1. A NEW LOOK AT RA Interactive Hot Topics Series
Rethinking the Treatment Paradigm in RA: What Is the Best Way to Initiate MTX Treatment?
I’d like to talk to you today about what I believe is the best way to initiate treatment with methotrexate in patients with rheumatoid arthritis.
MP-RA-0252

2. ACR Guidelines Support Methotrexate (MTX) As Initial DMARD for Established RA
MTX Monotherapy or Combination DMARD Therapy (Including Double or Triple Therapy) ‡
DMARD Monotherapy
Low Disease Activity Without Poor Prognosis†
Low Disease Activity With Poor Prognosis† or
Moderate/High Disease Activity
I think that most or all of us would agree that methotrexate remains the anchor disease modifying antirheumatic drug – or DMARD – for the treatment of patients with rheumatoid arthritis and this is clearly reflected in the guidelines from the American College of Rheumatology which recommend methotrexate as monotherapy or part of combination treatment for patients with established rheumatoid arthritis.
† Features of poor prognosis include functional limitation, extra-articular disease, positive rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and bony erosions by radiograph.
‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based.
DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis.
2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Singh JA, et al. Arthritis Care Res, 2016;64:1-25. © 2015, American College of Rheumatology.

3. ACR Guidelines Support MTX As Initial Treatment for Early RA
DMARD Monotherapy
DMARD Monotherapy or HCQ and MTX
Anti-TNF With or Without MTX or Combination DMARD Therapy (Including Double or Triple Therapy)‡
Monotherapy or HCQ and MTX
Without
With
High
Low
MTX Monotherapy or Combination DMARD Therapy (Including Double or Triple Therapy) ‡
Disease Activity
Features of Poor Prognosis†
The ACR guidelines also recommend methotrexate as monotherapy or as part of a combination regimen with other synthetic DMARDs or with a tumor necrosis factor inhibitor as initial treatment for patients with early rheumatoid arthritis.
While an update of the ACR guidelines will be published shortly, methotrexate will undoubtedly remain the first DMARD recommended for the great majority of patients with RA.
† Features of poor prognosis include functional limitation, extra-articular disease, positive rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and bony erosions by radiograph.
‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based.
RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Singh JA, et al. Arthritis Care Res ;68:1-25. © 2015, American College of Rheumatology.

4. Initial Treatment With MTX: Oral or Subcutaneous
The vast majority of RA patients in the United States initiate treatment with oral drug
Results for 39,440 RA patients starting MTX treatment in the United States:
The vast majority of patients with RA who initiate treatment with methotrexate receive the drug orally. This slide shows the results from a claims analysis carried out in the United States that assessed management of patients who started methotrexate treatment in More than 90% of about 39,000 patients included in the analysis received oral methotrexate and less than 10% received the drug via subcutaneous injection.
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Medac, Pharma, Inc. Data on file

5. Significantly Better Disease Control With SC vs Oral MTX
ACR Responses†
EULAR Remission†
While the great majority of patients with RA receive the drug orally, results from clinical trials suggest that this may not be the best way to deliver the drug.
This slide summarizes results from a 6-month, multicenter, randomized, double-blind, controlled clinical trial that compared the efficacy of subcutaneously and orally administered methotrexate in 384 patients with active RA who had not received previous treatment with the drug.
The patients initiated treatment at a methotrexate dose of 15 mg per week and at week 16, patients who did not meet the ACR20 criteria for improvement were switched from 15 mg of oral methotrexate to 15 mg delivered subcutaneously or from 15 to 20 mg of subcutaneous methotrexate for the remaining remaining 8 weeks of study. As can be seen in the slide, subcutaneously administered methotrexate was significantly superior to oral drug with respect to the percentages of patients meeting the ACR20 and ACR70 criteria for improvement and for the percentage of patients meeting the European League Against Rheumatism criteria for disease remission.
† 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.

6. Prospective Comparison of SC and Oral MTX
Prospective 6-month study to assess the efficacy, safety, and compliance of SC vs oral MTX in 92 patients with active RA according to ACR criteria
SC MTX (n=46)
Oral MTX (n=46)
Age years, mean ± SD
45.54 ± 12.42
44.63 ± 13.99
Male (%)
5 (11)
12 (26)
Disease duration months, mean
49.74
49.0
The results published by Braun and colleagues several years ago are very similar to those reported more recently in a prospective 6-month comparison of oral and subcutaneously administered methotrexate in 92 patients with established RA.
ACR, American College of Rheumatology; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous; SD, standard deviation
Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:

7. Prospective Comparison of SC and Oral MTX: ACR Responses
Patients %
Results from this trial also showed better tolerability for subcutaneous versus oral methotrexate, particularly with respect to gastrointestinal adverse events, including nausea, vomiting, and dyspepsia.
P=0.72
ACR, American College of Rheumatology; MTX, methotrexate; SC, subcutaneous; SD, standard deviation
Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:

8. Prospective Comparison of SC and Oral MTX: Adverse Events
Patients %
Results from this trial also showed better tolerability for subcutaneous versus oral methotrexate, particularly with respect to gastrointestinal adverse events, including nausea, vomiting, and dyspepsia.
MTX, methotrexate; SC, subcutaneous; SD
Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:

9. Hazard Ratio for Change in Treatment
Parenteral MTX: Higher Achieved Dose and Lower Risk for Change in Therapy vs Oral MTX
MTX Dosing
Hazard Ratio for Change in Treatment
P<0.01
Mean oral dose 16.6 mg/wk and mean parenteral dose 22.1 mg/wk (P<0.01)
The clinical response to methotrexate is dose related. This was demonstrated in a systematic review of clinical trials published by Visser and colleagues several years ago. A retrospective cohort analysis of 7,017 patients with newly diagnosed RA who were included in United States Department of Veterans Affairs administrative databases in 2009 indicated, not surprisingly, that the great majority of these patients were receiving oral drug. The study also showed that patients on subcutaneous methotrexate received higher doses versus those receiving oral drug. In addition, those receiving methotrexate subcutaneously were significantly less likely than those on oral methotrexate to switch treatment. Thus, use of injectable methotrexate and higher maximum methotrexate dose were independently associated with a higher likelihood of remaining on methotrexate monotherapy.
MTX, methotrexate
Adapted from Ng B, Chu A. Clin Rheumatol. 2014;33:21-30.
* Reference.

10. Initiation of Treatment With SC or Oral MTX: Real-world Results From the Canadian Early Arthritis Cohort (CATCH)
Multicenter prospective study of patients with early RA (symptoms ≤1 year) initiating MTX therapy
Comparison of the effectiveness of starting with SC or oral MTX over the first year
Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inefficacy or toxicity and treatment efficacy
The clinical trials and database analysis summarized in the preceding slides support a significant advantage of subcutaneously administered methotrexate over oral delivery for the initial treatment of patients with RA.
I would like to use the rest of my time with you to summarize our experience with the Canadian Early Arthritis Cohort or CATCH that also supports the use of subcutaneous methotrexate for the treatment of patients with RA.
CATCH is an ongoing, multicenter, prospective observational study of patients with early RA. This analysis assessed outcomes for patients initiating methotrexate with either subcutaneous or oral administration who were followed for 1 year after the start of treatment.
Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inadequate efficacy or toxicity.
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Hazlewood GS, et al. Ann Rheum Dis. 2016;75:

11. CATCH Cohort: Patient Characteristics
Oral MTX
(n=417)
SC MTX (n=249)
P-value
Age, mean years (SD)
54 (14)
51 (15)
0.068
Female, %
75.1
73.1
0.57
Number of comorbidities, mean (SD)
2.2 (1.8)
2.5 (1.9)
0.041
Symptom duration, mean months (SD)
5.2 (2.7)
5.2 (2.8)
0.61
Seropositive (RF or ACPA), %
78.8
82.0
0.35
Erosions present on hand or foot x-rays (%)
24.4
31.1
0.08
HAQ-Dl (0-3)
1.1 (0.69)
0.52
DAS28, mean (SD)
5.5 (1.4)
0.86
Starting dose of MTX, mean mg (SD)
>20, %
15-20, %
<15, %
17.2 (3.8)
5.0
56.8
38.1
22.3 (3.6)
45.2
27.8
27.0
<0.001
Concurrent use of systemic glucocorticoids, %
Oral, %
Intramuscular or intra-articular, %
48.0
24.2
51.8
13.7
41.4
0.34
0.001
Concurrent use of other DMARDs, %
53.0
42.6
0.009
Concurrent use of biological therapy, %
2.2
0.4
0.071
The study included 666 patients with a good balance of demographic and clinical characteristics for those who received oral or subcutaneous methotrexate.
It is of interest to note that the patients receiving subcutaneous methotrexate started treatment with a dose that was 5 mg higher than that for patients on oral drug.
ACPA, anti-citrullinated protein antibodies; DAS, Disease Activity Score; DMARD, disease-modifying antirheumatic drug; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; RF, rheumatoid factor; SC, subcutaneous; SD, standard deviation
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

12. Better Persistence Is Achieved With SC vs Oral MTX: CATCH Cohort
Time (months)
0.2
0.4
0.6
0.8 1 3 6 9 12
SC MTX (n=249)
Oral MTX (n=417)
Proportion of Initial Treatment
49%
77%
Failed Initial Treatment
Log-rank P<0.001
417
249
233
184
130
136
104
117 66 88 PO SC
One-year results for the CATCH cohort indicated significantly better persistence with subcutaneously administered versus oral methotrexate.
At the end of 1 year, 51% of the patients who received subcutaneous methotrexate remained on this treatment versus 23% of those who initiated treatment with oral drug.
MTX, methotrexate; SC, subcutaneous; PO, oral
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

