1) Combination DMARD therapy is superior to monotherapy in treating rheumatoid arthritis, with methotrexate as the cornerstone. Studies show combinations of traditional DMARDs can be as effective as combinations including biologics. 2) The COBRA trial demonstrated the benefits of initial intensive combination therapy including prednisolone, methotrexate, and sulfasalazine, followed by tapering medications. Benefits were seen even after medications were withdrawn. 3) Triple therapy with methotrexate, hydroxychloroquine and sulfasalazine is effective and durable for rheumatoid arthritis, shown in trials to be superior to double therapies and monotherapy.

1. Alternative Combinations
Safwat EL-ARABY
Rheumatology & Clinical Immunology
EGYPT

2. Strategy
Basic Therapy / Gene Therapy
Immunogenic Therapy / Pathways / Cells - Abs
Epigenetic Therapy / Risk & Trigger factors / MicroRNA
Organ therapy / Extra-articular
Pathological therapy / Pannus X Tendonitis
Symptomatic therapy
Pain therapy
Physical therapy / Fibrosis – contractures - deformities
Occupational therapy
Socioeconomic therapy

3. Basic Therapy
DMARDs
conventional synthetic-DMARDs ( cs )
biologic-DMARDs ( b )
targeted biologic-DMARDs ( tb )
Bridge Therapy
Organ Therapy
Pathological Therapy
Symptomatic
Physical Therapy

4. Strategy
Monotherapy
Combination ( double )
Combination ( Triple )
Combination ( Quart )
Stepped-up
Stepped - down
Sequential
Saw-toothed strategy
T2T
Timing for induction / alternation & withdrawal

5. Combination DMARD Therapy
in
Rheumatoid Arthritis

6. Combinations of DMARDs can have superior efficacy without increased toxicity
--------------------------------------------------------------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------
MTX is the cornerstone of combination therapy
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--------------------------------------------------------------------------------------------------
Combinations of traditional DMARDs are as effective as combinations of MTX plus biologic therapy
--------------------------------------------------------------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------
Current research is focused on the best strategies for : introduction, timing, and patient selection for
combination therapy
Kelley,s Textbook of Rheumatology : 2021

7. Currently, the timing and make-up of combinations selected to treat RA is one of the most important decisions that
clinicians face
----------------------------------------------------------------------------------------------
-------------------------------------
Four major studies have demonstrated the superiority of combinations of DMARDs versus monotherapy in head-to-head
comparisons.
----------------------------------------------------------------------------------------------
-------------------------------------
Trials with multiple conventional DMARDs and biologics have shown them to be more effective than placebo when added
to the baseline MTX in patients who have active disease despite MTX therapy.
----------------------------------------------------------------------------------------------
---------------------------------------
With very few exceptions, successful combination trials have included MTX , and it remains the cornerstone of
combination therapy.
Kelley,s Textbook of Rheumatology : 2021

8. COBRAtrial
Step-down approach
Pronounced example for insufficient Therapy
An initial 6‐month cycle of intensive combination treatment

9. Early Rheumatoid Arthritis
In the late 1990s,
step-down approach in the COBRA trial.
In this trial, patients with early disease were randomly assigned to two groups.
A combination of Prednisolone, MTX, and SSZ was compared with SSZ alone.
Prednisolone was started at 60 mg/day, ( tapered in 6 weeks to 7.5 mg/day )
rapidly tapered, and discontinued by week 28.
MTX ( 7.5 mg / week ) was given until week 40 , ( then stopped )
The dose of SSZ ( 2 gm / day ) was the same in the two groups.

10. Early Rheumatoid Arthritis
At 28 weeks,
the combination group was significantly better than the SSZ alone group.
While prednisolone and MTX were tapered, clinical responses became similar in the two groups; however, significant benefits in certain
parameters were noted in the combination group.
It is important to note that combination therapy was not more toxic.
Subsequent data confirm that the radiographic benefits conferred by COBRA in the initial trial continued for at least 5 years
Duration of follow up is 5 Y . So , it could be more

13. Remission : Duration of follow up is 5 Y . So , it could be more

15. Moreover, the COBRA combination is as effective as high-dose MTX in combination with infliximab and is cost effective compared with other
antirheumatic therapies.
Cobra Therapy for Rheumatoid Arthritis
June 1, 2010 • By Lilian H.D. van Tuyl, PhD, and Maarten Boers, MD,
PhD
Despite these features and its long-term benefits, COBRA therapy is not often prescribed in clinical practice,
“Why ?”
Rheumatologist in the Netherlands :
COBRA therapy was regarded as effective and safe but
Complicated to administer.
Patients’ possible negative reaction to the large number of pills to be taken
Doctors feared the reaction of patients,
Rheumatologists felt that they lacked the time to explain and prescribe COBRA
Rheumatologist felt uncomfortable prescribing high doses of prednisolone.

16. From these focus groups, it appears that the rheumatologist is more afraid of COBRA therapy than the patient is
and that the low prescription rate is mostly determined by the opinion of the rheumatologist.
Cobra Therapy for Rheumatoid Arthritis
June 1, 2010 • By Lilian H.D. van Tuyl, PhD, and Maarten Boers, MD,
PhD

17. The second important early RA study is the
Finland Rheumatoid Arthritis (Fin-RA) trial.
In this open trial, patients were randomly assigned to receive combination DMARD therapy (MTX, SSZ, HCQ, and low-dose prednisolone)
or monotherapy with SSZ with optional prednisolone.
The major endpoint of this trial was remission at 2 years.
Significantly, patients who received combination therapy achieved more frequent remissions.
A follow- up of this trial at 5 years demonstrated that patients treated initially with the combination were less likely to have evidence of C1-
C2 subluxation on cervical spine radiographs.

18. In a third trial, from Turkey,
patients with early RA were randomly assigned to receive :
single DMARD therapy (MTX, SSZ, or HCQ),
two-drug therapy (MTX and SSZ or MTX and HCQ), or
three-drug therapy (MTX, SSZ, and HCQ),
with remission at 2 years as the major outcome.
For all endpoints measured,
two drugs were statistically superior to monotherapy, and
three drugs were statistically superior to the two-drug regimens.

19. The TEAR (Treatment of Early Aggressive RA) trial
enrolled patients with early RA and compared initial combination therapy with
MTX, SSZ, and HCQ (triple) or
MTX and Etanercept with initial MTX monotherapy
with step-up to combination therapy at 6 months
for patients with a (DAS) 28-ESR of 3.2 or greater.
Results showed that either initial combination therapy was superior to MTX monotherapy at 6 months, with a reduction in DAS28-ESR for
combined groups of 4.2 versus 3.6 (P < 0.0001).
There were no differences in DAS28-ESR seen between either of the initial combination regimens.

20. Between weeks 48 and 102, there were no significant differences in DAS28-ESR between combination groups, whether started as initial or
step-up therapy.
By week 102, there was a statistically significant change from the baseline modified Sharp/van der Heijde score between the group receiving
initial MTX plus
etanercept versus triple (0.64 vs. 1.69; P = 0.047).287
In sum, combination therapy, whether step-up or initial therapy, has shown in multiple trials to be superior to MTX alone in early rheumatoid
arthritis.
Predictors of who may respond to MTX monotherapy alone and who needs early combination therapy are still lacking.

21. Combination DMARD therapy was first studied in groups of patients with active disease despite MTX therapy, or suboptimal MTX
responders.
Patients With Active Disease Despite MTX
OR Suboptimal MTX Responders
Studies : Showed the advantage of combination therapy with MTX and another DMARD compared with continued therapy with
MTX alone

22. Weinblatt (93) 24 weeks
Weinblatt (95) 24 weeks
Lipsky (77) 30 weeks
Cohen (94) 24 weeks
Tugwell (45) 24 weeks
O’Dell (96) 96 weeks
Kremer (90) 24 weeks
Lehman (26) 48 weeks
Kremer (97) 24 weeks
Emery (98) 24 weeks
Kay (99) 16 weeks
Genovese (100) 24 weeks
Keystone (101) 24 weeks
Kremer (103) 24 weeks
Schiff (102) 26 weeks
Etanercept
Infliximab
Anakinra
Adalimumab
CSA
SSZ / HCQ / SSZ &HCQ
Leflunomide
Gold
Abatacept
Rituximab
Golimumab
Tocilizumab
Certizumab
Abatacept
Tofacitinib
27 – 71
20 – 58
23 – 42
15 – 66
16 – 48
16 - 36 – 55 – 71
20 -47
30 – 61
40 – 68
28 – 55
27 – 61
25 – 61
14 – 60
42 – 59
31 - 52
ACR20 responders (%)
James R. O’Dell ; Treatment of Rheumatoid Arthritis : CHAPTER 71- P : 1187 KELLEY & FIRESTEIN’S Textbook of Rheumatology Tenth Edition : ISBN: 978-0-323-31696-5 Volume 1 Part Number:
9996112179 Volume 2 Part Number: 9996112055 : Copyright © 2017 by Elsevier / Eleventh Edition : 2021 ;
P:1192
Adding s & b DMARDS to MTX non-responders

23. Therapy with the combination of MTX, SSZ, and HCQ, so-called Triple Therapy, is
well tolerated and more effective than
MTX monotherapy or SSZ monotherapy
James R. O’Dell ; Treatment of Rheumatoid Arthritis : CHAPTER 71- P : 1187 KELLEY & FIRESTEIN’S Textbook of Rheumatology Tenth Edition : ISBN: 978-0-323-31696-5 Volume 1 Part Number:
9996112179 Volume 2 Part Number: 9996112055 : Copyright © 2017 by Elsevier / Eleventh Edition : 2021 ;
Triple Therapy :
in an open trial of patients with early disease, more effective than the double combination of MTX and SSZ or MTX
and HCQ.

