PHARMACEUTICAL CARE PD

SYSTEMIC LUPUS ERYTHEMATOSUS (

SLE)
 PENDAHULUAN

 Systemic lupus erythematosus

- Autoimmune diseases  connective tissue
diseases multisistem
- Disebabkan oleh kompleks autoantibodies dan
immune  abnormal immunologic function and
formation of antibodies against "self-antigens”
- Manifestasi penyakit tgt pd the tissues targeted
dan musculoskeletal involvement
- Pd umumnya melibatkan satu sistem organ pd
onset, ttp dpt mempengaruhi sistem organ lain
- Tjd pd wanita usia 16-45 thn
• Etiologi
-Genetic  histocompatibility complex
genes ( human leukocyte antigen genes),
non major histocompa-tibility complex
genes (immunoglobulin receptor genes
and mannose-binding protein genes)

- Environmental agentssunlight (i.e.,

ultraviolet light), drugs, hydrazine (found
in tobacco),aromatic amines (found in hair
dyes), diet, environmental
estrogens,infection with viruses or bacteria
(Epstein Barr virus ), hormonal
• Hormonal  androgen may inhibit and
estrogen may enhance the expression
of autoimmunity, elevated circulating
prolactin levelsassociated with
lupus in males and females
- SLE can be diagnosed if any 4 or more
of the 11 criteria are present, serially or
simultaneously, during any interval of
observation.
 PATOFISIOLOGI
• An excessive and abnormal
autoantibody produc-tion and the
formation of immune complexes

Against multiple nuclear, cytoplasmic,

surface components of multiple types of
cells in various organ systems in addition
to soluble markers (immunoglobulin G &
coagulation factors)  the multiple-
organ system involvement of the disease

o Excessive autoantibody production

results from hyperactive B lymphocytes
• Mekanisme hiperaktivitas sel B :

loss of immune self-tolerance and high

antigenic load
(environmental and self-antigens presented to B cells by other B
cells or specific antigen-presenting cells, a shift of T-helper type 1
cells to T-helper type 2 cells)

B-cell antibody production , defective B-

cell suppression

Impairment in other immune regulatory

processes ( T lymphocytes (suppressor T cells),
cytokines ( IL, interferon, TNF, transforming growth factor), natural
killer cells )
• Antinuclear antibodies (autoantibodies that
are directed against nuclear constituents of
the cell )

Penegakan diagnosis SLE

-The SLE patient  have > 1 antigen-specific
antinuclear antibody

Against nuclear constituents as

- double-stranded DNA (dsDNA)
- single-stranded, or denatured DNA
(ssDNA)
- RNA
- Antibodies to dsDNA  highly specific for SLE
( 70% to 80% of patients)
MANIFESTASI
KLINIK
• Diagnosis
- based on clinically sign & symptom
- serologic tests  the fluorescent
antinuclear antibody (ANA) test (
kurang spesifik krn bisa (+) pd peny
lain)
- dsDNA and to Sm antigen  quite
specific for diagnostic of SLE
 PROBLEMA MEDIK
1. SLE
2. CKD
3. Liver disease
4. Diabetes mellitus
5. Cardiovascular disease
6. Peptic ulcer disease
7. Melena
8. Haematologic disorder
9. Infection
10. Pregnancy
11. Marital status
 Penatalaksanaan Problema medik

