PHARMACEUTICAL CARE

PADA RHEUMATOID ARTHRITIS

 Rheumatoid arthritis
• Gangguan inflamasi sistemik kronik persisten, ditandai
dgn potentially deforming polyarthritis , inflamasi sendi
simetris dan manifestasinya ekstra artikular luas
• Penyebab utamanya adalah Autoimmune disease
 Dlm jangka lama tjd erosi tlg, destruksi tulang rawan,
hilangnya integritas sendi scr keseluruhan,-sistem
multiple organ dpt dipengaruhi  rheumatoid nodules,
vasculitis, inflamasi mata, neurologic dysfunction,
cardiopulmonary disease,lymphadenopathy,
splenomegali

• Etiologi
• genetik, lingkungan, penambahan usia, sistem immune
Kriteria diagnosis RA

1. Kekakuan pagi di sekitar sendi yang berlangsung ≥ 1 jam

sebelum keterlibatan maksimal
2. Bengkak jaringan lunak (arthritis) dari ≥ 3 area sendi
3. Bengkak (radang sendi) sendi proksimal interphalangeal,
metacarpophalangeal, atau pergelangan tangan (sendi perge-
langan)
4. Symmetric arthritis
5. nodul subkutan
6. Tes positif untuk faktor rheumatoid (RF)
7. Radiografi erosi atau osteopenia periartikular di sendi tangan
atau pergelangan tangan
Patofisiologi

(1) Sel imun (limfosit T atau B) bereaksi dgn protein yg

berkembang di thymus atau sumsum tulang

lepas dari destruksi ( terbunuh atau terinaktivasi )

teraktivasi bbrp tahun & timbul respon autoimun

(aktivasi disebabkan bakteri (Streptococcus) or virus (mengandung
protein dg AA serupa protein jar)

sumber aktivasi (self – targeted immune cell) capai sendi

komplek sel-sel (+)

RA (+)
 (2) Destruksi sendi (inflamasi lapisan sinovial )

lapisan tipis ruang sendi, berproliferasi (menebal) dan

terbentuk pannus sinovial (erosif)

invasi articular cartilage ( penyempitan ruang sendi (+)),

mengerosi tulang (osteoforosis (+)) & hancurkan struktur
periartikuler (ligament,tendon)

deformitas sendi (+)

 Terapi
- Guidelines terapi RA dipublikasikan o/ American
College of Rheumatology
-No treatment cures rheumatoid arthritis
-The therapeutic goals :
a.Remission of symptoms involving the joints
b.Return of full function
c.Maintenance of remission with DMARD therapy.

DMARD : disease modifying anti rheumatic drug

 PROBLEMA MEDIK
Problema medik pd RA hampir sama dgn OA :
1. Joint pain,stiffness,inflamation
2. CKD
3. Chirrosis hepatic
4. Diabetes mellitus
5. Cardiovascular disease (hypertension, HF dll)
6. Peptic ulcer disease
7. Melena
8. Anemia
9.Thrombocytopenia
10. Infection
1. Joint pain,stiffness,inflamation
Pengatasan nyeri, kekakuan dan inflamasi sendi
diterapi dgn :
a. Non farmakologi
- Regular exercise (minimalkan atrofi otot dan
kontraktur flexion, jaga fgs sendi), proteksi sendi dan
konservasi energi, emotional support

-Rest, occupational therapy, physical therapy,

penggunaan alat bantu, weight reduction, surgery
( tenosynovectomy, tendon repair, joint replace-
ments )
b. Farmakologi
- DMARDs should be started within the first 3 months of
symptom onset