24. What about prolonged trials ? :
a 2-year, randomized, double-blind, parallel study of 102 established patients with RA was done to compare :
Triple-Drug Therapy (MTX, SSZ, and HCQ) versus
Double Therapy (HCQ and SSZ) versus
Monotherapy with MTX.
Significantly more patients receiving triple-drug therapy achieved a modified Paulus 50% response, compared with those given double
therapy.
It is durable, with 62% of patients remaining on triple therapy for 5 years continuing to maintain a 50% efficacy response
Triple Therapy was well tolerated, and numerically fewer withdrawals occurred in the combination group compared with the
other two groups.
James R. O’Dell ; Treatment of Rheumatoid Arthritis : CHAPTER 71- P : 1187 KELLEY & FIRESTEIN’S Textbook of Rheumatology Tenth Edition : ISBN: 978-0-323-31696-5 Volume 1 Part Number:
9996112179 Volume 2 Part Number: 9996112055 : Copyright © 2017 by Elsevier / Eleventh Edition : 2021 ;

25. In follow-up, a 2-year, double-blind trial on patients with moderately advanced disease
was done in 2002, in which the triple combination group was compared with two
double-combination groups (MTX plus SSZ and MTX plus HCQ) in a head-to-head
comparison.289
Patients were stratified for previous MTX use, and previous users had to have active
disease despite receiving 17.5 mg/wk. The triple-therapy group and both double-
therapy groups tolerated their treatments well, with only 8% withdrawing for
toxicities, which were mostly minor.
Triple therapy is superior to either of the double combinations.
James R. O’Dell ; Treatment of Rheumatoid Arthritis : CHAPTER 71- P : 1187 KELLEY & FIRESTEIN’S Textbook of Rheumatology Tenth Edition : ISBN: 978-0-323-31696-5 Volume 1 Part Number:
9996112179 Volume 2 Part Number: 9996112055 : Copyright © 2017 by Elsevier / Eleventh Edition : 2021 ;
MT
X
MTX
+
HQ
MT
X
+
HQ
+
SA
Z
MTX
+
SAZ
‫؟‬ ‫الثالثة‬ ‫العقاقير‬ ‫الجتماع‬ ‫خاص‬ ‫مغزى‬ ‫هناك‬ ‫هل‬

26. A double-blind, placebo-controlled trial compared the addition of leflunomide or
placebo to baseline MTX in Suboptimal MTX responders
Leflunomide or placebo was added to MTX.
The combination group was statistically superior to the MTX-placebo group in
terms of (ACR20) set criteria for clinical response.
The combination was reasonably well tolerated, but side effects including diarrhea,
nausea, and dizziness were increased in the combination arm.
Elevated ALT levels (>1.2 times normal) occurred more frequently in patients on
combination therapy than in those on MTX alone, with increases leading to withdrawal
in 2.3% of patients who received the combination.
O’Dell J, Mikuls TR, Taylor TH, et al.: Therapies for active rheumatoid arthritis after methotrexate failure, N Engl J Med 369:307– 318, 2013.
MT
X
MTX
+
Place
bo
MTX
+
LEF

27. It was a 48-week double-blind, noninferiority trial of 353 established patients with RA with active disease despite MTX therapy
Groups were randomly assigned to receive triple DMARD therapy (MTX, SSZ, HCQ) versus MTX and etanercept.293
Patients who did not respond by week 24 were switched in a blinded fashion to the other therapy.
The primary outcome was improvement in the DAS28.
Both groups had significant improvement in the first 24 weeks, with only 27% in each group requiring a switch in therapy.
Improvement was seen in both of the groups who switched therapy (P < 0.001), and the response after switching did not differ significantly between the two groups
(P = 0.08).
The change in DAS28 (baseline to 48 weeks) was −2.1 with triple therapy and −2.3 with MTX plus etanercept.
Triple therapy is noninferior to MTX plus etanercept (P = 0.002).
Cost-effectiveness analyses have revealed that the strategy of first using triple therapy before adding etanercept is cost-effective with no differential effect on efficacy
or toxicity.
RA : Comparison of Active Therapies (RACAT) trial
O’Dell J, Mikuls TR, Taylor TH, et al.: Therapies for active rheumatoid arthritis after methotrexate failure, N Engl J Med 369:307– 318, 2013.
James R. O’Dell ; Treatment of Rheumatoid Arthritis : CHAPTER 71- P : 1187 KELLEY & FIRESTEIN’S Textbook of Rheumatology Tenth Edition : ISBN: 978-0-323-31696-5 Volume 1 Part Number: 9996112179 Volume 2 Part
Number: 9996112055 : Copyright © 2017 by Elsevier / Eleventh Edition : 2021 ;

