* Farmakoterapi Sistem

Organ Sistem Urologi

dan Muskuloskeletal:
Rheumatoid Arthritis
Oleh:
Rudy Salam
* Autoimmune disease
* CD4+ T-cells, activated B-lymphocytes, and
plasma cells/macrophages
* Cytokines

*Etiology of RA
*prevalence of 1-2% & does not have
any racial predilections
*any age ↑ 7th decade of life
*Women 3x higher than men
*HLA-DR4 antigen 3.5 times more
likely to develop rheumatoid arthritis

*Epidemiology of RA
HLA-DR
autoantibodies to IgGFc  rheumatoid factors (RF), and antibodies to
citrullinated peptides (ACPA)
TNF-α B-cell (type III hypersensitivity) & T-cell (type IV
hypersensitivity)

* Pathophysiology of RA
* Diagnosis of RA
Clinical History
Physical Exams
X-rays
CT/MRI scans
Specific Lab Tests
CBC
ESR
CRP
RA Factor
Anti CCP
•Key points:
• The sicker they are and the faster they
get that way, the worse the future will be
• Early intervention can make a difference
• Essential to establish a treatment plan
early in the disease

*Therapeutic Plan
* Confirm the diagnosis
* Determine where the patient stands The EULAR 2016
in the spectrum of disease Overarching principles
* When damage begins early, start
aggressive treatment early
* Use the safest treatment plan that the best care
matches the aggressiveness of the and MUST be
based on
disease based on a high individual,
disease activity Rheumatologists
shared decision medical and
and other  primarily care
* Monitor treatment for adverse between the
patient and the
patient factors
societal costs
effects rheumatologis
* Monitor disease activity, revise Rx as
needed

*Treatment Principles
• Education
• Build a cooperative long-term relationship
• Use materials from the Arthritis Foundation and the ACR

• Assistive devices

• Exercise
• conditioning, and strengthening exercises
• Medications
• Analgesic and/or anti-inflammatory
• Immunosuppressive, cytotoxic, and biologic

• Balance efficacy and safety with activity

* Critical Elements of a
Treatment Plan
Prevent bone & cartilage destruction

Maintain or restore joint function

Reduce pain

Decrease inflammation

*Goals of Therapy
•NSAIDs, glucocorticoids
•DMARDS as methotrexate,leflunomide,
hydroxychloroquine, sulfasalazine
•Newer biological agents with specific molecular
targets in RA pathogenesis:
– TNF-α antagonist/inhibitor
– Interleukin (IL) inhibitor and receptor antagonist
– B cell inhibitor (anti-CD20 antibodies)
– T cell directed therapies
– New molecules targeting JAKs  tsDMARDs

*Current Therapy of
RA
• NSAIDs
• Symptomatic relief, improved function
• No change in disease progression
• Glucocorticoid
• Low-dose glucocorticoid  prednisone (£10 mg qd)
• High-dose glucocorticoid  prednisone (> 10 - 60 mg qd)
• May substitute for NSAID
• Used as bridge therapy
• Short term (< 3 months)  If used long term, consider prophylactic
treatment for osteoporosis
• Intra-articular steroids
• Useful for flares

*Drug Treatment
Options
• csDisease modifying drugs (DMARDs)
• Minocycline
* Modest effect, may work best early
• Sulfasalazine, hydroxychloroquine
* Moderate effect, low cost
• Intramuscular gold
* Slow onset, decreases progression, rare
remission
* Requires close monitoring
• bDMARDs
• bsDMARDs
• tsDMARDs
*Drug Treatment
Paget. Primer on Rheum Dis. 11th edition. 1997:168.
DMARDS  started Treatment 
Monitoring  1- 3 MTX 1st
as soon as remission/ low
months treatment strategy
established disease activity

csDMARDs failed
Short-term csDMARDs failed
Leflunomide/sulfa with poor
glucocorticoids  without poor
salazine if MTX prognostic  (+)
initiating or prognostic 
(CI) bDMARDs/
changing csDMARD other csDMARDs
tsDMARD

bDMARDs + Tapering bDMARDs 

bDMARDs + Tapering
tsDMARDs  if if patient persistent
tsDMARDs failed  csDMARDs 
csDMARds (CI)  remission after
anothers bDMARDs tapered persistent
IL-6 inhibitors +
or tsDMARDs glucocorticoids remission
tsDMARDs

*The EULAR 2016

Recommendations
 Methotrexate, hydroxychloroquine, and sulfasalazine
Superior to any one or two alone for ACR 50% improvement response and
maintenance of the response
Side effects no greater
2-YearChart
Outcome
Title
90

80

70

60

50
Axis Title
40

30

20

10

0
Triple Rx SSA+HCQ MTX

Axis Title

* Treatment
New Options: Combinations
• Step-down prednisone with sulfasalazine
and low-dose methotrexate*
• Superior to sulfasalazine in early
disease*
• Methotrexate + hydroxychloroquine or
methotrexate + cyclosporine†
• May have additive beneficial effects†

* Treatment New Options:

Combinations

*Boers, et al. Lancet. 1997;350:309–318.

†
Stein, et al. Arth Rheum. 1997;40:1721–1723.
Drug Hem Liver Lung Renal Infect Ca Other
HCQ + - - - - - Eye
SSZ + + + - - - GI Sx
Gold ++ - + ++ - - Rash
MTX + + ++ - ++ ? Mucositis
AZA ++ + - - ++ + Pancreas
PcN ++ + + ++ - - SLE, MG
Cy +++ - - - +++ +++ Cystitis
CSA + ++ - +++ ++ + HTN
¶TNF* - - - - ? ? Local
Lef* ++ ++ - - ? ?
*Long-term data not available.

*Rheumatoid Arthritis:
Adverse Effects of DMARDs

Adapted from Paget. Primer on Rheum Dis. 11th edition. 1997:168.

Saag et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-
Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
Saag et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-
Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
Saag et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-
Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
*Ringkasan DMARDs
* TNF-α
http://www.sciencedirect.com/science/article/pii/S0264410X13009110
Antibody & Decoy Receptor Biologics  adalimumab, golimumab and infliximab
TACE inhibitor protease that cleaves and converts tmTNF into its circulating
form  , certolizumab, etanercept
DN-TNF monomer to heteromers

*TNF-α Inhibitor
 Side effect:
*TNF-α Inhibitor Injection site reactions
Increased risk of bacterial, viral, and/or fungal
Certolizumab pegol infections
Bone marrow suppression
Infliximab Generation of antibodies to drugs, resulting in
Adalimumab reduced efficacy over time
Drug-induced lupus-like syndromes
Golimumab
Emergence of lymphoma and skin cancers over
Eternacept long-term use
 * Interleukin & Interleukin Receptor Inhibitors
IL-1 makrofag & T-cell  stimulate immune response
IL-6 makrofag
intensive tissue damage IL uncontrolled
IL inhibitor relieving inflammation & preventing bone
degradation
IL6R inhibitors  tocilizumab & sarilumab
IL6 inhibitors  clazakizumab or sirukumab
used if patient has not improved after using other anti-
inflammatory medication such as TNF antagonists
Avoid COMBINATION with TNF antagonist considered ADR

odrick RS & Ruderman EM. Safety of biologic therapy in rheumatoid arthritis. Nature Reviews Rheumatology. 2011. 7: 639-652
Woodrick RS & Ruderman EM. Safety of biologic therapy in rheumatoid arthritis. Nature Reviews Rheumatology. 2011. 7: 639-652

* B-cell & T-cell Inhibitor

B-cell Express Fc receptors & CD20
T-cell trimoleculer complex + Co-stimulatory
molecules CD80 & CD86
MoA of B-cell inhibitor:
• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cell-mediated cytotoxicity
(ADCC)
• Induction of apoptosis
MoA of T-cell inhibitor down-regulation of T-cell
activation
 * Selected cytokines as therapeutic
targets in rheumatoid arthritis

McInnes IB & Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Rheumatol. 2007. 7: 429-442
 Novel Target for RA
JAK inhibitor down regulate inflammatory * Janus Kinase
reactions by Interferes with the signalling Inhibitors
pathways.
Tofacitinib & Baricitinib
(JAKs)
O’Shea, J. J. et al. (2013) Back to the future: oral targeted therapy for RA and other autoimmune diseases Nat.
* Clinical trials of
jakinibs in
autoimmunity and
cancer