- Early introduction of DMARDs results in a more

favorable outcome and can reduce mortality

- + NSAIDs and / or corticosteroids may be used for

symptomatic relief rapid improvement in symptoms
 DMARDs
- Turunkan inflamasi sendi, turunkan atau cegah kerusakan sendi, pelihara fgs
sendi dan integritasnya
- Digunakan slm 3 bulan saat diagonis tegak (respon klinik cepat & perlambat
erosi sendi)
- Bila dgn terapi tunggal MDARD tdk berhasil  tx kombinasi
- Monoterapi : MTX, leflunomida
- Dikombinasi dg NSAID lbh efektif dp monoterapi
- Obat : hydroxychloroquin, sulfasalazine, MTX,lefluno-mide, gold,
azathioprine, D-penicillamine
- - Methotrexate  superior clinically outcomes than the other DMARDs, lower cost
than biologic agents, reduction in cardiovascular morbidity and mortality
-OOA DMARD lambat (3-6 bln),efek manfaatnya dlm 1-2 bln
-tdk blh diberikan pd px dg infeksi aktif, rwyt kekambuhan infeksi,predisposisi
thd infeksi  imunosupresif
- Tdk direkomendasikan pd HF sedang ad berat, hati-hati pd mild HF
-OOA DMARD lambat (3-6 bln),efek manfaatnya dlm 1-2 bln
- tdk blh diberikan pd px dg infeksi aktif, rwyt kekambuhan infeksi,predisposisi
thd infeksi  imunosupresif
- Tdk direkomendasikan pd HF sedang ad berat, hati-hati pd mild HF
Biologic agents
● Effective for patients who fail treatment with other
DMARDs
 Obat anti-TNF etanercept, infliximab,
adalimumab,certolizumab,golimumab
 Costimulation modulator abatacept
 Rituximab depletes peripheral B cells
- Less frequently (less efficacy, high toxicity)
* IL-1 receptor antagonist anakinra
* Azathioprine, D-penicillamine, gold (auranofin), minocy-
cline, cyclosporine ,cyclophosphamide
- Infliximab + MTX to prevent development of antibodies
that may reduce drug efficacy or induce allergic reactions
- Combination therapy (two or more DMARDs )  effective
when single-DMARD treatment is unsuccessful
- cyclosporine + MTX , MTX + sulfasalazine + hydroxy-
chloroquine  effective
- Switching among DMARDs
* If after 3 months of DMARD monotherapy ( patients
without poor prognostic features)  develop to deteriorates
from low to moderate/high disease activity + MTX,HCQ, or
leflunomide

* If after 3 months of MTX or MTX/ DMARD combination

patient still has moderate or high disease activity  +
another non-MTX DMARD or switch to a different non-
methotrexate DMARD
- Switching from DMARDs to biologic agents
* Moderate or high disease activity after 3 months of MTX
monotherapy or DMARD combination therapy  add or
switching to an anti-TNF biologic, abatacept, or Ritu-ximab