13. Reasons for Treatment Failure: SC vs Oral MTX
Reason for Treatment Failure
SC MTX (n=249) %
Oral MTX (n=417)
P-Value
Total treatment failures
49%
77%
<0.001
Inadequate efficacy only
28%
59%
Toxicity only 3% 2%
0.63
Both inadequate efficacy and toxicity
18%
16%
0.57
Analysis of the reasons for switching treatment over the 1-year follow-up period indicated that changes in treatment for both groups were generally due to inadequate efficacy.
Change in treatment due to inadequate efficacy were recorded for 28% of patients who were treated with subcutaneous methotrexate versus 59% of those on oral drug. As for overall treatment failures, this difference between results for the two treatment groups was statistically significant.
SC, subcutaneous.
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

14. CATCH Cohort: Changes in TreatmentSC
MTX
Oral
P-value
Changed route of MTX 3 20
<0.001
Increased dose of MTX after 3 months 24 58
Added/switched a non-biological DMARD 22 33
0.004
Added a biologic 10 12
0.41
Decreased dose of MTX after 3 months* 4
0.006
Stopped a non-biological DMARD* 7 1
Analysis of changes in treatment over the 1-year follow-up period indicated that the patients receiving oral drug were significantly more likely than those on subcutaneous methotrexate to change the route of administration for methotrexate, increase the dose, and have a change in therapy that involved a switch in, or augmentation of, conventional DMARD treatment.
Patients may have had more than one change.
* Must have had another treatment change, side effect or increased DAS28 to be considered a treatment failure.
DAS, Disease Activity Score; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; SC, subcutaneous
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

15. Lower DAS28 Scores Are Achieved With SC vs Oral MTX: CATCH Cohort
Mean DAS28 Score
This and the following slide provide a more detail comparison of the efficacies of subcutaneously and orally administered methotrexate in the CATCH cohort. As can be seen here, treatment with subcutaneous methotrexate resulted in greater reductions than oral drug in DAS-28 scores. The difference between groups was statistically significant at the 9-month assessment.
P<0.05 for SC vs oral SC MTX at 3, 6, and 9 months
Month
MTX, methotrexate; SC, subcutaneous.
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

16. CATCH Cohort: DAS28 Outcomes
Estimate for SC
MTX (95% Cl)
P-value
DAS28, mean difference
-0.38 (-0.64 to -0.10)
0.04
DAS28 remission, OR
1.15 (1.05 to 1.25)
0.002
DAS28 sustained remission*, OR
1.02 (0.96 to 1.06)
0.43
HAQ-DI, mean difference
-0.02 (-0.13 to 0.10)
0.75
Evaluation DAS-28 outcomes indicated significant superiority of subcutaneous over oral methotrexate for DAS-28 scores and DAS-28 remission. There were no between-group differences for sustained DAS-28 remission, defined as a DAS-28 score less than 2.6 on two consecutive visits, or for results on the Health Assessment Questionnaire Disability Index.
* Defined as DAS28 <2.6 on 2 consecutive visits
CI, confidence interval; DAS, Disease Activity Score; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; OR, odds ratio; SC, subcutaneous
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

17. CATCH Cohort Sites: Relation Between SC MTX Use and Patient Outcomes
Percentage of Patients Receiving SC MTX
Mean Change from Baseline in DAS28 (0-6 months)
The CATCH study was carried out at multiple sites and patients received oral or subcutaneous methotrexate at the investigators’ discretion. A simple correlational analysis for the eight sites that contributed patients to the study showed a clear relationship between the frequency of subcutaneous methotrexate use and change from baseline in DAS-28 scores over the 1-year study period.
DAS, Disease Activity Score; MTX, methotrexate; SC, subcutaneous
Adapted from Harris JA, et al. J Rheumatol. 2013;40;

18. Conclusions
SC MTX is an attractive alternative to oral drug delivery for the treatment of RA
Initial treatment with SC vs oral MTX has been associated with:
Greater efficacy
Better disease control
Lower rates of treatment changes
Decreased frequency of gastrointestinal adverse events
The results that I have briefly summarized over that last 15 minutes support the use of subcutaneous over oral methotrexate for initial treatment with this DMARD in patients with RA. Results from both randomized, controlled clinical trials and the prospective observational analysis in the CATCH study indicate that subcutaneously administered methotrexate has significantly better efficacy than oral drug.
Subcutaneously administered methotrexate also has better tolerability than oral drug and results in a lower requirement for changes in treatment.
All of these results support careful reconsideration of the way in which we typically initiate methotrexate treatment in our patients with RA.
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous