1. A NEW LOOK AT RA Interactive Hot Topics Series
Treatment Alternatives for the Patient With an Inadequate Response to Oral MTX
I’m going to spend the next 15 minutes discussing approaches to managing RA patients who have inadequate responses to oral MTX. This is a problem that has been addressed in a very large number of clinical studies and there are a number of options for these patients.
MP-RA-0296

2. What Percent of Patients Initiating Treatment with Oral MTX Will Require a Change in Treatment
The first question to ask is: how big is the problem. That is, what percentage of patients are likely to have an inadequate response to oral MTX.

3. 72% of Patients Stepped up
TEAR: Design
Assess whether it is better to intensively treat all patients with early RA using combinations of drugs or to reserve this approach for MTX non-responders
2-year,
double-blind,
placebo-controlled RCT
(n=755)
IE Immediate
oral MTX ≤20 mg/wk + ETN 50 mg/wk sc
(n=244)
SE* Step-up from
oral MTX 20 mg/wk to oral MTX + ETN 50 mg/wk SC at
wk 24 (n=255)
72% of Patients Stepped up
IT Immediate triple tx
oral MTX ≤20 mg/wk
+ SSZ 500 mg BID
+ HCQ 200 mg BID
(n=132)
ST* Step-up from
oral MTX 20 mg/wk to triple tx oral MTX
+ SSZ + HCQ at
wk 24 (n=124)
Results from large-scale clinical trials provide some information. This slide shows the design of the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. One portion of this study assessed the efficacy of oral MTX monotherapy over 24 weeks. Patients remained on this treatment if they achieved low disease activity — a DAS28-ESR score <3.2. Results from TEAR indicated that 72% of the patients who started on oral MTX did not achieve this goal.
*Step up occurred if DAS28-ESR was ≥3.2 at week 24
ETN, etanercept; HCQ, hydrochloroquine; IE, immediate active etanercept; IT, immediate triple therapy; MTX, methotrexate; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy
Moreland LW, et al. Arthritis Rheum. 2012;64:

4. 53% of Patients Had Inadequate Responses to Oral MTX
SWEFOT: Design1,2
MTX monotherapy
(20 mg/wk for 3-4 months)
(n = 487)
53% of Patients Had Inadequate Responses to Oral MTX
MTX responders
DAS28 ≤3.2
(n = 229)
MTX-IR
DAS28 >3.2
(n=258)
Intolerant (n=27)
DAS28 ≤3.2 Continued MTX monotherapy
(n=145)
DAS28 > 3.2
MTX + SSZ + HCQ
(n=130)
DAS28 > 3.2
MTX + infliximab
(n=128)
The SWEFOT (Swedish Pharmacotherapy) trial had a somewhat similar design. Patients were treated with oral MTX for 3-4 months and those who did not achieve low-disease activity had either a TNF inhibitor or other synthetic DMARDs added to treatment. Of the 487 patients who started the study, 53% required additional treatment.
Withdrew for other reasons (n=57)
(Randomized SWEFOT trial)
DAS, Disease Activity Score; HCQ, hydrochloroquine; IR, inadequately responsive; MTX, methotrexate; SSZ, sulfasalazine.
1. van Vollenhoven RF et al. Lancet. 2009; 374:
2. van Vollenhoven RF et al. Lancet. 2012; 379:

5. Guidance on Next Step for These Patients
All RA guidelines provide advice on how to manage patients who have inadequate responses to oral MTX monotherapy.

6. ACR Guidelines for Early RA
DMARD-Naïve Early RA
Low Disease Activity
Moderate or High Disease Activity
DMARD Monotherapy†
DMARD Monotherapy†
Treat to Target#
Moderate or High Disease Activity*†
Combination Traditional DMARDs*† or TNF inhibitor +/- MTX*† or
Non-TNF Biologic +/- MTX*†
The ACR guidelines recommend combination therapy with conventional DMARDs or switching to or adding a TNF inhibitor or non-TNF inhibitor biologic agent — for example, abatacept — in patients with early RA who have moderate or high disease activity on MTX monotherapy.
Disease activity Treatment options or strategy Algorithm pathway for most patients
Disease state or prior treatment state Green box for strong recommendations Yellow box for conditional recommendations
* Consider adding low-dose glucocorticoids (≤10 mg/day of prednisone or equivalent) in patients with moderate or high RA disease activity when starting disease-modifying antirheumatic drugs (DMARDs) and in patients with DMARD failure or biologic failure
† Also consider using short-term glucocorticoids (defined as <3 months treatment) for RA disease flares. Glucocorticoids should be used at the lowest possible dose and for the shortest possible duration to provide the best benefit-risk ratio for the patient
# Treatment target should ideally be low disease activity or remission
Singh JA, et al. Arthritis Care Res. 2016;68:1-25 © 2015, American College of Rheumatology.

7. ACR Guidelines for Established RA
Low Disease Activity
Moderate or High Disease Activity
DMARD Monotherapy†
DMARD Monotherapy†
Treat to Target#
Moderate or High Disease Activity*†
Combination Traditional DMARDs*† or TNFi +/- MTX*† or Non-TNF Biologic +/- MTX*† or
Tofacitinib +/- MTX
The ACR guidelines for patients with established RA are similar. The single difference from those for patients with early disease is mention of tofacitinib (with or without MTX) as an additional option.
Disease activity Treatment options or strategy Algorithm pathway for most patients
Disease state or prior treatment state Green box for strong recommendations Yellow box for conditional recommendations
* Consider adding low-dose glucocorticoids (≤10 mg/day of prednisone or equivalent) in patients with moderate or high RA disease activity when starting disease-modifying antirheumatic drugs (DMARDs) and in patients with DMARD failure or biologic failure
† Also consider using short-term glucocorticoids (defined as <3 months treatment) for RA disease flares. Glucocorticoids should be used at the lowest possible dose and for the shortest possible duration to provide the best benefit-risk ratio for the patient
# Treatment target should ideally be low disease activity or remission
Singh JA, et al. Arthritis Care Res. 2016;68:1-25 © 2015, American College of Rheumatology.

8. Changing the Route of MTX Administration
Another approach to improving treatment efficacy in patients with inadequate responses to oral drug is to change the route of administration.

9. SC Administration Improves MTX Bioavailability
Single center, open- label, randomized, 2-period, 2-sequence, single-dose, crossover study in 4 dose groups (7.5 mg, 15 mg, mg, and 30 mg) with 54 healthy adults
Results from multiple studies have shown that systemic exposure to MTX does not rise linearly with oral dose and that bioavailability begins to decline with higher doses. This is not the case for SC administered MTX where the relationship between dose and area under the time versus plasma concentration curve is approximately linear. Thus, some patients may not achieve adequate exposure to MTX with oral delivery and may benefit from SC administration of the drug.
SC, subcutaneous.
Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

10. Interpatient Bioavailability of Oral MTX Is Variable
Oral Bioavailability of 10 mg/m2 MTX (Oral AUC/IV AUC)
In addition, The bioavailability of oral methotrexate varies greatly from one patient to another. This slide shows results from a study in which the pharmacokinetics and bioavailability of low-dose methotrexate (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received methotrexate in a single oral dose and a single IV dose one week apart. The results shown are the values for AUC after oral dosing divided by that for IV dosing. This is a measure of oral bioavailability and it is evident that it varies greatly from one subject to another.
Subject Number
AUC, area under the curve.
Adapted from Herman RA, et al. J Pharmaceutical Sci. 1989;78:

11. SC Administration Lowers Interpatient Variability in the AUC for MTX
SC administration of methotrexate has another important advantage over oral dosing: it results in much lower inter-patient variability in bioavailability. Inter-subject variability in the response to a given treatment can be determined by calculation of the coefficient of variation for the treatment group. This measure is simply the mean value divided by the standard deviation. The results on this slide are from one of several studies that provided information about bioavailability of SC methotrexate and they show that inter-patient variability in AUC for a given methotrexate dose is lower with SC versus oral administration.
SC, subcutaneous; AUC, area under the curve
Adapted from Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

12. Significantly Better Disease Control With SC vs Oral MTX
ACR Responses†
EULAR Remission†
The higher levels of long chain methotrexate polyglutamates achieved with subcutaneous vs oral methotrexate may be related to the improved clinical efficacy of subcutaneous vs oral drug observed in the single large-scale comparison of these two routes of administration in patients with rheumatoid arthritis.
† Week 16 results were carried forward for patients who switched from oral to SC MTX or had their SC MTX doses increased from 15 to 20 mg/wk.
SC, subcutaneous.
Braun J, et al. Arthritis Rheum. 2008;58: © 2008, American College of Rheumatology.
Adapted from Braun J. Clin Exp Rheumatol. 2010;28(suppl 61):S46-S51.

13. Significant Improvement in Disease Control Following Switch From Oral to SC MTX
Retrospective analysis of 103 RA patients switched from oral to SC MTX:
40 switched due to inadequate efficacy of oral MTX
63 patients switched due to gastrointestinal side effects of oral MTX
P=0.006
SC administration of MTX improves clinical outcomes for patients who cannot be managed with oral drug. This slide shows clinical results demonstrating significant improvement in DAS28 scores for patients who were switched from oral to subcutaneous administration of MTX and followed for 3 months. Improvements in DAS28 scores were observed for patients who switched treatment due to inadequate efficacy or intolerable side effects.
P=0.0001
SC, subcutaneous; DAS, disease activity score.
Hameed B, Jones H. Int J Rheum Dis. 2010;13:e83-e84. © 2010, Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.

14. Switching to SC MTX: Another Small Study, Same Result
Retrospective analysis of patient data collected between 2003 and 2011
N=112, 49 switched from oral to SC MTX due to intolerability (n=20) or inefficacy (n=29)
Pre-switch and 6-month post-switch DAS28 were collected and compared by Wilcoxon signed rank test
P<0.01
P<0.01
Median Score
Results from a second retrospective analysis of 112 patients switched from oral to SC MTX due to inadequate efficacy or intolerability demonstrated a similar outcome: a significant improvement in DAS28 scores over 6 months of follow-up.
Hammond A, Batley M. Presented at EULAR, 2014.

15. Adding or Switching to a Biologic

16. Adding a TNF Inhibitor: “Typical Results”
Multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to:
Adalimumab 40 mg SC every other week + MTX
Adalimumab 20 mg SC every week + MTX
MTX
The primary efficacy end points were:
Radiographic progression at week 52 (total Sharp score by a modified method [TSS])
Clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20])
Physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ])
There are dozens of trials that have evaluated addition of or switching to a biologic in patients with inadequate responses to oral MTX monotherapy. This slide summarizes the design of one of the earlier studies of adalimumab in 619 patients with an inadequate response to oral MTX. These patients were randomized to continued MTX monotherapy or MTX plus one of two dosing regimens for adalimumab. Radiographic and clinical outcomes were evaluated at 24 and 52 weeks.
Keystone EC, et al. Arthritis & Rheumatism. 2004;50:

17. Radiographic Progression52
2.0
1.5
1.0
0.5
Weeks
Mean Change
Joint Erosion Score 24 † ‡ 52
1.5
1.0
0.5
Weeks
Mean Change
Joint Space Narrowing Score 24 *
Modified Total Sharp Score * 52
1.5
1.0
0.5
Weeks
Mean Change 24 †
MTX
ADA 40 mg every other week + MTX
ADA 20 mg weekly + MTX
This slide summarizes the radiographic outcomes at 52 weeks. The combination of adalimumab plus MTX in either dosing regimen was significantly superior continued MTX alone with respect to changes in Total Sharp Scores at 24 and 52 weeks.
*P≤0.01, †P ≤0.001, and ‡P≤0.05 versus MTX alone
Keystone EC, et al. Arthritis & Rheumatism. 2004;50:

18. ACR Responses ACR20 ACR50 ACR704 8 12 16 20 24 28 36 40 44 52 48 32 60 70 50 30 10
Weeks
Patients (%)
ACR20 * 4 8 12 16 20 24 28 36 40 44 52 48 32 50 30 10
Weeks
Patients (%)
ACR50 * 4 8 12 16 20 24 28 36 40 44 52 48 32 30 25 15 10 5
Weeks
Patients (%)
ACR70 * †
MTX
ADA 40 mg every other week + MTX
ADA 20 mg weekly + MTX
Clinical results for ACR20, ACR50, and ACR70 also indicated significant superiority of each combination regimen over MTX alone at 24 and 52 weeks. Interestingly, about 20% of patients continued on MTX monotherapy achieved and maintained ACR20 responses.
*P≤0.01, †P≤0.001 versus MTX alone
Keystone EC, et al. Arthritis & Rheumatism. 2004;50:

19. Switching or Adding: Is There a Difference?
It does not appear to matter for tocilizumab
An important question that should be addressed when changing therapy in a patient with an inadequate response to oral MTX monotherapy is whether to switch to or add on the new agent. This slide shows results from a meta-analysis that provides pretty clear guidance with respect to this issue. In this analysis, 28 randomized controlled trials were identified that evaluated abatacept, anakinra, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib as monotherapy or part of combination treatment with oral MTX in patients with an inadequate response to MTX alone. With the exception of tocilizumab, combination treatment produced clinical results superior to those achieved with monotherapy.
ABT, abatacept; ACR20/50/70, 20%/50%/70% improvement in American College of Rheumatology criteria; ANA, anakinra; aTNF, anti-tumor necrosis factor; CrI, credible interval; MTX, methotrexate; TCZ, tocilizumab; TOF, tofacitinib
Buckley F, et al. J Manag Care Spec Pharm. 2015;21:

20. Adding Synthetic DMARDs
A number of studies have also compared the efficacy of combination therapy with MTX and a biologic versus MTX plus other synthetic DMARDs in patients with inadequate responses to oral MTX alone.

21. TEAR: Design IE Immediate SE* Step-up from IT Immediate triple tx
Assess whether it is better to intensively treat all patients with early RA using combinations of drugs or to reserve this approach for MTX non-responders
2-year,
double-blind,
placebo-controlled RCT
(n=755)
IE Immediate
oral MTX ≤20 mg/wk + ETN 50 mg/wk sc
(n=244)
SE* Step-up from
oral MTX 20 mg/wk to oral MTX + ETN 50 mg/wk SC at
wk 24 (n=255)
IT Immediate triple tx
oral MTX ≤20 mg/wk
+ SSZ 500 mg BID
+ HCQ 200 mg BID
(n=132)
ST* Step-up from
oral MTX 20 mg/wk to triple tx oral MTX
+ SSZ + HCQ at
wk 24 (n=124)
This slide shows the design of the TEAR trial, which I mentioned near the beginning of my talk. One aspect of this trial was a comparison of the addition of etanercept — the SE arm — vs hydrochloroquine and sulfasalazine — the ST arm — to oral MTX in patients with inadequate responses to MTX monotherapy.
*Step up occurred if DAS28-ESR was ≥3.2 at week 24
ETN, etanercept; HCQ, hydrochloroquine; IE, immediate active etanercept; IT, immediate triple therapy; MTX, methotrexate; RCT, randomized controlled trial; SE, step-up to etanercept; SSZ, sulfasalazine; ST, step-up to triple therapy; tx, therapy
Moreland LW, et al. Arthritis Rheum. 2012;64:

22. TEAR: Low Disease Activity in Early RA PatientsBL 72 2 3 6 7
DAS28-ESR
Visit Week 5 4 1 12 24 36
Year 1 60 84
Year 2
All groups Week 102 P=0.28
Step-up to multiple DMARDS at Week 24 if DAS28-ESR ≥ 3.2 for SE & ST groups IE SE ST IT
No significant difference between adding a biologic and conventional agents
The primary outcome of this study was the mean DAS28-ESR from week 48 to week Results at this time indicated no significant difference between outcomes for patients who had either etanercept or hydrochloroquine plus sulfasalazine added to treatment.
At week 24, 28% of patients initially in the MTX-only arms (SE and ST) had DAS28-ESR ≤3.2 and did not need to step up
41% and 43% of the immediate treatment (IE and IT) arms, respectively, had DAS28-ESR ≤3.2 at week 24
DAS, Disease Activity Score; IE, immediate active etanercept; IT, immediate triple therapy; MTX, methotrexate; SE, step-up etanercept; ST, step-up triple therapy
Moreland LW, et al. Arthritis Rheum. 2012;64: © 2012, American College of Rheumatology.

