1. PRACTICE INSIGHTS: BUILDING ON THE FOUNDATION FOR RA TREATMENT IN THE CLINIC
Speaker Notes
Welcome to Practice Insights: Building on the Foundation for RA treatment in the clinic.
MP-RA-0581

2. Jaime A Pachon, MD Arthritis & Rheumatic Care Center South Miami, Florida
Speaker Notes
Hello, my name is Jaime Pachon, and I am a rheumatologist in South Miami.

3. MTX: Foundation of Treatment in RA
Speaker Notes
Today I want to talk about methotrexate as the foundation of treatment in rheumatoid arthritis (RA).
Of my RA population, I would say 80 to 90 percent of the patients get methotrexate as their first DMARD. It is the DMARD we use first in all of our patients with RA.
We typically initiate therapy on 15 mg per week, with oral therapy. The reason we select oral MTX as the first therapy is that convenience and accessibility are our top priorities.
More often now, patients with RA have multiple medical problems and polypharmacy. They are looking for cost savings on their medications wherever they can find it. So cost is an important issue to keep in mind as well.

4. ACR Recommendations Support the Use of MTX as Initial DMARD Therapy in Patients with RA
Recommendations for Patients with Symptomatic Early RA
Level of Evidence (evidence reviewed)
Regardless of the disease activity level, use a treat-to-target strategy rather than a non-targeted approach
Low
If disease activity is low in patients who have never taken a DMARD:
Use DMARD monotherapy (MTX preferred) over double therapy
Use DMARD monotherapy (MTX preferred) over triple therapy
Low Low
If disease activity is moderate to high in patients who have never taken a DMARD:
Use DMARD monotherapy over double therapy
Use DMARD monotherapy over triple therapy
Moderate
High
Recommendations for Patients with Established RA
If disease activity remains moderate or high despite DMARD monotherapy, use combination traditional DMARDs or a TNFi or a non-TNF biologic or tofacitinib (all options are with or without MTX, in no particular order of preference), rather than continuing DMARD monotherapy alone
Moderate to
Very Low
Speaker Notes
This approach is consistent with the ACR 2016 guidelines.
The American College of Rheumatology (ACR) supports the use of methotrexate (MTX) in patients with either symptomatic early RA or established RA. It can be used as monotherapy and in combination with other agents.
Reference
Singh JA, Saag KG, Bridges SL Jr, et al American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68:1-26.
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; TNFi, tumor necrosis factor inhibitor.
Singh JA, et al. Arthritis Rheumatol. 2016;68:1-26.

5. Educating Patients on MTX
Speaker Notes
Educating the patients that are starting methotrexate is important: not just the drug, but managing their expectations regarding efficacy and side effects.
The approach we typically have in my practice is to provide a verbal explanation of what to expect with methotrexate, and provide information on the duration of treatment required to reach methotrexate optimization.
We also talk about the common adverse effects that they may experience.
Additionally, we provide patients with a handout on methotrexate that goes over what was explained to them verbally.
Then, we go a step further and begin to prepare them for the potential use of parenteral MTX. What I say to them is, “you know, there is no reason to be distraught if you feel the medication is not working after a prudent period. Changing to a different mode of administration may enhance the benefits of methotrexate.” That’s our approach to ensure that we set the stage for patients to move to subcutaneous methotrexate therapy and to manage their expectations.

6. Patient Education on MTX
Speaker Notes
This is an example of the patient education sheets for methotrexate. This covers oral versus subcutaneous methotrexate, duration of treatment required to optimize methotrexate, scheduling doses, etc.
You may request these from your Medac Pharma representative to provide to your patients.

7. Oral MTX: Initiation, Titration and Dosing
Speaker Notes
Once we start a patient on oral MTX we check them at about 6. weeks. At this visit we evaluate their progress, specifically tender/swollen joint counts, to have an objective measure of progress. We also measure their acute phase reactants to see if there are any improvements in those areas, and discuss any tolerability issues.
If the patient is not doing well based on those criteria, then I will titrate. Based on what we know about the bioavailability of oral methotrexate, I usually titrate up to 20 mg per week. I find that beyond 20 mg patients often have tolerability issues with oral methotrexate.

