A brief review of management of RA in Indonesia, including the challenges in getting biologic agents

1. Challenges and Gaps in RA
Goals and Management
(Guideline Implementation)

2. • Patients journey (apa saja hambatan pasien untuk bisa mendapatkan
pengobatan yang sesuai, terkecuali masalah harga)
• Implementasi guideline (apakah kita mengimplementasi guideline yang
ada, jika iya/tidak alasannya kenapa, guideline mana yang kita ikuti,
berapa banyak dokter yang mengikuti guideline)
• Apa saja tantangan/hambatan yang dijumpai dalam penerapan
guideline untuk tatalaksana AR ?
• Apa yang menjadi pertimbangan utama dalam menentukan tatalaksana
pasien AR ?
• Apakah nyeri yang berkurang atau membaik menjadi poin yang paling
utama dalam pencapaian goal of treatment di AR ?
Our topic

3. Rheumatoid arthritis (RA) is a systemic autoimmune disease
that causes joint inflammation and progressive erosion of
bone, leading to joint misalignment, loss of function, and
disability.
RA affects more 600.000 than million Indonesian adults.
Onset occurs most often between the ages of 30 and 50 years.
Women and older adults are more commonly affected.
Health Impact of Rheumatoid Arthritis
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at
www.effectivehealthcare.gov/dmardsra.cfm.

4. The goal of RA treatment is to:
Control pain & inflammation
Limit progressive damage
Reduce disease activity or induce remission
Maintain function
Treatment of Rheumatoid Arthritis
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

5. Disease-modifying anti-rheumatic drugs (DMARDs) interfere
with rheumatoid disease processes by blocking the production
or activity of the immune cells and their products that cause
inflammation and damage.
Treatment with DMARDs is increasing with the expectation that
they will lead to better disease control and more remissions.
Steroids—both low-dose systemic and intra-articular
formulations—are used as adjuncts to DMARD treatment.
DMARDs

6. Disease-modifying anti-rheumatic drugs (DMARDs) are in
common use for rheumatoid arthritis (RA), and several have
been approved by the U.S. Food and Drug Administration
for this indication.
DMARDs may be oral or biologic drugs.
The consensus of clinical experience has made
methotrexate, an oral DMARD, the first-line drug of choice
for treating RA.
DMARDs in Rheumatoid Arthritis Treatment (1 of 2)
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

7. Oral disease-modifying anti-rheumatic drugs (DMARDs) are small-
molecule chemical drugs.
The mechanism of action of each of these drugs is not well defined and is
unknown in some cases.
Biologic DMARDs block the activity of immunostimulatory
cytokines and other cell-signaling molecules.
Biologic DMARDs are genetically engineered antibodies and proteins.
Tumor necrosis factor-alpha blockers are the most typical members of
this drug class.
Other targets are interleukins 1 and 6 and the transmembrane proteins
CD20 and CD28.
DMARDs in Rheumatoid Arthritis Treatment (2 of 2)
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at
www.effectivehealthcare.gov/dmardsra.cfm.

8. Patients journey
• Apa saja hambatan pasien untuk bisa mendapatkan pengobatan yang
sesuai ?
• Keterlambatan diagnosis
• Keragaman pengetahuan dan kompetensi
• Akses ke fasilitas kesehatan yang tersedia KR
• Sistim rujukan
• Keterlambatan memulai DMARDs
• Pengetahuan dokter
• Ketersediaan DMARDs di faskes
• Kelemahan dalam follow up
• Timing
• Eskalasi
• Treat to target

9. Oral Disease-Modifying anti-rheumatic Drugs
Name Target of Activity
Hydroxychloroquine T-lymphocytes (?)
Leflunomide Pyridine synthesis
Methotrexate Dihydrofolate reductase; folate metabolism
Sulfasalazine Uncertain; multifactorial, including impairment of lymphocyte function and
cytokine synthesis
Oral DMARDs Included in the Comparative Effectiveness Review
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

10. Biologic DMARDs Included in the Comparative Effectiveness Review
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
Biologic Disease-Modifying anti-rheumatic Drugs
Name Trade Name Target of Activity
Adalimumab Humira® TNF-α
Certolizumab pegol Cimzia® TNF-α
Etanercept Enbrel® TNF-α
Golimumab Simponi® TNF-α
Infliximab Remicade® TNF-α
Abatacept Orencia® CD28
Anakinra Kineret® IL-1
Rituximab Rituxan® CD20
Tocilizumab Actemra®
RoActemra®
IL-6 receptor
Abbreviations: IL = interleukin; TNF-α = tumor necrosis factor-alpha