28. The strategy of first adding
conventional DMARDs was not
inferior to first adding ETAN
Further, no differences in radiographic
outcomes were found, with the modified
Sharp scores (P = 0.43),
During the RACAT trial,
more patients in the triple
group experienced GI
adverse effects (30% vs.
22%; P = 0.01), whereas
more patients in the ETAN
group had infections (37%
vs. 25%, P = 0.02).
Serious infections occurred in
12 patients in the ETAN
group and in 4 patients in
the triple therapy group.
Conventional Combinations should be tried first

29. Corticosteroids have not traditionally been considered DMARDs.
However, they clearly fulfill all of the criteria for DMARDs,
including halting radiographic progression.295 Few clinicians who care for patients with RA dispute their efficacy. Indeed, they
have
been used as baseline therapy for more than half of the patients
included in the combination trials discussed previously.
Prednisolone undoubtedly was a critical component for the
success of the combination therapy for early rheumatoid arthritis
(COBRA) protocol280 and may have played a role in the success of
the combination group in the Fin-RA trial.282 One study’s295,296
report of the ability of prednisolone to significantly retard radiographic
progression of RA compared with placebo is testament
to the efficacy of steroids when used in combination with other
DMARDs. Corticosteroids clearly deserve further formal investigation
as a component of combination therapy. The COBRA
trial and the Kirwan data have raised another interesting question:
Corticosteroids in DMARD Combinations

30. Biologic Agents in DMARD Combinations
Biologic agents that block TNF (etanercept, infliximab, adalimumab,
certolizumab, and golimumab) and IL-1 (anakinra) have
been studied in patients with early-stage and established RA in
combination with MTX298–306 (see Fig. 64.8). These trials have
shown superior improvements in clinical and radiographic endpoints
in the combination groups.303,304 Other biologic agents
and small molecules—rituximab, an anti-CD20 monoclonal antibody;
abatacept, a T cell co-stimulatory inhibitor; tocilizumab,
an IL-6 receptor antagonist; and tofacitinib, an oral Janus kinase
inhibitor—have been studied in combination with MTX and also
show superior improvements in clinical and radiographic outcomes.
307–310 There are additional biologic agents being studied
and approved in the treatment of RA. In almost every biologic
study, combination use with MTX leads to superior outcomes
when compared to therapy with the biologic agent alone.

31. Combination Therapy
Factors that predict a poor prognosis for patients with RA are
well accepted and include high titer rheumatoid factor and CCP,
elevated ESR and CRP, the number of joints involved, erosions,
and the presence of certain genetic markers. However, unless these
factors can predict response to certain therapies in a differential
fashion, they are of limited therapeutic use. Patient characteristics
recommending one therapeutic regimen versus another remain
to be fully elucidated. Genetic differences have been suggested to
influence outcomes in a differential fashion. Until this observation
can be corroborated and factors that predict response to other
therapies elucidated, choices will remain largely empiric.

32. Combination Therapy
Treatment of patients with RA by using MTX combinations
should be the gold standard against which future therapies are
compared. Available data demonstrate that a variety of combinations
are more effective than MTX alone. Until recently,
no direct head-to-head trials comparing combinations of traditional
DMARDs to MTX plus biologic agents existed. The
TEAR and RACAT trials have shown that the use of traditional
DMARD combinations (MTX, SSZ, HCQ) is as effective
as combinations that include biologic agents (MTX plus
etanercept) as initial therapy and, importantly, in MTX nonresponders.
Recent guidelines published by the ACR131 and
the European League against Rheumatism (EULAR)311 recommendations
for the use of DMARDs and biologic agents in RA
support this premise.

33. Although more information is available every day, many questions
remain to be answered regarding the appropriate timing
of combination therapy and the optimal combinations for specific
patients and for specific clinical situations.
Future research
is needed to clarify the role of corticosteroids and, particularly,
biologic response modifiers as components of and alternatives to
MTX combination regimens.