1. Treatment Pathways in Rheumatoid Arthritis
Defining the Role of Subcutaneous Methotrexate in Long-term Therapy
MP-RA-0284

2. ACR Guidelines Support MTX As Initial Treatment 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*†
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
Combination traditional DMARDs*† or
TNF inhibitor +/- MTX*† or
Non-TNF biologic +/- MTX*†
The American College of Rheumatology has long considered methotrexate (MTX) the anchor disease modifying antirheumatic drug or DMARD for the treatment of patients with rheumatoid arthritis (RA) and this remains the case in the updated guidelines released in 2015.
This slide shows the algorithm for patients with early RA.
* 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.

3. ACR Guidelines Support Methotrexate (MTX) As Initial DMARD for Established RA
DMARD-Naïve
Established RA
Low Disease Activity
Moderate to High Disease Activity
DMARD Monotherapy†
DMARD Monotherapy†
Treat to Target#
Moderate or High Disease Activity*†
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
Combination traditional DMARD therapy*† or
TNF inhibitor +/- MTX*† or
Non-TNF biologic +/- MTX*† or
Tofacitinib +/- MTX
Methotrexate is also the anchor drug for the treatment of patients with established RA.
* 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.

4. The Treat-to-Target Paradigm
Main target
Alternative target
Remission
Sustained remission
Low disease activity
Adapt therapy according to disease activity*
(consider comorbidities and other patient factors)
Adapt therapy if state is lost*
Assess disease activity about every 3 to 6 months
Use a composite measure of disease activity every 1 to 3 months
Sustained low disease activity
Active RA
* Shared decision with patient.
The treat-to-target paradigm originally published by Josef Smolen and colleagues and most recently updated in 2015.
Simply stated, this approach emphasizes iterative patient assessment and adjustment of treatment to achieve sustained remission or the alternative treatment goal of sustained low disease activity.
Key points in this approach include using a quantitative composite measure for patient evaluation and adapting therapy in accord with comorbidities and other patient-related factors.
RA, rheumatoid arthritis.
Reproduced from Smolen JS, et al. Ann Rheum Dis. 2016;75: © 2016 with permission from BMJ Publishing Group.

5. Treating to Target: A Core Concept in the Management of Patients With RA
The primary target for treatment of RA should be a state of clinical remission
Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity
Although remission should be a clear target, low disease activity may be an acceptable alternative therapeutic goal, based on available evidence, particularly for patients with established long-standing disease
Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months
This slide enumerates the key principles of the treat-to-target approach for management of patients with RA. They include the following:
The primary target for treatment of RA should be a state of clinical remission (defined as the absence of signs and symptoms of significant inflammatory disease activity).
Although remission should be a clear target, low disease activity may be an acceptable alternative therapeutic goal, based on available evidence, particularly for patients with established long-standing disease.
Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months.
RA, rheumatoid arthritis.
Smolen JS, et al. Ann Rheum Dis. 2010;69:

6. Advice From The American College of Rheumatology
Do not prescribe biologic agents for RA before a trial of MTX (or other conventional nonbiologic DMARD)
High-quality evidence suggests that MTX and other conventional nonbiologic DMARDs are effective in many patients with RA
Initial therapy for RA should be a conventional nonbiologic DMARD unless these agents are contraindicated
If a patient has had an inadequate response to methotrexate with or without other nonbiologic DMARDs during an initial 3-month trial, then biologic therapy can be considered
This slide provides simple treatment guidance from the American College of Rheumatology:
Do not prescribe biologic agents for RA before a trial of MTX (or other conventional nonbiologic DMARD).
High-quality evidence suggests that MTX and other conventional nonbiologic DMARDs are effective in many patients with RA.
Initial therapy for RA should be a conventional nonbiologic DMARD unless these agents are contraindicated.
If a patient has had an inadequate response to MTX with or without other nonbiologic DMARDs during an initial 3-month trial, then biologic therapy can be considered.
DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis.
Yazdany J, et al. Arthritis Care & Res. 2013;65:

7. Treating to Target: Common Current Practice
Initiate Treatment with Oral MTX / Dose Titration
Inadequate Response / Intolerance
MTX + Conventional DMARD or Biologic
Clinical Remission or LDA / Limited Radiographic Progression
This slide shows the most common approach to management of patients with RA being treated in the US.
Oral MTX is usually the first DMARD administered and a biologic is added or substituted if the patient has an inadequate response or is unable to tolerate this treatment.
LDA, low disease activity
Adapted from Yazici Y, Bata Y. Bull Hosp Jt Dis. 2013;71(Suppl 1):S46-48; Bykerk VP, et al. J Rheumatol. 2012;39: ; Alsaeedi S, Keystone EC. Nat Rev Rheumatol. 2014;10:

8. Percentage of Patients
Oral MTX Monotherapy Has Long-term Clinical Benefit in Patients With RA: TEAR
In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive:
MTX monotherapy
Combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine)
Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the DAS28-ESR was ≥3.2
Percentage of Patients
The objective of TEAR was to assess whether it is better to intensively treat all patients with early RA using combinations of drugs or to reserve this approach for patients who do not have an appropriate to MTX monotherapy, and to assess whether combination therapy with MTX plus etanercept (ETN) is superior to the combination of MTX plus sulfasalazine (SSZ) plus hydrochloroquine (HCQ).
TEAR was a 2-year, randomized, double-blind trial in which a 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus ETN, immediate oral triple therapy (MTX plus SSZ plus HCQ), or step- up from MTX monotherapy to one of the combination therapies at week 24 if the DAS28-ESR was ≥3.2.
The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102.
Results from TEAR after 2 years of follow-up showed that patients who responded to MTX monotherapy initially (n=81) had clinical responses at least equivalent to those initiated on or stepped up to combination therapy.
RA, rheumatoid arthritis; DAS, disease activity score.
O'Dell JR, et al. Arthritis Rheum. 2013;65:

9. Oral MTX Has Long-term Radiologic Benefit: 2-year Results From TEAR
Change from Baseline to 2 Years in TSS
Two-year radiologic results from TEAR showed further that patients who responded to and were maintained on MTX monotherapy had changes from baseline in Total Sharp Scores that were not different from those of patients treated immediately with, or stepped up to combination therapy.
TSS, total sharp score.
Adapted from O'Dell JR, et al. Arthritis Rheum. 2013;65:

10. Long-term Oral MTX Efficacy: Radiologic Outcomes in TEMPO At 3 Years
220
200 90 80 70 60 50 40 30 20 10
-10
-20
-30
-40
100
Change from Baseline in TSS
Cumulative Probability
MTX
Etanercept
Combination
~70% of MTX-treated patients had no radiographic evidence of progression
The objective of this study was to assess combination treatment with ETN and MTX versus the monotherapies in patients with RA.
Patients enrolled in TEMPO patients should had a less than satisfactory response at the discretion of the investigator to at least one DMARD drug other than MTX. Individuals previously treated with MTX could be enrolled provided they had not had clinically important toxic effects or lack of response, at the discretion of the investigator, and had not been treated with MTX within 6 months of enrollment.
The study used a double-blind, randomized, clinical efficacy, safety, and radiographic study, 686 patients with active RA were randomly allocated to treatment with ETN 25 mg (SC twice a week), oral MTX (up to 20 mg every week), or the combination.
The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score.
The cumulative probability plot of the 3-year results from TEMPO shows that for about 70% of the patients included in the trial, radiographic progression was the same regardless of whether treatment was with MTX, ETN, or the combination of these two agents.
The mean differences among the three groups result from differences in efficacy for about 20-30% of the total patient population.
TSS, total sharp score. van der Heijde D, et al. Arthritis Rheum. 2007;56: © 2007, American College of Rheumatology.

11. ARS Question
About what percent of patients receiving MTX are likely to have no radiologic progression over 2-3 years of follow-up?
20%
50%
70%*
90%

12. Higher MTX Doses Are Associated With Better Clinical Efficacy
Systematic review of the literature on optimal dosage of MTX in patients with RA
Starting doses of 25 mg/week, or fast escalation with 5 mg/month to mg/week, were associated with higher clinical effect sizes in comparison with doses of mg/week or slow escalation
2.5
2.0
1.5
1.0
0.5
-0.5
-1.0
Effect Size
SJC
TJC
Pain
Global
12.5–20 mg/wk
5–10 mg/wk
Placebo
A systematic literature search for articles published between 1950 and September 2007 was carried out in MEDLINE,EMBASE and the Cochrane Library, using a comprehensive search strategy in collaboration with an experienced librarian. The European League Against Rheumatism (EULAR) and ACR 2005–2006 meeting abstracts were also searched. The search was limited to randomized controlled trials, using a modification of the Cochrane highly sensitive search strategy.
The figure shows a clinical dose-effect relation with effect sizes ranging from in the placebo group, in the MTX 5-10 mg/week group, to in the 12.5–20 mg/week group.
Methotrexate mg/week had a significantly larger effect than placebo on TJC (pooled effect size 1.08; 95% CI 0.35 to 1.81), pain (pooled effect size 0.92; 95% CI 0.21 to 1.64) and global status (pooled effect size 1.58; 95% CI 0.80 to 2.37), whereas MTX 5-10 mg/week only had a significantly higher effect than placebo on pain and global status (pooled effect size 0.81; 95% CI 0.05 to 1.57 and 1.26; 95% CI 0.46 to 2.06, respectively).
RA, rheumatoid arthritis; SJC, swollen joint count; TJC, tender joint count.
Reproduced from Visser K, van der Heijde D. Ann Rheum Dis. 2009;68: © 2009 with permission from BMJ Publishing Group.

13. Initial Therapy With Oral MTX
Approximately 20% to 30% of patients will achieve clinical disease remission for at least 2 to 3 years
As many as 70% of patients will have no radiologic evidence of progression for at least 3 years
Can we improve these outcomes?
No note (read slide)

14. SC Delivery Of MTX: Enhancing Pharmacokinetics, Efficacy, and Tolerability of MTX
Initiate Treatment with Oral
MTX / Dose Titration
Inadequate Response / Intolerance
Switch to SC MTX
Clinical Remission or LDA / Limited Radiographic Progression
While a substantial fraction of RA patients can be managed effectively with oral MTX, others have inadequate responses to or intolerance of this drug. As noted in a prior slide, these patients are most frequently managed by adding a biologic to treatment or substituting such an agent for oral MTX.
Subcutaneous (SC) administration of MTX is another alternative for management of these patients and the following slides consider the pharmacokinetic and clinical advantages of SC MTX over oral delivery.
LDA, low disease activity
Adapted from Yazici Y, Bata Y. Bull Hosp Jt Dis. 2013;71(Suppl 1):S46-48; Bykerk VP, et al. J Rheumatol. 2012;39: ; Alsaeedi S, Keystone EC. Nat Rev Rheumatol ;10:

15. 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
Oral delivery of MTX has important limitations that may be overcome with SC delivery of the drug.
The bioavailability of MTX (the percent of the dose that reaches the bloodstream) declines as the oral dose rises, but this is not the case for SC administration.
The results shown on this slide illustrate the increased bioavailability of SC vs versus orally administered methotrexate.
In this single-dose, crossover study, healthy subjects aged 18 to 55 years were divided into one of four dose groups: 7.5 mg, 15 mg, 22.5 mg, or 30 mg of methotrexate and each subject received a single dose administered orally and SC.
A subject participated in only 1 of the 4 dose groups and received a single dose of MTX via pen (Rasuvo™) and oral MTX tablets.
Pharmacokinetic blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, and 48 hours post-dose.
Study results indicated higher bioavailability, as reflected by area under the time versus plasma concentration curve, with SC administration. The difference between the two routes of administration increased with higher MTX doses.
SC, subcutaneous.
Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

16. Interpatient Bioavailability of Oral MTX Is Variable
Oral Bioavailability of 10 mg/m2 MTX (Oral AUC/IV AUC)
The bioavailability of oral MTX also varies greatly from one patient to another.
This slide shows results from a study in which the pharmacokinetics and bioavailability of low-dose MTX (10 mg/m2) were evaluated in 41 subjects who had definite or classical RA as defined by the American Rheumatism Association criteria.
Subjects received MTX in a single oral dose and a single intravenous (IV) dose one week apart.
The results shown are the values for the area under the curve 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:

17. SC Administration Lowers Interpatient Variability in the AUC for MTX
Subcutaneous administration of MTX results in much lower inter-patient variability in bioavailability than oral delivery.
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 the same study that provided information about bioavailability and they show that inpatient variability in area under the curve for a given MTX dose is lower with SC vs oral administration.
SC, subcutaneous; AUC, area under the curve
Adapted from Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

18. ARS Question Interpatient variability in MTX bioavailability is…
Greater with oral vs SC administration*
Greater with SC vs oral administration
About the same with oral vs SC administration
Has not been compared for oral vs SC administration

19. Polyglutamation Is a Determinant of MTX Response
MTX is a prodrug that is activated to MTX polyglutamates (MTX-PGs) by the addition of new glutamyl groups1
The accumulation of MTX-PGs appears to be an important determinant of response to MTX treatment2
Polyglutamation leads to longer retention of MTX within cells, increasing with the number of glutamate moieties3
MTX
Glutamate Moieties
Methotrexate is a prodrug activated to MTX polyglutamates (MTX-PGs) by a folylpolyglutamate (FPGS)-mediated sequential addition of glutamic acid residues to the parent drug.
This process selectively modifies the properties of MTX and enhances its retention in cells.
Multiple studies have correlated levels of MTX-PGs in red blood cells (a surrogate for accumulation in inflammatory cells) with clinical response in patients with RA.
Dervieux T, et al. Rheumatol. 2010;49:
Dervieux T, et al. Pharmacogenet Genomics. 2009;19:
Stamp LK, et al. J Rheumatol. 2011;38:

20. Pathway From MTX-PG to Decreased Inflammation
MTX-PG inhibits AICAR transformylase (AICAR-T)
TNF-α (inflammatory)
IL-6 (inflammatory)
Adenosine 2A Receptor
IL-10 (anti-inflammatory)
This results in accumulation of AICAR
Leading to accumulation and release of adenosine
Adenosine acts at adenosine type 2A receptors to decrease synthesis of inflammatory cytokines and increase levels of anti-inflammatory cytokines
Methotrexate is actively transported into cell by the reduced folate carrier 1 or the proton-coupled folate transporter, and it is then polyglutamated by folylpolyglutamate synthetase form MTX-PGs.
Methotrexate may have up to 5 glutamate moieties added by folylpolyglutamate synthetase; and the number added; that is, the length of the polyglutamate chain; is important. A greater number of glutamate moieties added to methotrexate results in an increased likelihood that methotrexate polyglutamate will remain inside the cell. In addition, longer chain methotrexate polyglutamates are more potent inhibitors of 5-aminoimidazole-4-carbox-amide ribonucleotide transformylase than shorter chain molecules.
One action of methotrexate polyglutamates is to increase intracellular and extracellular levels of adenosine, a molecule that has significant anti-inflammatory actions. Methotrexate polyglutamates inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, causing accumulation of 5-aminoimidazole-4-carbox-amide ribonucleotide, which results in increased secretion of adenosine, a strong anti-inflammatory mediator.
Adenosine acts at specific receptors on inflammatory cells to decrease levels of tumor necrosis factor-α and interleukin (IL) -6 and increase IL-10.
AICAR-T, 5-aminoimidazole-4-carboxamide ribonucleotide - transformylase
Romão VC, et al. BMC Medicine. 2013;11:17.  
Chan ESL, Cronstein BN. Arthritis Res. 2002;4: 18

21. MTX Dose Is Correlated With Levels of Polyglutamates
There were also significant correlations between MTX dose and levels of MTX-PG3 and MTX4-5 (both P<0.001). There was a negative correlation between dose and MTX-PG2 (P<0.001).
n=247
25 mg/wk
n=86
15 mg/wk
10 mg/wk
n=7
300
275
250
225
200
175
150
125
100 75 50 25
Dose of MTX
Total MTX-PG in RBC Pellet (nM)
Patients with RA treated with MTX from 2 longitudinal cohorts were included
MTX-PG concentrations were measured at 3 months of treatment using liquid chromatography / mass spectrometry
This study aimed to define the determinants of erythrocyte MTX-PG concentrations in 2 prospective cohorts of patients with RA.
Patients with RA treated with MTX from 2 longitudinal cohorts were included 93 from the MTX-R study (Rotterdam, the Netherlands derivation cohort), and 247 from the treatment in Rotterdam Early Arthritis Cohort study (validation cohort).
MTX-PG concentrations were measured at 3 months of treatment using liquid chromatography/mass spectrometry.
Study results indicated that oral MTX dose was significantly related to higher levels of MTX-PGs in red blood cells.
RA, rheumatoid arthritis.
den Boer E, et al. J Rheumatol. 2014;41:

22. SC Administration of MTX Increases Concentrations of Long-Chain MTX-PGs
Effect of switching from oral (baseline dose mg/week, baseline treatment duration 27 weeks) to parenteral administration (mean dose 19.0 mg/week) of MTX on RBC MTX-PGs levels in 10 patients with RA
P=0.004
P=0.049
P=0.008
MTX pharmacokinetics were evaluated in 47 MTX-naıve patients enrolled in an MTX dose-escalation study for an average of 20 weeks and 223 patients enrolled in a cross-sectional study under long-term MTX therapy.
Short-chain (MTXPG1-2), long-chain (MTXPG3), and very long-chain (MTXPG4-5) concentrations were measured in circulating red blood cells using liquid chromatography.
In 10 patients, a switch from oral to SC MTX was associated with a 37% increase in long-chain MTX-PGs, a 132% increase in very long-chain MTX-PGs and a concomitant 31% reduction in disease activity (P<0.02).
MTX-PG1-2
MTX-PG3
MTX-PG4-5
SC, subcutaneous; PG, polyglutamate; RA, rheumatoid arthritis.
Adapted from Dervieux T, et al. Rheumatology. 2010;49:

23. MTX Response Correlates With MTX-Glu3-5
N=108 adults with RA treated with MTX for ≥3 months
100 80 60 40 20
Probability of Good Response (%)
120
140
RBC MTX-PG (nmol/L)
The likelihood of a good therapeutic response (Physician Global Assessment VAS ≤2 cm) correlated with the concentration of long-chain MTX-PG in RBCs
This study assessed the relationship between levels of MTX PG including three glutamate moieties and clinical response in 108 patients with RA.
In this study, patients with a visual analog scale score of less than or equal to 2 for physician’s assessment of their response to MTX were considered responders.
The graph on the right hand side of the slide demonstrates a clear relationship between longer chain MTX PG levels and clinical response to methotrexate.
PG, polyglutamate; RBC, red blood cell; VAS, visual analog scale.
Dervieux T, et al. Arthritis Rheum. 2004;50:

24. ARS Question Levels of long-chain MTX-PGs are…
increased with SC vs oral MTX administration
correlated with clinical response
correlated with MTX dose
all of the above*

25. Significantly Better Disease Control With SC vs Oral MTX
ACR Responses†
EULAR Remission†
This slide shows results for the only relatively large-scale comparison of oral and SC MTX in patients with RA.
MTX-naive patients with active RA (Disease Activity Score in 28 joints >4) were eligible for the study if they had not previously taken biologic agents and had not taken DMARDs for 2 weeks prior to randomization.
Patients were randomly assigned to receive 15 mg/week of MTX either orally (n=187 patients) or SC (prefilled syringe, n=188 patients) for 24 weeks.
At week 16, patients who did not meet the American College of Rheumatology criteria for 20% improvement (ACR20) were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for the remaining 8 weeks, still in a blinded manner
The primary outcome was an ACR20 response at 24 weeks.
At week 24, SC MTX was superior to oral drug with respect to the percentages of patients achieving ACR20 and ACR70 and for the percent of patients achieving EULAR 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.

26. 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
P=0.0001
This retrospective analysis included 103 RA patients who were switched from oral to subcutaneous methotrexate at a mean dose 15 mg/week a single center in the UK.
Disease control was assessed before and 3 months after switching and patients were divided in to two groups based on reason for switching, inadequate efficacy or intolerance of oral drug.
40 switched due to inadequate efficacy of oral MTX and they had a significant improvement in DAS28 by 3 months after switch (P=0.006).
63 patients switched to intolerance of oral MTX due to GI side effects and they also had a significant improvement in DAS28 by 3 months after switch (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.

27. Improved Gastrointestinal Tolerability With SC vs Oral MTX
VAS Score (0-100)
P=0.053
A retrospective postal survey was sent to patients who had changed from oral MTX to SC MTX.
Gastrointestinal adverse events were rated by visual analogue scale (VAS) and included frequency and intensity of nausea, frequency of vomiting, and frequency of discomfort. Of the sample 39/57 (68.4%) responded and 37 provided usable data.
Significant reductions in VAS were found in three of four primary outcome measures for gastrointestinal adverse events. Only frequency of vomiting was not significantly reduced.
SC, subcutaneous; VAS, visual analog scale.
Adapted from Kromann CB, et al. J Dermatolog Treat. 2014;17:1-3.

28. 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
This study was carried out determine the comparative effectiveness of oral vs SC MTX as initial therapy for patients with early RA.
Patients with RA symptoms for ≤1 year initiating MTX therapy were included from a multicenter prospective cohort study. A total of 666 patients were included (417 oral MTX, 249 SC MTX).
Patients prescribed SC MTX were prescribed a higher dose of MTX (mean dose over first three months 22.3 mg vs 17.2 mg/week).
At 1 year, 49% of patients initially treated with SC MTX had changed treatment compared with 77% treated with oral MTX.
MTX, methotrexate; SC, subcutaneous; PO, oral
Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75: © 2016with permission from BMJ Publishing Group.

29. Lower DAS28 Scores Are Achieved With SC vs Oral MTX: CATCH Cohort
Mean DAS28 Score
Assessment of DAS28 scores for the two patient groups described in the preceding slide indicated significantly better DAS28 scores for the patients treated with SC MTX at the 3, 6, and 9 month evaluations.
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: © 2016with permission from BMJ Publishing Group.

30. 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
Results from a multivariable mixed model analysis indicated that SC MTX was independently associated with a greater reduction in average DAS28 scores of (95% CI 0.10 to 0.64) and a higher odds of DAS-28 remission (odds ratio = 1.15; 1.05 to 1.25) over the first year compared with oral MTX.
The effect on DAS28 remission was small, and there was no significant difference between SC oral MTX for sustained remission. However, patients who achieved DAS28 remission with initial oral MTX at 1 year, however, required more treatment changes than patients treated with initial SC MTX (P=0.003).
There was no association between route of MTX administration and exposure and HAQ-DI scores.
* 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: © 2016with permission from BMJ Publishing Group.

31. Hazard Ratio for Change in Treatment
Parenteral MTX: Higher Achieved Dose and Lower Risk for Change in Therapy vs Oral Drug
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)
This study explored factors associated with differences in MTX dosing and compared MTX-dosing patterns between those who remained on MTX monotherapy and those who were switched or had additional therapy.
A retrospective cohort of 7,017 patients with newly diagnosed RA was identified in the United States Department of Veterans Affairs administrative databases between 1 October 1999 and 30 September 2009.
Study results indicated injectable MTX use resulted in higher weekly drug doses than oral administration and conferred lower risk of therapeutic change (hazard ratio = 0.64, 95% CI 0.52–0.78).
* Reference.
Adapted from Ng B, Chu A. Clin Rheumatol. 2014;33:21-30.

32. SC MTX Therapy: An Alternative to Initiating a Biologic
301 Patients Failing Oral MTX
68 Patients on SC MTX
20 (29%)
Discontinued SC MTX
33 (49%) Stabilized on SC MTX
15 (22%) Advanced to MTX + Biologic
These investigators carried out a retrospective analysis of records of 301 patients with RA at Gartnavel General Hospital, Glasgow, to determine the possible financial and health benefits of using SC MTX before resorting to anti-TNF-α therapy.
From this cohort, a total of 256 patients who failed oral MTX advanced to anti-TNF-α therapy and 68 had had SC MTX. Most patients had switched to SC from oral MTX because it was ineffective or intolerable because of adverse effects.
Of the 68 patients who had tried SC MTX, 29% had subsequently discontinued treatment, mostly as a result of adverse effects. Of the remaining patients still on SC MTX, 22% were also on anti-TNF-a therapy, while 49% were established with stable disease taking SC MTX alone.
SC, subcutaneous.
Adapted from Hassanzadeh R, et al. J Rheumatol. 2012;39:

33. ARS Question SC MTX administration results in…
higher risk for gastrointestinal adverse event vs oral drug
longer persistence with therapy vs oral drug*
clinical efficacy equivalent to that for oral drug
low risk for mucositis

34. Overcoming Barriers to SC Delivery of Medication: Needles
586 patients with moderate-to-severe, active RA who were either biologic naïve or biologic experienced (ie, receiving biologic therapy) participated in a patient needs survey. Of the 316 patients receiving SC therapy (biologic):
~25% relied on caregivers or healthcare providers to administer medication injection
Of patients who self-injected:
24% of patients experienced pain upon injection
20% experienced irritation at the injection site
This study was carried out gain insight into the management of RA from the perspective of patients with moderate to severe disease.
Patients with moderate-to-severe, active RA who were either biologic naive or biologic experienced (i.e., receiving biologic therapy) were recruited and then surveyed their perceptions of their disease and its management through a questionnaire.
The survey was administered by computer-assisted telephone interview of patients in 9 countries (N=586) and covered diagnosis, treatment, physician interaction, and lifestyle with RA.
Of the 316 patients receiving biologic treatment, ~25% relied on caregivers or healthcare providers to administer medication injection.
Of patients who self-injected, 24% of patients experienced pain upon injection and 20% experienced irritation at the injection site.
RA, rheumatoid arthritis; SC, subcutaneous
McInnes IB, et al. Clin Exp Rheumatol. 2013;31:

35. Overcoming Barriers to SC Delivery of Medication: Impaired Dexterity
Duration of RA
Many patients with RA have impaired dexterity that may impair the ability to deliver SC MTX with a syringe and vial.
The results shown in this slide are from a study carried out to determine the prevalence of hand and wrist symptoms and impairments, and the resulting activity limitations in relation to disease duration in patients with RA.
A cross-sectional study included 200 consecutive patients with rheumatoid arthritis in 4 categories of disease duration: 2-4, 4-6, 6-8, and ≥8 years.
Patients were asked about the presence of various hand and wrist symptoms, and underwent a standardized physical examination.
Overall, 94% of patients suffered from at least one symptom, and 67% had at least one impairment, mostly from the earliest stage of disease onwards.
SC, subcutaneous; pROM, passive range of motion; RA, rheumatoid arthritis.
Adapted from Horsten NCA, et al. J Rehabil Med. 2010;42:

36. Delivery of SC MTX With Auto-Injector Pen vs Prefilled Syringe: Patient Preference
Preference for pen N %
95% CI
Overall
109 83
76.1
(67.0, 83.8)
Age
≤55 yr 63 50
79.4
(67.3, 88.5)
>55 yr 46 33
71.7
(56.5, 84.0)
Gender
Female 79 59
74.7
(63.6, 83.8)
Male 30 24
80.0
(61.4, 92.3)
BMI
<30 kg/m2 73 54
74.0
(62.4, 83.5)
≥30 kg/m2 36 29
80.6
(64.0, 91.8)
Previous oral MTX treatment
Yes 89 66
74.2
(63.8, 82.9) No 20 17
85.0
(62.1, 96.8)
DAS28
≤3.2 13 11
84.6
(54.6, 98.1)
>3.2 to ≤5.1 67 49
73.1
(60.9, 83.2)
>5.1 23
79.3
(60.3, 92.0)
Preferring Syringe
Box size reflects number of subjects in analysis
This slide shows results from a multicenter, randomized, crossover study that compared preference, ease of use, acceptability, satisfaction, and safety of repeated SC self-administrations with prefilled pens and prefilled syringes delivering MTX, in patients with RA.
The study enrolled 120 patients requiring initiation or intensification of MTX therapy for RA.
Patients were randomized to receive the test drug, a prefilled pen or a prefilled syringe at doses of 15, 17.5, or 20 mg MTX SC once a week for 3 weeks and they were then crossed over to the alternative treatment.
Overall patient preference for the MTX prefilled pen was 75% (P=0.0001). In a six-item questionnaire, 73% to 76% of the patients preferred the prefilled pen in relation to use, acceptability, and satisfaction, and 67% of the patients confirmed that it did not take much effort to overcome SC self-injection with the pen.
In addition, 92% of physicians and study nurses indicated that they would recommend the MTX prefilled pen to patients for future MTX treatment. The formulations were generally well tolerated.
Preferring Pen 25 50 75
100
Percentage
SC, subcutaneous; BMI, body mass index; CI, confidence interval; DAS, disease activity score.
Demary W, et al. Patient Prefer Adherence. 2014;8:

37. Summary
MTX is the anchor drug for treatment of patients with RA and should be the first DMARD used for most patients
A significant percentage of patients treated with MTX achieve sustained clinical remission and do not exhibit radiologic progression
SC MTX is a useful alternative to oral delivery with:
Increased bioavailability and lower interpatient variability in exposure
Improved efficacy
Better tolerability
Longer persistence with treatment
No Notes (read slide)
DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis.

38. Discussion: Place in Therapy for SC MTX
What do you see as potential benefits of SC MTX:
To your patients?
To your practice?
To the healthcare system?
In your opinion, which patients would benefit most from a switch from oral to SC MTX?
No notes (read slide)
SC, subcutaneous.