11. Implementasi guideline
• Apakah kita mengimplementasi guideline yang ada?
• Ya sebagian kecil
• Jika iya/tidak alasannya kenapa
• Akses terhadap update guideline
• Guideline mana yang kita ikuti
• IRA. EULAR, ACR, ARA ?, CRA ?
• Berapa banyak dokter yang mengikuti guideline?
• Belum ada survey.
• Rheumatologist umumnya sesuai

12. EULAR RECOMMENDATION FOR THE
MANAGEMENT OF RA
(Phase 1)
Smolen JS, et al. Ann Rheum Dis 2013;0:1-18

13. EULAR RECOMMENDATION FOR THE
MANAGEMENT OF RA
(Phase 2)
Smolen JS, et al. Ann Rheum Dis 2013;0:1-18

14. EULAR RECOMMENDATION FOR THE
MANAGEMENT OF RA
(Phase 3)
Smolen JS, et al. Ann Rheum Dis 2013;0:1-18

15. 2012 ACR Update

16. Tantangan
• Hambatan yang dijumpai dalam penerapan guideline
untuk tatalaksana AR ?
• Ketersediaan guideline
• Aksesibilitas
• Ketersediaan obat yang dianjurkandalam guideline

17. Apa yang menjadi pertimbangan utama dalam
menentukan tatalaksana pasien AR ?
• Kondisi pasien :
• Disease activity
• Disease damage
• Comorbidity
• Aspek DMARDs
• Efficacy, safety profile, drug interaction
• Ketersediaan obat dalam formularium:
• FORNAS
• Formularium Rumah Sakit
• Dukungan finansial / insurance

18. The strength of evidence for each of the following findings is low:
Patients with moderate rheumatoid arthritis (RA) had better overall
improvement and better functional status than patients with severe RA.
However, patients with severe RA had the greatest degree of
improvement from baseline.
In treatment with methotrexate (MTX), as the age of patients increased,
the likelihood of major clinical improvement decreased slightly; however,
overall age did not affect efficacy or risk of adverse effects.
Patient Characteristics on Outcomes of DMARD Treatment
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at
www.effectivehealthcare.gov/dmardsra.cfm.

19. Biologics showed no apparent influence on the risk of cardiovascular
events in the elderly (≥65 years of age).
Toxicity of MTX was more likely in patients with greater renal impairment.
High-risk comorbidities (cardiovascular disease, diabetes, malignancies,
and renal impairment) did not increase the risk of serious adverse events
or infections in patients treated with b-DMARDs.
Concomitant antidiabetic, antihypertensive, or statin medications given
to patients treated with b-DMARDs did not increase the risk of adverse
events.

20. Head-to-Head Comparisons of Oral DMARDs for Rheumatoid Arthritis
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.
Comparison
N Studies; Patients
Reduced Symptoms or
Disease Activity
Limiting Radiographic
Progression Improved Function
Improved Quality of
Life
SSZ vs. MTX*
3; 1,001
(disease duration <3
years)
NSD (DAS)
SOE = Moderate
NSD
SOE = Moderate
NSD
(3 RCTs; 479 patients)
SOE = Moderate
NR
LEF vs. MTX*
2; 1,481
NSD (ACR20 rates)
SOE = Low
NSD
SOE = Low
Greater improvement with
LEF at 12 months (HAQ) but
less than the MCID
SOE = Low
Greater with LEF at 12
months
(SF-36 physical
component )
SOE = Low
LEF vs. SSZ
1; 358
SOE = Insufficient
NSD
SOE = Low
Greater improvement with
LEF (HAQ) to 24 months
SOE =Low
NR
*Methotrexate was used at 7.5 to 25 mg per week in the reported studies.
ACR20 = American College of Rheumatology 20-percent improvement criteria; DAS = disease activity score; HAQ = Health Assessment Questionnaire; LEF =
leflunomide; MCID = minimum clinically important difference; MTX = methotrexate;
NR = not reported; NSD = no statistically significant difference; RCT = randomized controlled trial; SOE = strength of evidence; SSZ = sulfasalazine

21. Head-to-Head Comparisons of Combination Treatment With Oral DMARDs
Intervention
N Studies;
Patients Comparator
Patient
Characteristics
Reduced Symptoms
or Disease Activity
Limiting
Radiographic
Progression Improved Function‡
SSZ plus
MTX*
4; 709
SSZ or MTX*
monotherapy
DMARD-naïve,
early RA†
NSD
SOE = Moderate
NSD
SOE = Moderate
NSD
SOE = Moderate
2 or 3 oral
DMARDs in
combination
(MTX*, SSZ,
HCQ)
2; 273
1 or 2 oral
DMARDs
Patients with
longstanding
active RA
3 oral DMARDs are
favored over 2 to
improve disease
activity.
SOE = Moderate
NR
Difference less than
MCID
SOE = Moderate
* Methotrexate was used at 7.5 to 25mg per week in the reported studies.
† Early rheumatoid arthritis is defined as <3 years.
‡ Health-related quality of life was not reported.
DMARD = disease-modifying anti-rheumatic drug; HCQ = hydroxychloroquine; LEF = leflunomide;
MCID = minimum clinically important difference; MTX = methotrexate; NR = not reported; NSD = no statistically significant
difference; RA = rheumatoid arthritis; SOE = strength of evidence; SSZ = sulfasalazine
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

