1. A NEW LOOK AT RA Interactive Hot Topics Series
Why Do We Use Methotrexate Differently in Adults and Children?
Good evening, I’m Dr. Ruy Carrasco from the Dell Children’s Medical Center in Austin, Texas; and I’m going to take the next 15 to 20 minutes to compare how methotrexate is used in the treatment of children with polyarticular juvenile idiopathic arthritis – pJIA – and adults with rheumatoid arthritis – RA. I think that there are some important lessons that we have learned in the treatment of pJIA that might also be applied to adults with RA.
Ruy Carrasco, MD
Division of Rheumatology, Rheumatology,
Dell Children's Medical Center of Central Texas,
Austin, TX
MP-RA-0348

2. How do we treat pediatric patients with pJIA vs adults with RA?
The first couple of slides demonstrate that there is a clear difference in how we manage these two groups of patients.

3. Initial Treatment of Adults 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:
Results from a claims analysis carried out in the United States and which covered the period from 2009 through 2014, showed that more than 90% of adult patients with RA receive methotrexate drug orally.
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
O’Dell J, et al. Presented at ACR Annual Meeting

4. Initial Treatment of Pediatric Patients With MTX: Oral or Subcutaneous
About one-half of providers in the United States initiate MTX treatment using the oral route for patients with pJIA
CARRA survey was completed by 138 of 230 voting CARRA members (60% response rate):
In contrast, results from a survey of physicians involved in Childhood Arthritis and Rheumatology Research Alliance indicated that about one-half of physicians deliver methotrexate to their patients with pJIA via subcutaneous injection.
pJIA, polyarticular juvenile idiopathic arthritis
Adapted from Ringold S, et al. Arthritis Care & Res. 2014;66:

5. Are there any differences between how adult and pediatric patients respond to methotrexate?
It is not clear how this substantial difference in practice developed, but, as will become clear in the next few slides, it does not result from any clear difference in the way that adults and children process methotrexate.

6. Pharmacokinetics
The pharmacokinetic profile for methotrexate, particularly differences observed with subcutaneous versus oral administration, are very similar in adults and pediatric patients.

7. Bioavailability of MTX Declines with Oral Dose in Adults with RA
Transport of substrates via the RFC and PCFT are both saturable and the activities of both transporters are decreased in the presence of excess substrate1,2
This saturation is reflected by declining bioavailability with oral MTX dose (reflected by AUC/dose)3,4
AUC0-24/Dose3
AUC0-t/Dose4
This slide shows what happens when increasing doses of methotrexate are delivered orally to adults. There is a decline in bioavailability as the dose increases over the range used in clinical practice. This nonlinear relationship between the oral methotrexate dose and blood levels of the drug is believed to be due to the limited capacity or saturability of two transporters that carry methotrexate out of the intestine and into the bloodstream, the reduced folate carrier and the proton-coupled folate transporter.
Oral MTX Dose (mg)
Oral MTX Dose (mg)
AUC, area under the curve; PCFT, proton-coupled folate transporter; RFC, reduced folate carrier
1. Dev S, et al. Br J. Nutr. 2011;105:
2. Murakami T, Mori N. Pharmaceuticals. 2012;5:
3. Schiff MH, et al. Ann Rheum Dis. 2014;73:
4. Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

8. Bioavailability of MTX Declines with Oral Dose in Children with pJIA
Seventeen pJIA patients were administered oral ( mg/m2) MTX
Blood samples were drawn pre-dose, and at 1, 2, and 4 hours after administration
0.6
0.5
0.4
0.3
0.2
0.1
AUC0-4h (h • µmol/L)/Dose
Dose (mg/m2) 5 10 15 20 25 30
As is evident in this slide, the nonlinear relationship between methotrexate dose and blood levels seen in adults is also the case in children. The results shown here are for 17 patients with pJIA and they close match those for adults with RA.
Adapted from Tuková J, et al. Clin Exp Rheumatol. 2009;27:

9. Bioavailability of MTX Does Not Decline with SC MTX Dose in Adults with RA
AUC0-t/Dose (%)
This slide again shows results for adults with RA. It illustrates the relationship between methotrexate and dose-normalized area under the plasma concentration versus time curve for oral and subcutaneous methotrexate. The plot makes clear that the dose-normalized drug exposure declines with increasing oral doses, but not for subcutaneous doses across the same range.
Dose (mg)
No. patients
Adapted from Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

10. AUC0-4h (h • µmol/L)/Dose
Bioavailability of MTX Does Not Decline with SC MTX Dose in Children with pJIA
Seventeen pJIA patients were administered oral ( mg/m2) or SC ( mg/m2) MTX
Blood samples were drawn pre-dose, and at 1, 2, and 4 hours after administration
0.6
0.5
0.4
0.3
0.2
0.1
AUC0-4h (h • µmol/L)/Dose
Dose (mg/m2) 5 10 15 20 25 30
Oral MTX
SC MTX
Subcutaneous administration of methotrexate to pediatric patients also results in a more linear relationship between dose and exposure versus oral administration. I showed you this plot a moment ago, with only the results of oral administration. Now the results for subcutaneous administration have been added. There is no decline in bioavailability with increasing dose.
This difference between results for oral and administration of methotrexate in both adults and children is due to the fact that subcutaneous administration of the drug bypasses the saturable transporters in the intestine.
Tuková J, et al. Clin Exp Rheumatol. 2009;27:

11. Blood Levels of MTX Are Related to Efficacy
76 patients with RA were included in this open prospective study
Laboratory analyses, intracellular MTX concentrations in erythrocytes (Ery-MTX), and clinical examinations including toxicity data were performed prospectively for 52 weeks
Response to MTX was evaluated according to preliminary ACR core criteria; response categories were none, 20%, or 50%
Patients were classified as responders if they fulfilled the core criteria on at least one occasion during the followup period
P=0.002
AUC (mg/L・hour)
Bioavailability and exposure to methotrexate are important since efficacy of the drug has been related to exposure, as reflected by area under the time versus plasma concentration curve.
ACR, American College of Rheumatology; Ery, erythrocyte
Adapted from Hornung N, et al. J Rheumatol. 2008;35:

12. Polyglutamation of MTX
Methotrexate is a prodrug and it is converted to the active agent inside blood cells.

13. 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 activated to methotrexate polyglutamates by a folylpolyglutamate (FPGS)-mediated sequential addition of glutamic acid residues to the parent drug. This process selectively modifies the properties of methotrexate and enhances its retention in cells and its ability to decrease inflammation.
PG, polyglutamate
1. Dervieux T, et al. Rheumatol. 2010;49:
2. Dervieux T, et al. Pharmacogenet Genomics. 2009;19:
3. Stamp LK, et al. J Rheumatol. 2011;38:

14. 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
Subcutaneous administration of methotrexate in either adult or pediatric patients results in higher levels of long-chain methotrexate polyglutamates. This slide shows results for adult patients with RA…
MTX-PG1-2
MTX-PG3
MTX-PG4-5
RBC, red blood cell
Adapted from Dervieux T, et al. Rheumatology. 2010;49:

15. Higher Levels of Long-chain MTX-PGs with SC vs Oral Administration
Patients with pJIA from a single center (N=99; mean age months, 69 female)
Mean ± SD dose of MTX was 0.51 ± 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range months)
MTX was administered SC in 66 patients (67%)
350
300
250
200
150
100 50
MTXglu1-2 (nmol/L per mg/kg) PO SC
P=0.003
800
700
600
500
400
300
200
MTXglu3-6 (nmol/L per mg/kg) PO SC
P<0.0001
100
… and this slide shows similar data from pediatric patients with pJIA. In both studies, subcutaneous administration of methotrexate resulted in significant increases in methotrexate with at least three glutamate moieties added.
PO, oral; SD, standard deviation
Becker ML, et al. Arthritis Rheum. 2010;62:

16. 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
A study in adults with RA assessed the relationship between levels of methotrexate polyglutamates including three glutamate moieties and clinical response in 108 patients with rheumatoid arthritis. 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 methotrexate were considered responders. The graph on the right hand side of the slide demonstrates a clear relationship between longer chain methotrexate polyglutamate levels and clinical response to methotrexate.
VAS, visual analog scale
Dervieux T, et al. Arthritis Rheum. 2004;50:

17. JDAS-27 Scores and MTX-PG Levels
Juvenile Arthritis Disease Activity Score (JADAS) -27 at 3 months corresponding to MTX-PGs divided into tertiles
Bars show geometric means (back-transformed logarithmic JADAS-27) and 95% CIs *
MTX-PG1
MTX-PG2
MTX-PG3
MTX-PG4
MTX-PG5
MTX-PG3-5
Total MTX-PG 12 8 4
JADAS-27
1st tertile
2nd tertile
3rd tertile
Results from 113 patients with pJIA have also indicated a significant relationship between disease activity scores and levels of long-chain methotrexate polyglutamates. While the data were analyzed and are presented in a different way from those in adults, the relationship is the same.
*P<0.05
CI, confidence interval
Ćalasan MB, et al. Ann Rheum Dis. 2015;74:

18. Efficacy of oral and SC methotrexate
An important question that I’ll address in detail in the next several slides is the extent to which the pharmacokinetic and pharmacodynamic differences between oral and subcutaneous methotrexate translate into significantly better clinical efficacy and safety for subcutaneous drug administration.

19. SC MTX Achieved Better Disease Control vs Oral MTX
ACR Responses†
EULAR Remission†
P <0.05
Results from a head-to-head comparison of subcutaneous vs oral methotrexate in patients with RA has shown that subcutaneous administration results in significantly higher percentages of patients achieving American College of Rheumatology 20% and 70% improvement – ACR20 and ACR70 – improvement in their clinical condition vs oral drug. Subcutaneous delivery of methotrexate also resulted in a significantly higher percentage of patients achieving European League Against Rheumatism criteria for remission.
Week 24 results1
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/week.
EULAR, European League Against Rheumatism
Braun J, et al. Arthritis Rheum. 2008;58: © 2008, American College of Rheumatology.
Braun J. Clin Exp Rheumatol. 2010;28(suppl 61):S46-S51.

20. Efficacy of Oral and SC MTX in pJIA
Retrospective analysis of data from the German Methotrexate Registry comparing oral (0.4 mg/kg) and SC MTX (0.42 mg/kg) treatment in 411 patients with pJIA
Results for 107 patients with pJIA:
Percent of Patients
The efficacy of oral versus subcutaneous methotrexate has not been evaluated in a large-scale prospective study in patients with pJIA. This slide shows results from a retrospective analysis which suggested no significant difference between clinical results from these two routes of methotrexate administration.
ACR Pedi, ACR Pediatric Criteria
Adapted from Klein A, et al. Arthritis Care & Res. 2012;64:

21. Significant Improvement in Disease Control Following Switch From Oral to SC MTX in Adults with RA
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 slide shows clinical results demonstrating significant improvement in Disease Activity Scores (28 joints) – DAS-28 – scores for patients who were switched from oral to subcutaneous administration of methotrexate and followed for 3 months. Improvements in DAS-28 scores were observed for patients who switched treatment due to inadequate efficacy or intolerable side effects.
DAS, disease activity score.
Hameed B, Jones H. Int J Rheum Dis. 2010;13:e © 2010 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.

22. Percent of Patients Switched from Oral to SC MTX
Significant Improvement in Disease Control Following Switch From Oral to SC MTX in Patients with pJIA
Retrospective analysis of 61 pJIA patients
30 patients switched from oral (mean maximum dose =13.8 mg/m2 per week) to SC (mean maximum dose = 15.4 mg/m2 per week) due to inadequate efficacy or intolerance
Improvement defined as ≥30% improvement in 3 of the following: physician global assessment (PGDA), number of joints with active arthritis, number of joints with limited range of motion, duration of early morning stiffness, ESR
Switching to SC MTX also improved tolerability:
11 patients had nausea on oral MTX, 9 patients had complete resolution of their symptoms after switching to SC MTX and the other two reported decreased severity
Percent of Patients Switched from Oral to SC MTX
Switching from oral to subcutaneous methotrexate administration also improves outcomes in patients with pJIA. Results from a retrospective analysis of 61 patients indicated that 77% of those who switched treatment experienced clinical improvement. The switch from oral to subcutaneously administered methotrexate also reduced nausea in these patients.
≥30% Improvement
ESR, erythrocyte sedimentation rate
Adapted from Alsufyani K, et al. J Rheumatol. 2004;31:

23. Safety/tolerability of SC and oral MTX
There are numerous anecdotal reports suggesting that subcutaneous administration decreases the frequency and/or severity of gastrointestinal adverse events in patients with RA. Recent clinical results have provided support for this difference in tolerability.

24. Prospective Comparison of SC and Oral MTX: Adverse Events in Adults with RA
Percent of Patients
A prospective comparison of results from a cohort of 92 adult patients with RA who received oral or subcutaneous methotrexate indicated lower frequencies of nausea, vomiting, and dyspepsia.
Islam MS, et al. Mymensingh Med J. 2013;22:

25. Percent with Adverse Event
Gastrointestinal Tolerability with SC vs Oral MTX in Children with pJIA
P=0.229
P=0.411
Percent with Adverse Event
P=NS
P=NS
Findings from a prospective study of 55 patients with pJIA indicated that subcutaneous methotrexate had lower risk for gastrointestinal toxicity, mainly nausea, versus oral drug.
Adapted from Fronova J, et al. Pediatr Rheumatol. 2016;14:36.

26. Use of methotrexate with a biologic
Many patients being treated with methotrexate have their therapy advanced to include a biologic agent. An important issue for clinical management is whether methotrexate should be continued in these patients.

27. Adding a TNF Inhibitor Is Superior to Switching in Adults with RA
Continuing MTX results in improved clinical outcomes in patients receiving TNF inhibitors
An important question that should be addressed when changing therapy in a patient with an inadequate response to oral methotrexate 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 methotrexate in patients with an inadequate response to methotrexate alone. With the exception of tocilizumab, combination treatment produced improved clinical outcomes versus those achieved with monotherapy.
ABT, abatacept; ANA, anakinra; aTNF, anti-tumor necrosis factor; CrI, credible interval; TCZ, tocilizumab; TOF, tofacitinib
Buckley F, et al. J Manag Care Spec Pharm. 2015;21:

28. Patients with ACR Pedi Responses at Wk 16 (%)
Combining MTX and a Biologic Improves Outcomes Over Biologic Monotherapy in pJIA
Patients with ACR Pedi Responses at Wk 16 (%)
As in adults with RA, combination therapy with methotrexate and a biologic improves outcomes over a biologic agent alone in patients with pJIA. In this randomized, double-blind, placebo controlled, multicenter, medication withdrawal study, patients 4 to 17 years of age with active pJIA were stratified by methotrexate use, and given adalimumab. Results for ACR Pedi 30-, 50-, 70- and 90- in each group are show here at 16 weeks.
Lovell DJ, et al. N Engl J Med. 2008;359:

29. Practical considerations in methotrexate administration
Pharmacokinetic, pharmacodynamic, and clinical results all support the use of subcutaneous methotrexate for patients with RA and pJIA. However, there are also practical considerations that may make this approach to methotrexate delivery difficult in some patients.

30. Barriers to SC Delivery of Medication in Adults with RA
586 patients with moderate-to-severe, active RA who were either biologic naïve or biologic experienced (i.e., 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
Delivery of medications subcutaneously using a syringe and vial is difficult for some patients with RA . A substantial number require assistance with these injections and patients may also experience pain and irritation as a result of these injections.
McInnes IB, et al. Clin Exp Rheumatol. 2013;31:

31. Barriers to Self-Injection
Physical reasons
Psychological reasons
Results from an another patient survey indicated that many patients have physical difficulty with self injection and that many also have a fear of needles and/or a lack of confidence in their ability to self-inject.
N=422 Patients
Respondents could give more than one reason (values total more than 100%). Physical (total) score is the percentage of respondents selecting 1 or both of the 2 physical reasons; psychological (total) score is the percentage of patients selecting one or more of the psychological reasons.
Verdun di Cantogno E, Russell et al. Patient Prefer Adherence. 2011;5:

32. Barriers to SC Delivery of Medication in Pediatric Patients with pJIA
Invasive procedures to administer medications, including SC injections can be painful causing distress to young people. These procedures if performed regularly may cause anticipatory anxiety in some young people1
Anxiety about injections in children with pJIA:2
The transition from pediatric to adult care may also be difficult as some patients may refuse to self-inject using a syringe and vial3
Percent of Patients
Anxiety about subcutaneous administration also extends to children with pJIA. Mothers’ reports about their children indicated that 23% of children always had anxiety about their methotrexate injections.
O’Hara M. Doctor Dissertation. National University of Ireland, Galway Available at:
Adapted from Mulligan K, et al. Pediatric Rheumatol. 2013;11:23.
McDonagh JE, et al. Ann Rheum Dis. 2000;59:86-93.

33. Pain Associated with SC MTX Injection
Faces Pain Scale – Revised (FPS- R):
6 gender-neutral faces depicting “no pain” to “most pain possible”
The child points to the face that represents how much pain he/she feels. Ordered faces are scored
FLACC Behavioral Scale:
Observational scale comprises 5 items: (F) Face; (L) Legs; (A) Activity; (C) Cry; and (C) Consolability
Each of these five behavioral categories is rated on a scale 0-2 to provide an overall pain score ranging from 0 to 10
Results for 41 patients (mean age = years; 30 with pJIA):
11 of 41 (27%) had moderate to severe pain 12 10 8 6 4 2
Number of Participants 1 3 5 7 9
Pain Scale Score
FPS-R
FLACC
Children’s anxiety about methotrexate injection may result from the pain associated with this approach to administration. Results from one survey indicated that more than 25% of a sample of 41 patients with pJIA reported moderate-to-severe pain with methotrexate injection.
Bechard MA, et al. Pediatric Rheumatol. 2014, 12:54.

34. 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
Changing our approach to subcutaneous administration of methotrexate has the potential to improve patient tolerance and satisfaction with this treatment. This slide shows results from a comparison of patient responses to delivery of methotrexate with a syringe or an auto-injector. The vast majority of patients preferred the auto-injector.
Preferring Pen 25 50 75
100
Percentage
BMI, body mass index; DAS, disease activity score
Demary W, et al. Patient Prefer Adherence. 2014;8:

35. Summary

36. Summary
SC MTX provides improved outcomes over oral drug administration in RA and pJIA
Linear pharmacokinetics and higher bioavailability
Increased polyglutamation
Better clinical efficacy (most clearly demonstrated in adults with RA)
Improved gastrointestinal tolerability
SC MTX is employed extensively in children with pJIA, but much less often in adults with RA
Practical considerations may address barriers to SC administration that have the potential to increase the use of this route of delivery in both groups of patients
The data that I’ve reviewed here indicate improved outcomes of subcutaneous administration of methotrexate versus oral delivery in both adults and children. Nevertheless, there are barriers to subcutaneous administration of medications. Addressing practical considerations that may create barriers to subcutaneous delivery of methotrexate has the potential to increase the use of this route of delivery in both groups of patients.