8. EULAR Guidance on MTX Dosing
MTX should be part of the first treatment strategy
MTX continues to be the anchor (‘first’) drug for patients with RA both as monotherapy as well as in combination with other drugs
MTX should be rapidly escalated, usually to mg/week, orally or subcutaneously administered, with folic acid supplementation
The maximal MTX dose, if tolerated, should be sustained for about 8–12 weeks to judge the MTX treatment response
When MTX is rapidly escalated to 25 mg/week, the response rate may even be higher
Speaker Notes
There are a number of important points from the updated EULAR guidelines with regard to the use of methotrexate.
Methotrexate should be first line of treatment in patients with RA.
Methotrexate dose (oral or SC) should be rapidly increased to mg per week. At these doses, the response rate may be higher (~40% LDA) than typically seen with MTX monotherapy (~30% in most trials).
Maximum dose (based on tolerability) should be sustained for 8-12 weeks before reviewing treatment response.
Reference
Smolen JS,  Landewé R, Bijlsma J, et al. Ann Rheum Dis :
Smolen JS, et al. Ann Rheum Dis :

9. Optimizing MTX Dosing Significantly Improves Clinical Response
Optimal MTX dose:
MTX introduction during the first 3 months after inclusion in the ESPOIR cohort
Initial dosage ≥10 mg/wk
Achieving ≥20 mg/wk or 0.3 mg/kg/wk MTX with DAS28 >2.6 at 6 months (or any dose with DAS28 <2.6 at 6 months)
Benefit of optimal MTX dose at 1 and 2 years of follow-up was evaluated as the proportion of patients:
In remission according to the ACR/EULAR Boolean, SDAI, and DAS28 definitions
With normal functioning (ie, HAQ ≤0.5)
With no rapid radiographic progression (change in SHS score <5 per year)
Speaker Notes
This study evaluated the symptomatic and structural impact of optimal MTX dosing in patients with early RA in daily clinical practice over 2 years.
Patients included in the early arthritis ESPOIR cohort who fulfilled the ACR-EULAR criteria for RA, and received MTX as a first disease-modifying anti-rheumatic drug (DMARD) were assessed.
An optimal MTX dose was defined as ≥10 mg per week during the first 3 months, with escalation to ≥20 mg per week or 0.3 mg/kg/week at 6 months without Disease Activity Score in 28 joints (DAS28) remission. Symptomatic and structural efficacy with and without optimal MTX dose was assessed by generalised logistic regression.
Reference
Gaujoux-Viala C, Rincheval N, Dougados M, Combe B, Fautrel B. Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort. Ann Rheum Dis. 2017;76:
SDAI, Simplified Disease Activity Index; HAQ, health assessment questionnaire; SHS, Shar score modified by van der Heijde.
Gaujoux-Viala C, et al. Ann Rheum Dis. 2017;76:

10. Optimizing MTX Dosing Significantly Improves Clinical Response
Results from the ESPOIR early arthritis cohort were used to evaluate the symptomatic and structural impact of optimal MTX dose in patients with early RA in daily clinical practice over 2 years
Patients included in the early arthritis ESPOIR cohort who fulfilled the ACR- EULAR criteria for RA and received MTX as a first DMARD were assessed
Optimal MTX dose was defined as ≥10 mg/week during the first 3 months, with escalation to ≥20 mg/week or 0.3 mg/kg/week at 6 in patients who did not achieve DAS28 remission
Only 26.4% of 314 patients evaluate received optimal MTX dosing  
OR for Achievement of Treatment Goal (optimal vs non-optimal MTX dosing)
Speaker Notes
Results from the ESPOIR early RA cohort were used to evaluate the symptomatic and structural impacts of optimal MTX dosing in patients with early disease.
An optimal MTX dose was defined as ≥10 mg per week during the first 3 months, with escalation to ≥20 mg/week or 0.3 mg/kg/week at 6 months in patients who did not achieve DAS28 remission.
Optimal MTX dosing significantly increased the odds for achievement of ACR-EULAR remission and normal functioning vs non-optimal dosing.
Reference
Gaujoux-Viala C, Rincheval N, Dougados M, Combe B, Fautrel B. Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort. Ann Rheum Dis. 2017;76:
ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; HAQ, Health Assessment Questionnaire
Gaujoux-Viala C, et al. Ann Rheum Dis. 2017;76:

11. Suboptimal Pharmacokinetics May Lead to Failure of Treatment with Oral MTX
Speaker Notes
Let’s move on to the pharmacokinetics of methotrexate, which are important to understand to optimize use of this drug.
We often consider the limited bioavailability of oral methotrexate when we do not see a response to treatment.
Let’s take a look at some of the relevant PK data here.

12. Increasing the Dose of Oral MTX Above 20 mg May Not Result in a Substantial Difference in Drug Exposure
In this randomized, multicenter, open-label, 3-way crossover study, patients ≥18 years with adult RA undergoing treatment with MTX for ≥3 months were assigned to receive MTX 10, 15, 20, or 25 mg weekly in a random sequence of 3 treatments:
Oral
SC into the abdomen
SC into the thigh
For 24 hours after administration of each treatment, blood samples were collected for pharmacokinetic analysis
3000
MTX Dose (mg/wk)
AUC (ngh/mL)
2600
2200
1800
1400
1000 10 15 20 25
Results for Orally Administered MTX
Speaker Notes
This slide shows results for oral MTX administration in a study that compared the relative bioavailability (BA) of MTX delivered by an auto-injector with the BA of oral MTX in adult patients with RA.
It was a 12 week, randomized, open-label 3-way crossover study of 49 patients, all of whom were undergoing treatment with MTX for ≥3 months prior to randomization.
Results from this study show that the bioavailability of oral MTX plateaued at doses ≥15 mg.
Reference
Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73:
AUC, area under the curve.
Schiff MH, et al. Ann Rheum Dis. 2014;73:

13. There is a Clear ‘Ceiling’ for the Efficacy of Oral MTX
Speaker Notes
In this study, endpoints of various outcome measures were stratified on the basis of the dose of oral MTX as part of the COMET study. This bar chart shows the MTX monotherapy response.
Patients achieved higher treatment responses with medium and high doses of MTX, but there was a clear ceiling where increasing the dose no longer increased response, and increasing dose may also increase adverse events.
Reference
Fleischmann R, et al. Presented at ACR/ARHP Scientific Meeting Abstract 441.
ACR70, American College of Rheumatology; HAQ-DI, health assessment questionnaire disability index; methotrexate; mTSS, multi-tiered system of supports
Fleischmann R, et al. Presented at ACR/ARHP Scientific Meeting Abstract 441.

14. Interpatient Bioavailability of Oral MTX Is Variable
Oral Bioavailability of 10 mg/m2 MTX (Oral AUC/IV AUC)
Speaker Notes
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 BA 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.
Reference
Herman RA, Veng-Pedersen P, Hoffman J, Koehnke R, Furst DE. Pharmacokinetics of low- dose methotrexate in rheumatoid arthritis patients. J Pharm Sci. 1989;78:  
Subject Number
AUC, area under the curve; IV, intravenous.
Adapted from Herman RA, et al. J Pharmaceutical Sci. 1989;78:

15. SC MTX: A Logical Next Step after Failure of Oral Drug
Speaker Notes
If, at 20 mg per week of methotrexate I still have not seen the clinical response nor the laboratory response that I expect, then I am quick to switch patients to subcutaneous (SC) administration.
I think the patient will help to guide you in this aspect. If I have a patient who has a partial response to methotrexate, I’m more inclined to keep him on methotrexate and switch to SC. To me, that just signals that I need to optimize their methotrexate.
Another scenario would be where, again, cost becomes an issue. Biologics, are even more expensive than subcutaneous, so cost is always part of the dialogue with the patient.
The other consideration is the individual patient. If I have a high-risk patient, someone with an infection, an elderly patient, or someone for whom I just think that the biologic immunosuppression may be too much, I will not go that route.
The way I approach it, my patients go from oral methotrexate to SC methotrexate. I’ll start with whatever their oral dose was, so if it was 20 mg per week, that’s my starting point for subcutaneous methotrexate.
This occurs in about 50 percent of my patients. A lot of folks do very well with the oral, but for those that are not well-controlled on oral, about half of those would go on to subcutaneous. For those that switch to subcutaneous drug from oral methotrexate, around 65 percent of those patients get to goal.
If I don’t have success for whatever reason with those steps, then I move on to a biologic DMARD.
Next, we will review some of the key data on switching from oral to SC methotrexate.