22. Head-to-Head Comparisons of Biologic DMARDs
In patients with active RA (>3 years), with failed or inadequate disease response to DMARDs who did not receive an
anti–TNF-α DMARD, head-to-head comparisons of DMARDs produced the following results:
Intervention Comparator
Symptoms or
Disease Activity*
(N Studies; N Patients)
Function
(N Studies; N Patients)
Quality of Life
(N Studies; N Patients)
Etanercept Infliximab
Faster response with etanercept, but
NSD in the longer term
(6; 5,883) SOE = Low
2 of 3 studies reported NSD
(3; 2,239) Insufficient
Insufficient
Etanercept Adalimumab
ACR70 at 6 months showed NSD
(1; 2,326) SOE = Low
NSD
(1; 707) SOE = Low
NSD
(1; 707) SOE = Low
Adalimumab Infliximab
Symptom response (ACR20 at 6
months) and DAS at 1 year greater
with adalimumab
(2; 3,033) SOE = Low
Greater improvement at 12
months with adalimumab but
not greater than the MCID
(1; 707) SOE = Low
SF-36 physical component at 12
months favors adalimumab
(1; 707) SOE = Insufficient
Abatacept Infliximab
Greater decrease in DAS and greater
remission rate, both at 1 year, with
abatacept.
(3; 3,464) SOE = Low
NSD at 1 year
(1; 431) SOE = Low
SF-36 physical component at 1 year
favors abatacept but not greater
than the MCID
(1; 431) SOE = Low
*Radiographic progression not reported.
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

23. Head-to-Head Comparisons of Oral and Biologic DMARDs
Intervention
(N Studies,
N Patients) Comparator Symptoms or Disease Activity
Radiographic
Evidence of
Progression Functional Capacity
In patients with longstanding active RA who required a change in therapy*:
Biologic DMARDs
as a class
Oral DMARDs
as a class Higher chance of remission with biologics
than with oral DMARDs
SOE = Moderate
NR Insufficient
1 retrospective cohort study
N = 1,083
Biologic DMARDs Oral DMARDs
Higher response rates for biologic DMARDs
SOE = Moderate
NR Insufficient
4 RCTs, 2 cohort studies
N = 3,696
* Health-related quality of life was not reported.
DMARD = disease-modifying anti-rheumatic drug; NR = not reported; RA = rheumatoid arthritis; RCT = randomized controlled trial; SOE = strength of evidence
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

24. DMARD Combinations Versus Monotherapies
Intervention* Comparator
Symptoms or
Disease Activity
(N Studies;
N Participants)
Radiographic
Progression
(N Studies;
N Participants)
Function
(N Studies;
N Participants)
Quality of Life
(N Studies;
N Participants)
Biologic
DMARD plus
MTX†
Biologic
DMARD
Monotherapy
(5 RCT, 4 cohort; 9,804)
Combination is
more effective
SOE = Moderate
(2; 1, 495)
Less change with a
combination
SOE = Moderate
(2; 1,495)
Combination
treatment is more
effective
SOE = Moderate
(2; 1,495)
Combination
treatment is more
effective.
SOE = Low
Biologic
DMARD plus
MTX or SSZ
MTX† or SSZ
Monotherapy
(7; 4,482)
Combination is
more effective
SOE = High
(7; 4,482)
Less change with
combination
SOE = Moderate
(7 RCT, 1 cohort; 7,516)
Combination
treatment is more
effective
SOE = High
(7 RCT, 1 cohort;
7, 516)
Combination
treatment is more
effective
SOE = Moderate
* Patients with active disease whose disease did not respond to an oral DMARD did not benefit from including that oral
DMARD in combination with a biologic DMARD.
† MTX was used at a dose of 7.5 to 25mg per week in the reported studies.
In patients with longstanding active rheumatoid arthritis with inadequate disease control, head-to-head comparisons of
combined DMARDs and DMARD monotherapy were conducted.
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

25. DMARD Combinations Versus Monotherapies
In patients with early rheumatoid arthritis who had not been treated with methotrexate (MTX), or who had
not received MTX in the previous 3 months, head–to–head comparisons of combination therapy and MTX
monotherapy were examined for effects on function and quality of life.
Intervention Comparator Patient Characteristics
Function
(N Studies;
N Participants)
Quality of Life
(N Studies;
N Participants)
Biologic DMARD
plus MTX*
MTX* monotherapy
Early RA†
MTX Naïve or not recently
on MTX*
(2; 1,495)
Combination is more
effective.
SOE = Moderate
(2; 1,495)
Combination is more
effective.
SOE = Low
* Methotrexate was used at 7.5 to 25mg per week in the reported studies.
† Early RA is defined as disease of as less than 3 years’ duration.
DMARD = disease-modifying anti-rheumatic drug; MTX = methotrexate; RA = rheumatoid arthritis; SOE = strength of evidence
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

26. Comparative Benefits of Oral and Biologic DMARDs in Early RA
Patient Characteristics Intervention Comparator
Reduced Symptoms or
Disease Activity
Limiting
Radiographic
Progression Improved Function
Patients with early
RA*
2 to 3 oral DMARDs
plus corticosteroids
Oral DMARD
Monotherapy
Combination is more
effective at 28 but not 52
weeks.
(2; 354) SOE = Low
Combination is more
effective
(2; 354)
SOE = Low
Combination is
more effective† (2;
354)
SOE = Low
MTX-naïve patients
with aggressive early
RA
MTX‡ Adalimumab,
Etanercept
Results are similar
(2; 1,431)
SOE = Moderate
Biologic DMARD is
more effective at
limiting progression.
(2; 1,431)
SOE = Low
Results are similar
with MTX and
adalimumab§
(2; 1,431)
SOE = Low
MTX-naïve patients
with aggressive early
RA
MTX‡ plus biologic
DMARD
Biologic DMARD
Monotherapy
Combination is more
effective
(also improves remission
rates)
(1; 799) SOE = Low
Combination is more
effective.
(1; 799)
SOE = Low
NR§
* Early RA is disease of less than 3 years’ duration.
† Combination treatment is also more effective at improving quality of life.
‡ Methotrexate was used at a dose of 7.5 to 25mg per week in the reported studies.
§ Quality-of-life outcomes were not reported.
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

27. Combining methotrexate (MTX) or other oral disease-modifying anti-
rheumatic drugs (DMARDs) with a biologic DMARD does not alter the
adverse event rate found with the biologic DMARD alone.
Strength of Evidence = Low
Combining MTX and biologic DMARDs demonstrates a better
tolerability profile than MTX alone.
Strength of Evidence = Low
Evidence is insufficient to estimate differences in rates of specific
adverse events between the biologic and oral DMARDs.
Comparative Adverse Effects of Combining DMARDs
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

28. Withdrawal due to adverse events
Time to withdrawal
Infusion and injection-site reactions
Infections
Malignancy
Mortality
Cardiovascular and cerebrovascular events
Rare but serious adverse events: demyelination,
autoimmunity, pancytopenia, and hepatotoxicity
Adverse Effects of Interest in the Comparative Effectiveness Review
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

29. Apakah nyeri yang berkurang atau membaik menjadi poin yang
paling utama dalam pencapaian goal of treatment di AR ?
• Dari sisi pasien jawabannya: YA
• NYERI merupakan KELUHAN UTAMA disamping STIFFNESS pada pasien
dengan RA
• Dari sisi dokter : disease control
• Disease activity (inflammation)
• Function
• Disease damage

30. The natural history of rheumatoid arthritis (RA) and the role of
disease-modifying anti-rheumatic drugs (DMARDs) in reducing
symptoms and improving disease control
The potential benefits and adverse effects of DMARDs
Changes in lifestyle that can help relieve RA symptoms, such as
diet and exercise
Patient and family preferences and values regarding treatment
What To Discuss With Your Patients and Their Family
Donahue KE, Jonas D, Hansen RA, et al. Comparative Effectiveness Review No. 55. Available at www.effectivehealthcare.gov/dmardsra.cfm.

31. How to monitor Tt in RA?
• Disease activity is assessed by several parameters…
• Duration of morning stiffness
• Tender joints count
• Swollen joints count
• Observer global assessment
• Patient global assessment
• Visual analogue scale for pain
• Health assessment questionnaire
• ESR
• NSAID pill count etc
• Patient on MTX, SSZ or leflunamide show clinical improvement in 6-8 wks.
• Patient should be observed for 6 months before declaring a DMARD ineffective.

32. How long should Tt. be continued?
• Once remission is achieved , maintenance dose for long period is recommended.
• Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is discontinued
in most instances.
• DMARDs are discontinued by patients because of toxicity or secondary
failure(common after 1-2 yrs) and such patients might have to shift over different
DMARDs over 5-10 yrs.
• Disease flare may require escalation of DMARD dose with short course of
steroids.

33. Thank you.