrome (120 mg
PDNeq)
During tapering GC dose
Maintenance therapy (i.e., 15
mg PDNeq for GN)

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition,
Lippincot Williams & Wilkins 2007
Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy Maintenance Therapy

Proliferative nephritis Low-dose corticosteroids (i.e.


Mild prednisolone 0.125 mg/kg/day)
High-dose corticosteroids (i.e. Consider further gradual
0.5-1 mg/kg/day) tapering at the end of each year
If no remission within 3 months,
of remission
treat as moderately severe
Moderate MMF (2g/day) (or AZA) with If in remission after first 6-
corticoids as above. If no 12 months, MMF may be tapered
remission after first 6 months, to 1.5g/day for 6-12 months
advance to next therapy and then to 1 g/day
Pulse CY alone or in combination Consider further tapering at
with pulse corticosteroids for first the end of each year in
6 months (total 7 pulses) remission, or
In white patients, low-dose IVCY AZA, or
(6 fortnightly pulses at fixed dose Quarterly pulses of CY
of 500 mg each) might also be
considered
Background corticosteroids 0.5
mg/kg/day for 4 weeks, then taper

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Recommended Therapy for Lupus Nephritis

Disease Induction Therapy Maintenance


severity Therapy
Severe Monthly pulses of CY in Quarterly pulses
combination with pulse of CY for at least
corticosteroids for 6-12 1 year beyond
months remission, or
If no response, consider AZA, or
MMF (2-3 g/day) or MMF
rituximab

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic


approaches for lupus nephritis: what therapy and for whom?, Nature publishing group, 2005
Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy Maintenance Therapy
Membranous
nephropathy
Mild High-dose Low-dose
corticosteroids alone corticosteroids
or in combination with alone or with AZA
Moderate- AZA Low-dose
severe Bimonthly pulse CY ( 6 corticosteroids
pulses) alone or in alone or with
combination with MP AZA, or
Ciclosporine A (3-5 AZA
mg/kg/day) alone or
with AZA
High-dose
corticosteroids with
MMF
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Management LUPUS
Chan et all: MMF 2 gr/ day 6 month
Taper : 1 gr / day
Ginzler : MMF 3 gr /day
Contreas : MMF 1,5 2 gr / day
(max 2 gr)
6 month 0,25 05 gr.
(Pisoni Cn, Karim Y, Cuadrado MJ. Lupus
2005, 14, s9 s11.)
Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathioprine
PRD was started at 0,8 mg /Kg BW/day
p.o. and tapered to reach 10 mg / day at
approximately six months and then taper
then maintained
Complete remission :
- Urinary protein exertion < 0,3 gr / 24
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction
therapy. Lupus 2005. 14, s27-s32
Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathioprine
PRD was started at 0,8 mg /Kg BW/day
p.o. and tapered to reach 10 mg / day at
approximately six months and then taper
then maintained
Complete remission :
- Urinary protein exertion < 0,3 gr / 24
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction
therapy. Lupus 2005. 14, s27-s32
Autoimmune pathogenesis paradigm. APC, antigen-
presenting cell; MHC, major histocompability complex
EVOLVING
AUTOIMMUNE AUTOIMMUNITY
SPECTRUM OF
*DIATHESIS* WITHOUT DISEASE
AUTOIMMUNE
DISEASE
Genetic Risk Factors :
Autoreactive
- MHC
Lymphocytes
- Other

Tolerance Breakdown Autoimmune Disease


Trigger
- APC stimulation Susceptible End - Lupus
Factor
- Molecular mimicry Organs - Sjrgrens
(Infective
- Cryptic antigen recognition (Skin, joint, - Scleroderma
Ischaemic
- Immune / apoptotic others) - Rheumatoid
latrogenic)
- dysregulation - Polymyositis

Autoreactive Autoreactive
Lymphocytes Lymphocytes

Modulating and Perpetuating Factors acting at multiple levels: e.g. UV radiation, hormones, drugs,
Reeves G.E.M. Update on the immunology, diagnosis and management of systemic lupus erythematosus. Internal Medicine Journal 2004;34:338-347