Download Initiation of Treatment With SC or Oral MTX

Interactive Hot Topics Series
Rethinking the Treatment
Paradigm in RA:
What Is the Best Way to
Initiate MTX Treatment?
MP-RA-0252
ACR Guidelines Support Methotrexate (MTX)
As Initial DMARD for Established RA
Low Disease
Activity Without
Poor Prognosis†
DMARD Monotherapy
Low Disease
Activity With Poor
Prognosis†
or
Moderate/High
Disease Activity
MTX Monotherapy or
Combination DMARD Therapy
(Including Double or
Triple Therapy) ‡
†
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.
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ACR Guidelines Support MTX As Initial Treatment
for Early RA
Low
Without
DMARD
Monotherapy
Disease
Activity
High
With
Without
MTX Monotherapy or
Combination DMARD
Therapy (Including Double
or Triple Therapy) ‡
DMARD
Monotherapy
or HCQ and
MTX
Features
of Poor
Prognosis†
Features
of Poor
Prognosis†
With
Anti-TNF With or Without MTX or
Combination DMARD Therapy
(Including Double or Triple Therapy)‡
Monotherapy or HCQ and MTX
†
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. 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;68:1-25. © 2015, American College of Rheumatology.
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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:
9.6%
SC MTX
Oral MTX
90.4%
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Medac, Pharma, Inc. Data on file. 2015.
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Significantly Better Disease Control With
SC vs Oral MTX
ACR Responses†
EULAR Remission†
40
*P<0.05
*
80
78
70
59
60
62
*
41
40
33
20
Percentage of Patients
Percentage of Patients
100
0
34
30
24
20
10
0
ACR20
ACR50
ACR70
Week 24 Results1
Oral MTX 15 mg (n=187)
†
P<0.05
SC MTX 15 mg (n=188)
Oral MTX 15 mg
(n=187)
SC MTX 15 mg
(n=188)
Week 24 Results2
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.
1. Braun J, et al. Arthritis Rheum. 2008;58:73-81. © 2008, American College of Rheumatology.
2. Adapted from Braun J. Clin Exp Rheumatol. 2010;28(suppl 61):S46-S51.
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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)
45.54 ± 12.42
44.63 ± 13.99
Male (%)
5 (11)
12 (26)
Disease duration
months, mean
49.74
49.0
Age years, mean ± SD
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;22:483-488.
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Prospective Comparison of SC and Oral MTX:
ACR Responses
P=0.02
100%
93%
89%
90%
80%
P=0.03
SC MTX (n=46)
80%
Oral MTX (n=46)
72%
Patients %
70%
60%
50%
40%
30%
P=0.72
20%
11%
10%
9%
0%
ACR20
ACR50
ACR, American College of Rheumatology; MTX, methotrexate; SC, subcutaneous; SD, standard deviation
Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:483-488.
ACR70
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Prospective Comparison of SC and Oral MTX:
Adverse Events
90%
85%
SC MTX (n=46)
80%
Oral MTX (n=46)
Patients %
70%
72%
63%
60%
52%
48%
50%
41%
40%
37%
30%
30%
29%
20%
11%
10%
0%
Nausea
Vomiting
MTX, methotrexate; SC, subcutaneous; SD
Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:483-488.
Dyspepsia
Dizziness
Alopecia
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Parenteral MTX: Higher Achieved Dose and
Lower Risk for Change in Therapy vs Oral MTX
Hazard Ratio for
Change in Treatment
MTX Dosing
100%
Oral (n=6741)
90%
70%
60%
1
Parenteral (n=276)
80%
0.8
Mean oral dose 16.6 mg/wk
and mean parenteral dose
22.1 mg/wk (P<0.01)
0.64
0.6
40%
40%
31.70%
28.30%
18.50%
20%
10%
P<0.01
76.10%
50%
30%
*
1.00
0.4
0.2
5.40%
0
0%
<15 mg
15 to <20 mg
MTX, methotrexate
Adapted from Ng B, Chu A. Clin Rheumatol. 2014;33:21-30.
≥20 mg
Oral MTX
(n=6741)
* Reference.
Parenteral MTX
(n=276)
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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
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008.
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CATCH Cohort: Patient Characteristics
Oral MTX
(n=417)
SC MTX
(n=249)
P-value
54 (14)
51 (15)
0.068
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)
1.1 (0.69)
0.52
DAS28, mean (SD)
5.5 (1.4)
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
27.8
51.8
13.7
41.4
0.34
0.001
<0.001
Concurrent use of other DMARDs, %
53.0
42.6
0.009
Concurrent use of biological therapy, %
2.2
0.4
0.071
Characteristic
Age, mean years (SD)
Female, %
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;75:1003-1008. © 2016 with permission from BMJ Publishing Group.
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Better Persistence Is Achieved With SC vs Oral MTX:
CATCH Cohort
Proportion of Initial Treatment
1
SC MTX (n=249)
Oral MTX (n=417)
0.8
Failed Initial
Treatment
0.6
49%
0.4
Log-rank P<0.001
77%
0.2
0
417
249
233
184
130
136
104
117
66
88
0
3
6
9
12
PO
SC
Time (months)
MTX, methotrexate; SC, subcutaneous; PO, oral
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group.
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Reasons for Treatment Failure: SC vs Oral MTX
SC MTX
(n=249)
%
Oral MTX
(n=417)
%
P-Value
Total treatment failures
49%
77%
<0.001
Inadequate efficacy only
28%
59%
<0.001
Toxicity only
3%
2%
0.63
Both inadequate efficacy
and toxicity
18%
16%
0.57
Reason for
Treatment Failure
SC, subcutaneous.
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group.
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CATCH Cohort: Changes in Treatment
SC
MTX
Oral
MTX
P-value
Changed route of MTX
3
20
<0.001
Increased dose of MTX after 3 months
24
58
<0.001
Added/switched a non-biological
DMARD
22
33
0.004
Added a biologic
10
12
0.41
Decreased dose of MTX after
3 months*
10
4
0.006
Stopped a non-biological DMARD*
7
7
1
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;75:1003-1008. © 2016 with permission from BMJ Publishing Group.
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Mean DAS28 Score
Lower DAS28 Scores Are Achieved With SC vs Oral
MTX: CATCH Cohort
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;75:1003-1008. © 2016 with permission from BMJ Publishing Group.
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CATCH Cohort: DAS28 Outcomes
Estimate for SC
MTX (95% Cl)
P-value
-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
-0.02 (-0.13 to 0.10)
0.75
Outcome
DAS28, mean
difference
HAQ-DI, mean
difference
* 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;75:1003-1008. © 2016 with permission from BMJ Publishing Group.
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CATCH Cohort Sites: Relation Between
SC MTX Use and Patient Outcomes
Percentage of Patients Receiving SC MTX
0
10
20
30
40
50
60
70
Mean Change from
Baseline in DAS28
(0-6 months)
0
-0.5
-1
-1.5
-2
-2.5
DAS, Disease Activity Score; MTX, methotrexate; SC, subcutaneous
Adapted from Harris JA, et al. J Rheumatol. 2013;40;1823-1830.
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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
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
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