* After 3 months of intensified DMARD combination or after a

second DMARDstill has moderate or high disease activity
add or switch to an anti-TNF biologic
 DMARD’S
• Hydroxychloroquine
• Methotrexate
• Azathioprine
• Cyclosporine
• Sulfasalazine
• Leflunomide
 Hydroxychloroquine
~sering dipakai walau kurang poten
~for low RA, good prognose
~inhibition of migration of neutrophils and eosi-nophils, histamine and
serotonin blockade, or inhibition of PG synthesis
~Partially metabolized in the liver and is excreted by the kidney
~ Lack of myelosuppressive,hepatic, and renal toxicities
~ Safe in pregnancy
~ ESO
- retinopathy (>800 g)
-gastrointestinal effects ( nausea,vomiting, diarrhea), ocular
toxicity ( blurred vision), night blindness
- neurologic adverse effects (headache, vertigo, and insomnia
~ aritmia dosis tinggi
~ dosis : 400-600 mg/hari ( 310-465 mg base),dosis
rumatan(155-310 mg base) < 24 bln )
* Methotrexate
~ Now considered the DMARD of choice for treating severe RA
~ Antiinflammatory properties inhibits cytokine produc-tion, inhibits purine biosynthesis,
folic acid antagonist ,stimulate release of adenosine
~ rapid onset (1-2 bln), efikasi tinggi
~ Dosis : p.o 7,5 mg /minggu atau 3x2,5 mg/hari/mgg.Dpt ditingkatkan 15mg/mgg (atau
3x5 mg) slm 12 mgg.
~ Toxicities mainly GIT,hematologic,hepatic ,mukositis, alopecia ringan,
myelosupression, pneumonitis, hepatic fibrosis, CH, pe ↑ enz transaminase(> 3x)
~ It may be given i.m, s.c, or orally
~ + an as folat  cegah gangguan sal cerna , mukositis, alopesia krn MTX.
~ as. Folat (1 mg/hari) or folinic acid 2,5 mg/mgg (leucovorin) dpt turunkan ALT
~ MTX +HCQ →moderate to high disease activity ,low disease activity and disease > 24 months
~ MTX + SSZ is → for poor prognosis and all disease durations
~ MTX +HCQ+SSZ →moderate to high disease activity levels and poor prognosis
- Interaksi obat
~ NSAID tingkatkan consent MTX serum  toks (adjust dosis)
~ dg trimetropin tingkatkan MTX induce supresi bone marrow
*Azathioprine
~Utk severe RA,cadangan bila tx lain yg lebih aman
tdk berrespon
~Dosis 1 mg/kg/hari (single, terbagi). Dpt diting-
katkan 0,5 mg/kg/hari stlh 6-8 mgg. MD 2,5
mg/kg/hari.
~ ESO: gangg GI,myelosupression, hepatotoxicity
~ + allopurinol : metab & eliminasi AZA 
toksisitas me ↑  adjust dosis ad 75%
• Cyclosporine
- For severe, refractory RA
- Inhibition of production and release of IL-II and inhibit
IL-II induced activation resting T-lympho-cytes
- ESO : renal insufficiency, hypertension, female
reproductive disorder
- Monitor : kadar Cr, TD
* Sulfasalazine
~ prodrug, is diubah oleh bakteri di kolon jd sulfapyridine
dan 5-aminosalicylic acid
~ anti rheumatic the exact mechanism of action is
unknown (active metabolites mesalamine →inhibit COX and
lipoxygenase )
~onset > cpt dp HCQ (1 bln),efek anti RA terlihat dlm 2 bln,
respon klinik bertahan ad 4 bln
~ESO :skin rash, leukopenia, trombositopenia alopecia,
stomatitis, elevated hepatic enzymes
~ May cause the patient’s urine and skin to turn a yellow-
orange color
~ Dosis : awal 500 mg/hari atau 1 g/hari dan ditingkatkan
500-1000 mg tiap mgg ,2-3 x sehari.
• Leflunomide
-Inhibits pyrimidine synthesis to decrease in
lymphocyte proliferation and modulation of
inflammation.
- The efficacy similar to MTX
-Contraindicated in patients with preexisting liver
disease  liver toxicity
-Teratogenic
- Bone marrow toxicity
- Antidotum : Cholestyramine
 Agen biologis
- Bekerja pd cytokines proinflammatory spt TNF - , IL-1 ( IL-1, IL-
1) dan IL-6 yg berperan dlm mediator inflamasi pd RA.
- Penggunaan mono or komb dg MTX lbh cepat perbaiki gjl & symptom serta
perlambat progre-sifitas RA dp DMARD
- Utk moderate to severe diasease
- Efikasi jk lama blm tahu
- Obat : etanercept, anakinra, rituximab, Infliximab,
adalimumab,abatacept
 Efek samping
- sekunder sepsis, TBC, infeksi mycobacterium atypical, infeksi jamur,
infeksi oportunistik  tjd pd px dg DM tak terkontrol , tx bersamaan
dg kortiko atau DMARD

- tdk blh diberikan pd px dg infeksi aktif, rwyt kekambuhan

infeksi,predisposisi thd infeksi.
- tdk direkomendasikan pd px HF moderate to severe, caution pd mild
-Terapi kombinasi
~ pengawalan kombinasi tx percepat outcome px
ok erosi sendi tjd pd 2 thn pertama.
~Komb MTX, HCQ, SSZ sgt efektif.
~NSAID digunakan sbg tx tambahan utk relief
simptomatik
 Anti nyeri
• Nsaid
• Kortikosteroid
• Alkyllating cytotoxic agent
 NSAID
-It possess both analgesic and antiinflammatory
properties and reduce stiffness associated with
RA
-Utk relief nyeri dg cepat dan turunkan inflamasi
sendi
-It seldom be used as monotherapy  they do not
alter the course of the diseaseadjuncts to
DMARD treatment
- Sering timbulkan GI discomfort ( dispepsia )
 Obat :
- Aspirin (jrg digunakan), COX-2 inhibitors; non aspirin NSAID
mis: gol asam propionate (ketoprofen, ibuprofen), gol as.asetat
(diklofenak, ketorolak), oxicam (piroxicam), COX-2 inhibitor
(celecoxib)
- Tdk ada perbedaan efikasi
- Piroksikam timbulkan PUD dan GI bleeding
- NSAID lain spt celecoxib ,dosis tinggi ibuprofen dan diklofenac
 picu myocard infark
-ESO
* Dispepsia, komplikasi GI serius , ARF
-Faktor resiko induce ulser GI :
*usia > 60 th, rwyt ulser, obat (kortikosteroid, NSAID dosis
tinggi, anticoagulan,NSAID > 1 bersamaan)
-Monitor ketat px dg HF, peny liver dg ascites, compromised
renal function , diuretik scr bersa-maan
- Data lab yg diperiksa : Cr, LFT tiap minggu
 NSAID baru
- Nitric oxide NSAID (COX inhibiting nitric oxide donors)
Mendonasi NO ke mukosa gaster, nitric oxide-NSAID
produksi efek gastoprotektif spt PG
- Hambatan jalur enzymatic metabolisme asam arakhidonat
(COX, 5-lypoxygenase)
- Aman pd sal cerna