1. SLE
- Desired treatment outcomes of SLE :
) Management of symptoms & induction of remis-
sion during times of disease flare
) Maintenance of remission for as long as possible
between disease flares
- Macam terapi :
a. Nonpharmacologic Therapy
- A balanced routine of rest and exercise, while
avoiding overexertion
- Avoidance of smoking ( hydrazines in tobacco
smoke  trigger of lupus and accelerated CAD
- Limit exposure to sunlight and use sunscreens
b. Pharmacology
• NSAIDS
- Mild disease, arthritis
- Short therm used
- Patients with SLE  higher incidence
of hepato-toxicity because of NSAIDs
than do other ,asso-ciated with aseptic
meningitis ( reaksi hipersensitivi-tas)
- Monitor : efektivitas, ESO → lihat pd
pharm care RA / OA
• Antimalarial Drugs
- chloroquine,hydroxychloroquine
- manifestations of SLE that can be
managed with antimalarials 
cutaneous , arthralgia, fatigue, fever
- long-term used
- Response to chloroquine 1 to 3
months
- Maximal effect of hydroxychloroquine
may occur for 6 to 12 months
- Hydroxychloroquine first choice (
safer than chlo-roquine )
-The mechanism of action
 interfere with T-lymphocyte activation
 inhibition of cytokines
 decreased sensitivity to ultraviolet light
 anti-inflammatory activity
 antiplatelet effects
 antihyperlipidemic activity
 immunomodulation without causing overt
immuno-suppression
- Dosage and duration of therapy depend on :
 patient response
 tolerance of side effects
 development of retinal toxicity ( irreversible )
 long-term therapy (chloroquine )
 Dose : - hydroxychloroquine 200 to 400 mg/day
- chloroquine 250 to 500 mg/day ( btk
basa )
- After 1 or 2 years of treatment 
gradual tapering of dosage
- 1 or 2 tablets / week to suppress
cutaneous manifestations
 ESO :
- CNS effects (headache, nervousness,
insomnia)
- reversible ocular toxicities such as cycloplegia
and corneal deposits
- Potentially serious retinal toxicity (permanent damage )
 retinopathy ophthalmologic evaluation
every 3 months (chloroquine ), 12 months (
HCQ )
• Corticosteroids
-For mild disease (fever, arthralgia,
pleuritis, or skin manifestations)  as
NSAIDs or antimalarials

-For severe lupus nephritis, but evidence

suggests  corticosteroids are also
effective in the management of severe
cases (CNS disease, pneumonitis, myo-
sitis, vasculitis, thrombocytopenia )

- The goal of treatment  to suppress and

maintain suppression of active disease
with the lowest dose possible
- Dose :
* For mild disease  low-dose therapy
(prednisone 10 to 20 mg/day)

* For more severe disease (severe hemolytic

anemia or cardiac involvement) higher doses
( prednisone 1 to 2 mg/kg daily)

- Once adequate suppression of disease is

achieved,  the dose should be tapered to the
minimum amount required for continued
disease suppression
- In clinical practice → methyl prednisolon (
commonly used ) → dose equivalency with
prednison
( prednison 10 mg ~ 8 mg methyl prednisolon )
-Consider to conditions of corticosteroid therapy
 infection, hypertension, atherosclerotic
disease, dia-betes, obesity, osteoporosis,
psychiatric disease

-Steroid pulse therapy

* short-term, high-dose i.v corticosteroids
* inducing remission in SLE patients with serious,
life-threatening disease ( severe active nephritis,
CNS in-volvement, hemolytic disease)
- A standard pulse regimen i.v
methylprednisolone 500 to 1,000 mg for 3 to 6
consecutive days
- Pulse therapy usually is followed by high-dose
prednisone (1 to 1.5 mg/kg/day) therapy that is
tapered to low-dose maintenance therapy
- Potential advantages :
 quicker response and avoidance of
side effects ( longterm therapy
required with oral steroids)

- ESO : infection, gastrointestinal

disturbances, rapid increases in BP,
arrhythmias, seizures, sudden death,
hyperglycemia
Immunosuppressant Agents
- Act as immunosuppressives, cytotoxic and
anti-inflammatory agents
- It’s indicated if disease symptoms are :
*severe, organ damage is occurring, symp-
toms are not responding to other therapies

 Cytotoxic Drugs
- Alkylating agent (cyclophosphamide ) , anti-
metabolite (azathioprine)
  Cyclophosphamide
- The mechanism of actioninvolve cross-linking of
DNA, which may interfere with growth of normal
and neoplastic cells
- i.v (intermittent pulse doses) to minimize toxicity
- To decrease the risk of bladder toxicity :
 hydrated with oral or intravenous fluids
 monitor urinary output
 + Mesna  prevent hemorrhagic cystitis
 dose : 20% of the total cyclophos-
phamide
- Combination prednisone +
cyclophosphamide *standard treatment for
focal and diffuse proliferative lupus
nephritis
* It’s superior to prednisone  the
mainstays of immunosuppressive therapy
* to suppress and stabilize extrarenal
disease activity
* focused on lupus nephritis  a major
factor asso-ciated with morbidity and
mortality in SLE
* Controlled clinical trials 
cyclophosphamide im-proves long-term
outcomes in lupus nephritis
- No studies have evaluated
cyclophosphamide in earlier stages of
nephritis

