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 :
[Link] of symptoms involving the joints
[Link] of full function
[Link] 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
[Link]
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/[Link] 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 [Link]
(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