 Vaksin RA
- induces a specific immune response against T cells
- masih trial fase II
 Corticosteroids
-antiinflammatory and immunosuppressive
- Interfere with antigen presentation to T lymphocytes, inhibit PG and
leukotriene synthesis, inhibit neutrophil and monocyte superoxide
radical generation
- Impair cell migration and cause redistribution of monocytes,
lymphocytes, and neutrophils  blunting the inflammatory and
autoimmune responses
~ bridging therapy  used to control pain and synovitis while DMARDs
are taking effect

~ Alternate-day dosing of low-dose oral cortico-steroids ineffective in

RA ( symptoms usually flare on days without medication )

~ High dose corticosteroid bursts are used to suppress disease flares

~ High doses are sustained for several days until symptoms are
controlledfollowed by a taper to the lowest effective dose
-Pemakaian alternate days trnkan resiko supresi hypothalamic-
pituitary-axis dg allowing kel adrenal berrespon thd mediator
hypothalamic & pituitary
-Pemakaian long term : osteoporosis
-Penamb suplemen Ca (1000 mg/hari), vit D (800 IU/hari), bntk
aktif vit D (calcitriol ) cgh bone loss pd px dg kortiko ≥ 5 mg/hari.
- biphosponat efektif cegah & tx kortiko induce bone loss
- kortiko intra-artikular utk flaring occurs pd satu atau few joint
triamcinolone acetonide, triamcinolone hexacetonide
-Bila efektif, injeksi i.a dpt diulangi tiap 3 bln

-Sendi yg sama tdk boleh diinjeksi > 2-3 x per tahun  percepat joint
destruction and atrophy of tendons

- Dosis tunggal pagi hari menutupi sekresi kortisol secara fisiologis dan
minimalkan supresi hypotha-lamic-pituitary-axis.
 Alkyllating cytotoxic agent
- Cyclophosphamide, chlorambucil : efektif utk RA
severe, resiko toksisitas (malignancy, infeksi)
* ESO : haemorrhagic cystitis

- Pd RA progresif yg tdk berrespon dg tx konservatif,

komplikasi RA yg ancam jiwa (rheumatoid vasculitis)
Terapi lain
- Minocyclin
*Terapi adjunctive RA yg disebabkan oleh infeksi.
- Cyclosporine
* efektif sendirian atau kombinasi dg MTX
* ESO serius : dose related renal toxicity, HT
• Pd refractory RA
• Dosis : 100–200 mg daily
 Monitor
- Efektivitas terapi
* Duration and intensity of morning stiffness
* Number of painful or tender joints
* Number of swollen joints; severity of joint swelling
* Time to onset of fatigue
* ESR or CRP,Anti-CCP
* Radiographic changes: osteopenia, joint space narrowing,
bony erosions
2. CKD
- Problema medik pemakaian NSAID pada penyakit RA dgn CKD identik dgn OA
- 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 penambahan dosis
- Pada chloroquin : - Clcr < 10 ml/mnt: turunkan dosis 50%.
- - Terdialisis minimal
- Sulfasalazine : Clcr 10-30 ml/mnt : 2x1
Clcr < 10 ml/mnt : once daily
- Metilprednisolon dpt meningkatkan TD, retensi Na yg dpt tingkatkan 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
- Monitor : kadar Cr, BUN ( tiap 3 hari) , vol urin, TD,- oedema
3. Hepatic cirrhosis / hepatic impairment
-Pemberian NSAID akan meretensi Na ( perberat asci - tes
) dan picu hematemesis melena
-Azathioprine bisa sebabkan hepatotoxicity
-Methotrexate akan sebabkan cirrhosis & portal fibrosis
( jk lama ), peningkatan akut liver enzyme ( dosis besar )
-Sulfasalazine : avoid use
-Kortikosteroid : ulcerative esophagitis, picu gastric
bleeding