23. TEAR: ACR20/50/70 Responses IE IT SE ST % Meeting Criteria ACR20 90
100
% Meeting Criteria 80 70 60 50 40 30 20 10
Year 2
Month 6
ACR50
ACR70
SE vs ST
P=0.0109 IE IT SE ST
This slide shows the percentage of participants achieving ACR20, ACR50, and ACR70 at the time of initiation of step-up therapy (6 months) and at the 2-year conclusion of the study. By year 2, there was no difference in the proportions of participants meeting ACR20 and ACR50 response criteria. The only significant treatment difference at week 102 was for ACR70 where addition of etanercept resulted in a higher percentage of responders (18.2%) vs triple therapy (11.3%).
At month 6, both immediate-treatment (IE and IT) arms had significantly higher proportions of patients achieving ACR20/50/70 responses vs the step-up arms (all P<0.0001), regardless of the type of treatment
By year 2, only the ACR70 responses of the IE/SE and IT/ST arms (18.2% versus 11.3%; P= 0.01) differed significantly
ACR20/50/70, 20, 50, or 70% improvement in disease activity per American College of Rheumatology criteria; IE, immediate active etanercept; IT, immediate triple therapy; SE, step-up etanercept; ST, step-up triple therapy
Moreland LW, et al. Arthritis Rheum. 2012;64: © 2012, American College of Rheumatology.

24. Adding Conventional DMARDs vs a Biologic: CSP 551 RA: Comparison of Active Therapies (RACAT)
Methods
48-week, double-blind, non-inferiority trial in which 353 participants with RA who had active disease despite MTX therapy were switched to:
Triple regimen of MTX, sulfasalazine, and hydrochloroquine
Etanercept (ETN) plus MTX
The primary outcome was improvement in DAS28 joint counts at week 48
The RACAT trial had a design very similar to that for TEAR.
DAS, Disease Activity Score; ETN, etanercept; MTX, methotrexate, RA, rheumatoid arthritis
O'Dell JR, et al. N Engl J Med. 2013;369:

25. Adding Conventional DMARDs vs a Biologic: RACAT Primary Endpoint7
Triple therapy
ETN-MTX 6 5 4
DAS28 Mean Score 3 2 1
And it produced very similar results. At 24 and 48 weeks after augmentation of treatment, that was no significant difference between mean DAS28 scores for patients who had etanercept or hydrochloroquine plus sulfasalazine added to oral MTX. 24 48
Week
No. Evaluated
Triple therapy
Etanercept-MTX
178
175
157
161
154
155
ETN, etanercept; MTX, methotrexate; RA, rheumatoid arthritis
O'Dell JR, et al. N Engl J Med. 2013;369: Copyright © 2013 Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society.

26. TEAR: Radiologic Outcomes
Total Sharp Score
Changes from baseline in Total Sharp Scores indicated an advantage for MTX plus etanercept vs triple therapy with conventional DMARDs, but this difference was small — about 1 point.
IE, immediate active etanercept; IT, immediate triple therapy; SE, step-up etanercept; ST, step-up triple therapy
Adapted from Moreland LW, et al. Arthritis Rheum. 2012;64:

27. Percent without Radiologic Progression*
Percent with No Radiographic Progression
Determination of the percentage of patients with no radiologic progression; that is, a change in Total Sharp Score of 0 or less, also indicated only a slight difference between the two strategies for augmentation of MTX treatment.
IE, immediate active etanercept; IT, immediate triple therapy; SE, step-up etanercept; ST, step-up triple therapy
Adapted from Moreland LW, et al. Arthritis Rheum. 2012;64:

28. Summary

29. Summary
Many patients with RA have inadequate responses to MTX monotherapy and require treatment augmentation to control their disease
Augmentation of therapy may be carried out by adding:
Synthetic DMARDs
A biologic agent
With the exception of tocilizumab, adding a biologic to MTX results in better clinical outcomes than switching treatment
Switching to SC MTX increases bioavailability and may improve clinical response in patients with inadequate responses to oral therapy
Many patients with RA have inadequate responses to MTX monotherapy and require additional treatment to control their disease. Treatment can be advanced by adding synthetic DMARDs or a biologic agent. Both of these approaches improve clinical outcomes and limit radiologic progression. Switching to SC MTX increases bioavailability and may improve clinical responses in some of these patients.