-Corticosteroids  treatment of choice

for the initial treatment of nephritis

- Pulse i.v cyclophosphamide +

prednisone  more effective at slowing
progression to end-stage renal disease
than either prednisone alone or
prednisone plus azathioprine
- Dose :
 combination with corticosteroids
 cyclophosphamide : 1 to 3 mg/kg for p.o and
0.5 to 1 g/m2 BSA (i.v) better than oral )
 the optimal duration of treatment  no
evidence
 empirical experience dosed monthly for 6
to 7 months and then every 3 months for a
period of either 2 years or for 1 year after the
nephritis is in remission

 ESO : serious toxic effects  suppression of

hema-topoiesis, opportunistic infections,
bladder compli-cations ( hemorrhagic cystitis
and cancer), sterility, teratogenesis
 Azathioprine
- Antagonizes purine metabolism and inhibits
syn-thesis of DNA, RNA, proteins  decrease
prolife-ration of immune cells lower
autoimmune activity
- It has “steroid-sparing" agent reduction of
cortico-steroid doses
- Data do not support the use of azathioprine
as a part of an induction regimen
- Long-term maintenance therapy → prevent
renal flares after successful induction with
cyclophos-phamide
- Dose : 1 to 3 mg/kg per day,combination
with corticosteroids ( severe disease)
- less toxic than cyclophosphamide, but adverse
reactions may be serious → myelosuppression,
opportunistic infections including (herpes zoster),
cancer, hepatotoxicity, and ovarian failure