- Monitor : BB, warna faeses, ALT, AST,

4. Diabetes mellitus
-Penggunaan kortikosteroid akan perparah hi-
perglikemia ( hambat sekresi insulin )
-Pemberian insulin perlu dilakukan ( back up )
-Monitor ketat kadar glukosa darah
5. Cardiovascular disease (hypertension, HF)
-Penggunaan NSAID akan meretensi Na, hambat prosta-
glandin →tingkatkan TD, perburuk HF
-Cyclophosphamide akan perberat HF
-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
6. Peptic ulcer disease / Melena
-Pemasalahan pemakaian NSAID pd pasien RA dgn PUD ~
OA
-Kortikosteroid : perparah PUD terkait hambat PG
-Methotrexate : sebabkan perforasi intestinal
-Perlu pemberian profilaksis stress ulcer
-Monitor : GI discomfort, gastric bleeding ( warna faeses )
-Azathioprine : bleeding, trombositopenia, leukopenia,
pansitopeni terkait efek myelosspressive
-Chloroquinon : anemia aplastik, thrombositopenia,
neutropenia
7. Hematologic disorder
-Penggunaan NSAID menyebabkan anemia, trombosito-
penia
-Azathioprine : bleeding, trombositopenia, leukopenia,
pansitopenia terkait efek myelosupressive
-Chloroquine : anemia aplastik, trombositopenia, neutro-
penia
-Cyclophosphamide : trombositopenia, anemia
-Methotrexate : leukopenia, trombositopenia
-Monitor secara ketat leukosit, trombosit, Hb, eritrosit
8. Infection
-Penggunaan obat imunosupressan ( t.u kortikosteroid )
dpt menekan sistem imun → picu infeksi
-Dosis yg digunakan sekecil mgkn dan jk pendek bila
memungkinkan
9. Marrietal status
-Pemberian imunosupresive drug pd pasien RA sering
menimbulkan problema fertilitas
-Cyclophosphamide : menyebabkan infertilitas ( ganggu
oogenesis & spermatogenesis, irreversible, supresi
gonad ( amenorrhea)
-Methotrexate : defective oogenesis / spermatogenesis
-Sulfasalazine : oligosperma ( reversible)
 Asessement
 Drug related problem
1. Ketidakcukupan regimen obat dlm penanganan nyeri dan
inflamasi, bisa disebabkan :
- terlambatnya manajemen awal terapi obat  kombinasi
DMARD ( dlm 3 bln)
- dosis dan frekuensi obat subterapeutik
- lama terapi yg kurang
- unresponsive therapy

 Rekomendasi
- Tingkatkan dosis dan frekuensinya
- Penggantian atau kombinasi obat DMARD ( 2 atau 3 obat)

 Monitoring
- Data klinik : -outcome nyeri dan inflamasi sekitar lokasi
-ESO : gastritis, perdarahan lambung
(warna BAB), nyeri kepala,
hemorrhagic cystitis
2. Drug induce
- Bisa berupa :
gangguan hematologi (anemia, trombositopenia, leukositosis, leukopenia)
gastric bleeding
gastritis
aritmia
Drug induce hyperglikemia
DILI peningkatan ALT, bilirubin > 3 x nilai baseline
Drug induce kidney diseaseBUN dan Cr  (  30%)
Drug induce hipertensi

 Rekomendasi
- Stop dan / atau ganti obat yg dicurigai dgn obat yg lbh aman
- Pemberian obat utk mengatasi drug induce
- Turunkan dosis obat ( dechallenge)
- Ubah rute obat ( oral suppositoria)

 Monitoring ketat
- Data klinik : TD, warna BAB, abdominal discomfort, nyeri, inflamasi
- Data lab : nilai ALT/ALP, bilirubin, Cr serum, BUN, Hb, trombosit, leukosit, glukosa drh
3. Ketidaktepatan dlm pemilihan obat, terkait dgn :
- Usia pasien : elderly fgs organ turun
- Penyakit komorbid ( CKD, CH, HT, HF, DM)  percepat
progresivitas penyakit
- Marrietal status → blm nikah

 Rekomendasi
- Stop dan / atau ganti obat yg aman utk elderly
- Ganti dgn obat yg tdk timbulkan fertilitas
- Penurunan dosis obat
- Pilih obat yg tdk KI dgn penyakit komorbid bila tdk bs dihindari,
monitoring ketat dan bila perlu diberikan terapi tambahan ( back up
therapy)

 Monitoring ketat
- Data klinik : ESO ( rash, erythema, SJS dll ), TD,
perdarahan lambung, nyeri, inflamasi
- Data lab : Cr, BUN,ALT/ASP,bilirubin, Hb, gluko-sa drh