O’Shea, J. J. et al. (2013) Back to the future: oral targeted therapy for RA and other autoimmune diseases Nat.
 *Biologic Agents
Approved by FDA
Consumer Reports Best Buy Drugs. Using Biologics to Treat: Rheumatoid Arthritis. 2013
Consumer Reports Best Buy Drugs. Using Biologics to Treat: Rheumatoid Arthritis. 2013
Consumer Reports Best Buy Drugs. Using Biologics to Treat: Rheumatoid Arthritis. 2013
Consumer Reports Best Buy Drugs. Using Biologics to Treat: Rheumatoid Arthritis. 2013
* Important Considerations
for Choosing a Biologic

Consumer Reports Best Buy Drugs. Using Biologics to Treat: Rheumatoid Arthritis. 2013
 * Rekomendasi Penatalaksanaan AR (The EULAR 2016):
Fase I

Smolen, J. S., et al. (2017). "EULAR recommendations for the management of rheumatoid arthritis with synthetic and
biological disease-modifying antirheumatic drugs: 2016 update." Annals of the Rheumatic Diseases.
 * Rekomendasi Penatalaksanaan AR (The EULAR 2016):
Fase II

Smolen, J. S., et al. (2017). "EULAR recommendations for the management of rheumatoid arthritis with synthetic and
biological disease-modifying antirheumatic drugs: 2016 update." Annals of the Rheumatic Diseases.
 * Rekomendasi Penatalaksanaan AR (The EULAR 2016):
Fase III

Smolen, J. S., et al. (2017). "EULAR recommendations for the management of rheumatoid arthritis with synthetic and
biological disease-modifying antirheumatic drugs: 2016 update." Annals of the Rheumatic Diseases.
 * the treatment
of Early RA
(disease
duration < 6
months)

Saag et al. American College of Rheumatology 2015 Recommendations for the Use of Nonbiologic and Biologic Disease-
Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
 * the treatment
of Established
RA

Saag et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-
Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
Saag et al. American College of Rheumatology 2008 Recommendations for the Use of
Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid
Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
h et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of
ase-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis. Arthritis Rheum. 2012. 64 (5): 625-6
Woodrick, R. S. & Ruderman, E. M. (2011) Safety of biologic therapy in rheumatoid arthritis Nat. Rev. Rheumatol.
doi:10.1038/nrrheum.2011.145
* Recommendations for screening for tuberculosis (TB) among RA
patients being considered for biologic DMARDs

Saag et al. American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-
Modifying Antirheumatic Drugs in Rheumatoid Arthritis. Arthritis Rheum. 2008. 59 (6): 762-784
h et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of
ase-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis. Arthritis Rheum. 2012. 64 (5): 625-6
 Olive leaf extract
Aloe Vera
Green Tea
Omega 3
Ginger Root Extract
Cats Claw

*Alternative Medicine
CIPLUKAN (Physalis minima Linn)???

(American College of Rheumatology, 2012)

Tocilizumab 5,6-Epxoyphysalin B

* In silico study:
IL-6 inhibitor
5,6-Epxoyphysalin B

Tocilizumab

* Interaction Parameter Ligand-

Receptor
 Being overweight strains joints and leads to further inflammation

•Walking
4 times a week for
•Light jogging
30 minutes •Water aerobics
•Cycling
•Yoga
•Tai chi
•stretching

*Exercise
(Arthritis Foundation, 2012)
 *Nutrition
The most commonly observed vitamin and mineral
deficiencies in patients with RA are:
o folic acid
o vitamin C
o vitamin D
o vitamin B6
o vitamin B12
o vitamin E
o calcium
o magnesium
o zinc
o selenium
(Johns Hopkins Arthritis Center, 2012)
 *Synovectomy
•Increases function of the joint
•Decreases pain and inflammation
•Beneficial as an early treatment option
•Not a cure!

(Day et al., 2010; Sung-Jae, 2007)

* Braces/casts/splints
Support injured joints and weak
muscles
Improve joint mobility and stability
Help to alleviate pain, swelling and
muscle spasm
May prevent further damage and
deformity

(Johns Hopkins Arthritis Center, 2012)