• Methotrexate
- used for managing resistant arthritis, serositis,
cuta-neous
- It blocks purine synthesis and 5-aminoimidazole-
4-carboxamide ribonucleotide (AICAR) 
increasing anti-inflammatory adenosine
concentration at sites of inflammation
- Dose : 5–15 mg orally ( single weekly dose) or
three divided doses per week every 12 hours
 Mycophenolate mofetil
- Inhibits inosine monophosphate dehydrogenase
(IMPDH) and suppresses de novo purine synthesis
by lymphocytes inhibiting their proliferation and
antibody production.
- effective treatment → severe renal and nonrenal
lupus refractory to conventional cytotoxic agents
- In an open-label trial  more effective than
standard cyclophosphamide therapy ( higher rate of
complete and partial remissions)
- + corticosteroid  mild to moderate nephritis and
good renal function
New therapeutic agents (phase I, II, III trials)
(As immunomodulator)
- restore the potential to minimize self-immunity
 Belimumab
- it was approved by FDA in 2011
- It is a human monoclonal antibody
- It is a B-lymphocyte stimulator (BLyS)
specific
Inhibitor
- It is indicated to treat patients with active
disease,who are auto-antibody (+), and
already receiving treatment for SLE
- ADR : risk of serious infections,
hypersensitivity reactions, depression and
suicide
Monitor Adverse drug reaction
2. CKD
- Problema medik pemakaian NSAID pada penyakit
SLE dgn CKD identik dgn OA/RA
- Methotrexate menyebabkan renal disfunction →
kenaikan Cr dan BUN , penurunan vol. urin ( dosis
tinggi, presipitasi obat)
- Penyesuaian dosis MTX perlu dilakukan pd CKD
* Clcr 10-50 ml/mnt : turunkan dosis ad 30-50%
* ClCr < 10 ml/mnt : avoid use
* pada HD , PD : tdk terdialisa, tdk perlu
penambah-an dosis
- Pada chloroquin :
* Clcr < 10 ml/mnt: turunkan dosis 50%
* Terdialisis minimal
- Metilprednisolon dpt tingkatkan TD, retensi Na
yg dpt percepat progresivitas renal disease
- Azathioprine : -Clcr 10-50 ml/mnt : 75% dr dosis lazim
- Clcr < 10 ml/mnt : 50% dr dosis lazim
- Cyclophosphamide : menyebabkan SIADH (
dosis > 50 mg/kg), renal tubular necrosis
* Clcr : < 10 ml/mnt : gunakan 75% dr dosis
lazim
* terdialisis moderat ( 20-50%), perlu
penambahan dosis
- Mycophenolate mofetil : not removed by
haemodia-lysis and PD, tingkatkan BUN, Cr
- Monitor : kadar Cr, BUN ( tiap 3 hari) , vol urin,
TD,- oedema
• Liver disease
- - Pemberian NSAID akan meretensi Na (
perberat ascites ) dan picu
hematemesis melena pd CH
- Azathioprine bisa sebabkan
hepatotoxicity
- Methotrexate akan sebabkan cirrhosis &
portal fibrosis ( jk lama ), peningkatan
akut liver enzyme ( dosis besar )
- Kortikosteroid : ulcerative esophagitis,
picu gastric bleeding ( pada pasein CH)
- Mycophenolate : LFT abnormal ( 25%),
hepatotoxi-city ( transaminase, ALP
,bilirubin and GGT increased, jaundice ,
cholestatic jaundice → 3-20%)
- Cyclophosphamide :
* Hepatotociicity ( < 1%)
* PK unchanged in hepatic insufficiency
* Bilirubin 3,1-5 mg/dL or transaminase > 3
x ULN → administer 75% dose
* avoid use if serum bilirubin > 5 mg/dL
- Monitor : BB, warna faeses, ALT,
AST,bilirubin total, ALP, GGT)
3. Diabetes mellitus
- Penggunaan kortikosteroid akan perparah hiper-
glikemia
- Mechanism of action :
* Impairs both glucose transport in fat and muscle
cells and the ability of glucose to stimulate its own
utilization (glucose effectiveness) →reducing glu-
cose clearance
* To direct harmful effects on insulin-secreting beta
cells of the pancreatic islets by inducing apoptosis
* Reduced GLUT-2 expression and decrease in
glucose transport into the beta cells
- The risk of corticosteroids - induced
hyperglycemia increases :
* corticosteroid dosage
* duration of therapy
* advanced patient age
* family history of DM
* obesity
* high blood glucose concentrations
before therapy
* it depends on the route of
administration
- Monitor ketat kadar glukosa darah
4. Cardiovascular disease
- Penggunaan NSAID akan meretensi Na,
hambat prosta-glandin →tingkatkan TD,
perburuk HF
- Cyclophosphamide akan perberat HF
- Mychophenolate → cause HT, aritmia,
CHF, AF dll
- Chloroquin bs sebabkan cardiomyopathy
( fre-quency not defined), aritmia
- Kortikosteroid ( t.u sediaan injeksi) →
retensi Na → tingkatkan TD, edema

- Monitor ketat : TD, edema, profil ECG

5. Peptic ulcer disease
- Pemasalahan pemakaian NSAID pd
pasien SLE dgn PUD ~ OA
- Kortikosteroid : perparah PUD terkait
hambat PG
- Methotrexate : sebabkan perforasi
intestinal
- Cyclophosphamida : mual dan muntah
- Mycophenolate : esofagitis, gastritis, GIT
haemor-rhage, melena
- Perlu pemberian profilaksis stress ulcer
- Monitor : GI discomfort, gastric bleeding (
warna faeses )
6. Melena
- Pemberian NSAID akan perparah melena →
life threatening → pemakaian ditunda
- Tramadol , Cox-2 inhibitor adalah pilihan bila
kondisi melena teratasi
- Monitor : warna faeses
7. Haematologic disorder
- Penggunaan NSAID menyebabkan anemia, trom-
bositopenia
- Penggunaan immunosupressant menyebabkan
myelosupressant effect → haematologic disorder
- Azathioprine : bleeding, trombositopenia,
leukopenia, pansitopenia terkait efek
myelosupressive
- Cyclophosphamide : trombositopenia, anemia
- Methotrexate : leukopenia, trombositopenia
- Chloroquine : anemia aplastik, trombositopenia,
neutropenia
- Mychophenolate : leukopenia, thrombocytopenia
- Monitor secara ketat leukosit, trombosit, Hb,
eritrosit
8. Infection
- Penggunaan obat imunosupressan ( t.u
kortikosteroid ) dpt menekan sistem imun
(immuno-deficiency → picu opportunistic
infection
- Dosis yg digunakan sekecil mgkn dan jk
pendek bila memungkinkan
- Monitor : tanda – tanda infeksi ( leukosit,
suhu,kondisi umum )
9. Pregnancy
- exacerbation of SLE :
 early postpartum period
 a greater incidence of spontaneous abortion
 a greater chance of developing preeclampsia or pregnancy-
induced hypertension
- Disease exacerbations,managed by :
 aggressively with corticosteroids
 hydroxychloroquine
- Cyclosporine, methotrexate, mycophenolate mofetil 
contraindicated in pregnancy ( teratogen,fetal loss)
- Azathioprine  safe
- NSAIDs  safe in pregnancy
 discontinued during the last weeks of
pregnancy due to risk of premature closure of the ductus
arteriosus
10. Marital status
- Pemberian imunosupresive drug pd pasien
SLE sering menimbulkan problema fertilitas
• Cyclophosphamide : menyebabkan infer-
tilitas ( ganggu oogenesis & spermatoge-
nesis), irreversible, supresi gonad ( ame-
norrhea) ,premature ovarian failure
- Methotrexate : defective oogenesis & sper-
matogenesis
- Mycophenolate : impotence ( 3% - < 20%)
 asessement
Drug related problem
1.Drug induce
a. Drug-Induced Lupus ( DIL)
- Procainamide and hydralazine  most commonly with
DIL (definite)
- Chlorpromazine, methyldopa, INH, mynocy-cline,
quinidine (definite)
- Estrogen-containing oral contraceptives
* Uncontrolled trials oral contraceptives exacerbate
SLE
- Symptoms : musculoskeletal (i.e.,
arthralgias,myalgias), constitutional (i.e., fatigue and
fever), pleuropericarditis → procainamide
- The patient may have an ANA (+), but will rarely test
positive for the lupus-specific antibodies
risk of thrombotic events for estrogen-
treated women and thrombosis in SLE 
antiphospholipid antibodies should be
measured  oral contraceptives should
be avoided if antibodies (+)

- Recomendation : stop the drug ( if

factual), closely monitored the simptoms
of SLE, ANA/dsDNA ,the simptom of
SLE ( if potential )
- It is not advisable to rechallenge with the
drug, especially when alternatives are
available
- Monitor : simptoms of SLE, ANA/dsDNA
test
b. Gangguan hematologi (anemia,
trombositopenia, leukositosis,
leukopenia)
- pemakaian immunosupresan,
kortikosteroid, NSAID
c. Gastric bleeding : pemakaian NSAIDs,
kortikoste-roid
d. Gastritis : pemakain NSAIDs,
kortikosteroid
e.Drug induce hyperglikemia : pemakaian
kortiko-steroid
f. DILI peningkatan ALT, bilirubin > 3 x
nilai baseline
- Pemakaian MTX, azathioprine,
mycophenolate, kortikosteroid
g.Drug induce kidney diseaseBUN dan
Cr  (  30%)
- pemakaian NSAID, MTS, azathioprine,
cyclophos-phamide
h.Drug induce hipertensi
- Pemakaian NSAID, kortikosteroid ( t.u
injeksi),-
cyclophosphamide,mycophenolate,chlor
oquin

 Rekomendasi
- Stop obat yg dicurigai penginduce
- Ganti dgn obat lain yg lbh aman
- Pemberian obat utk mengatasi akibat
drug induce
- Turunkan dosis obat ( dechallenge) bila
masih diperlukan & tdk ada alternatif lain
Monitoring ketat
- Data klinik : TD, warna BAB,
abdominal discomfort, nyeri,
inflamasi
- Data lab : nilai ALT/ALP, bil. total, Cr
serum, BUN, Hb, trombosit, leukosit,
glukosa drh
2. Kegagalan terapi
 dosis subterapetik
 tidak respon / resisten pd obat
 non adherence
 lama terapi kurang
 adanya underlying disease, komorbid
 sosio – ekonomi
 Rekomendasi
- Tingkatkan dosis
- Tingkatkan dosis / kombinasi / ganti dgn alternatif obat lain
- Edukasi ttg penyakit & tujuan terapi obat
- Pengatasan underlying disease/komorbid dgn terapi obat yg
tdk berinteraksi scr bermakna dgn obat utk SLE
- Pilihkan dgn obat yg lbh murah tapi cost-effective
 Monitor
- Respon obat thd progresifitas SLE
 Kondisi klinik : malar rash, alopecia,athralgia,-arthritis,
photosensitivity, neurologic dysorder
 data lab : leukosit, Hb, trombosit, Cr, BUN, ALT/AST
3. Inappropriate drug
 pemberian imunosupresan yg mengganggu
proses reproduksi → cyclophosphamide,
MTX
 Rekomendasi
- stop obat dan ganti dgn azathioprine atau
myco-phenolat ( bila pasien wanita )
4. Overdose
 dosis obat lebih pd SLE dgn renal
impairment
 Rekomendasi
- Dose adjustment
 Monitor
- Data klinik : symptom of SLE
- Data lab : Cr, BUN
• Konseling
- Non farmakologi : hentikan merokok,
limitasi ter-papar matahari ( gunakan
sunscreen)
- Farmakologi :
 kepatuhan minum obat  longtherm
therapy
 efek samping obat 
hepatotoksisitas krn azathioprine
1. Ny. Es usia 23 tahun, tinggi 160 cm, BB 55
kg, masuk rumah sakit husada dengan
keluhan atralgia, kekakuan sendi, demam
naik turun selama 1 minggu. Riwayat
penyakit adalah gastritis. Pasien adalah ibu
muda yang belum punya anak . Data klinik :
malar ( butterfly) rash ,pada kedua pipi,
fotosensitivitas pada kedua tangan dan kaki,
suhu 38 C, nadi 90x / mnt, RR 20 x / mnt,
TD 150 / 100 mmHg, . Data lab : leukosit
14.000 / mm3 , Hb 8,5 g/dL, trombosit 90.000
g/dL, dsDNA (+). Pasien didiagnosis SLE.
Dokter memberi terapi : NaCl : RL = 2 : 2,
metilprednisolon 3 x 16 mg, siklofosfamida 1
x 800 mg infus i.v, amoksisillin 3 x 500 mg.
2. Pasien a.n Nn S, usia 26 thn, MRS di RS Semangat tgl 6
Oktober 2014 dgn keluhan kemerahan pada kulit wajah
dan dada, kejang. Pasien rujukan dari RS. Buana yg sdh
mendapat terapi prednison oral.Pasien memiliki riwayat
perawatan kulit wajah dgn kosmetka. Pasien belum
menikah. Data klinik : TD, nadi, RR dbn, suhu 38oC; data
lab. WBC 11.300 / mm3,, HB 7,5 g/dL ,GDA 96 g/dL, ANA
test (+) . Pasien terdiagnosis SLE dan mendapat terapi
metilprednisolon inj. i.v 2 x 500 mg selama 3 hari,
fenitoin inj. 3 x 2 amp dilanjutkan fenitoin kapsul 3 x
1,cefoperazon 3 x 1 g, mychophenolate tab. 2 x 1,
chloroquin 2 x 250 mg. Kondisi pasien makin menurun,
malar rash pada wajah semakin melebar.
3. Pasien a.n Nn S, usia 29 thn, MRS di
RS Saudara tgl 10 Nopember 2015 dgn
keluhan nyeri pada persendian lengan
dan kaki , terdapat bercak kehitaman
pada kulit tangan. Keluhan dirasakan 2
minggu sebelum MRS. Pasien baru
nikah dan hamil 4 bulan. Data klinik : TD,
nadi, RR dbn, suhu 38oC. Data lab. WBC
12.000 / mm3,, HB 8,3 g/dL, glukosa dbn,
trombosit 50.000 / mm3,ANA test (+) .
Pasien mendapat terapi kloroquin 2 x
250 mg , metilprednisolon inj. i.v 2 x 250
mg selama 3 hari, micophenolat mofetil 1
x 1 tab, ceftriaxone 1 x 2 g. Setelah
terapi, pasien tetap demam dan TD
150/90 mmHg.