16. SC Administration Improves MTX Bioavailability
Single-center, open-label, randomized, 2-period, sequence, single-dose, crossover study in SC MTX dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg) among 54 healthy adults
Speaker Notes
Oral delivery of MTX has important limitations that may be overcome with SC delivery of the drug.
The BA of MTX declines as the oral dose rises, but this is not the case for SC administration. The results shown on this slide illustrate the increased BA of SC vs orally administered MTX.
In this single-dose, crossover study, healthy subjects aged 18 to 55 years were assigned to 1 of 4 dose groups: 7.5 mg, 15 mg, 22.5 mg, or 30 mg of MTX and each subject received a single dose administered orally and SC.
Each subject participated in only 1 of the 4 dose groups and received the single dose of MTX via autoinjector and oral dose by 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 BA, 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.
Reference
Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clin Exp Rheumatol. 2014;32:
Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

17. Blood Levels of MTX Are Related to Efficacy
76 patients with RA were included in this open-label, 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 American College of Rheumatology (ACR) core criteria; response categories were none, 20%, and 50%
Patients were classified as responders if they fulfilled the core criteria on at least 1 occasion during the follow-up period
P=0.002
AUC (mg/L・hour)
Speaker Notes
Seventy-six patients with RA were included in this open-label, prospective study.1
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%, and 50%. These criteria measure improvement in tender or swollen joint counts and improvement in at least three of the following parameters: patient assessment, physician assessment, pain scale, disability/functional questionnaire, and acute phase reactant (erythrocyte sedimentation rate or C-reactive protein).1,2
ACR 20 has a positive outcome if 20% improvement in tender or swollen joint counts were achieved as well as a 20% improvement in at least three of the other five criteria; ACR 50 has a positive outcome if 50% improvement in tender or swollen joint counts were achieved as well as a 50% improvement in at least three of the other five criteria; ACR 70 has a positive outcome if 70% improvement in tender or swollen joint counts were achieved as well as a 70% improvement in at least three of the other five criteria.2
Patients were classified as responders if they fulfilled the core criteria on at least 1 occasion during the follow-up period.1
Reference
Hornung N, Ellingsen T, Attermann J, Stengaard-Pedersen K, Poulsen JH. Patients with rheumatoid arthritis treated with methotrexate (MTX): concentrations of steady-state erythrocyte MTX correlate to plasma concentrations and clinical efficacy. J Rheumatol. 2008;35:
Hornung N, et al. J Rheumatol. 2008;35:

18. CAMERA: Improvement in DAS28 When Switching from Oral MTX to SC MTX5
Oral MTX
Switch to SC MTX
4.5
P<0.05 4
DAS28 Score (mean)
Switched to SC MTX due to adverse events
(n=21; mean dosage, 25 mg/wk)
3.5
Total SC MTX group (n=57) 3
P<0.01
Switched to SC MTX due to insufficient effect (n=36; mean dosage, 30 mg/wk)
Speaker Notes
Of 151 patients in the CAMERA trial, 57 needed the SC MTX strategy step and 40 followed cyclosporin strategy.
The decrease in DAS28 after taking the SC MTX strategy step was 0.30 points (P<0.05); whereas no significant change in DAS28 was seen after the cyclosporin strategy step.
Reference
Bakker MF, Jacobs JW, Weising PM, et al. Are switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotrexate useful steps in a tight control treatment strategy for rheumatoid arthritis? A post hoc analysis of the CAMERA study. Ann Rheum Dis. 2010;69: -3 -2 -1
start 1 2 3 4
Time (months)
Included the tight-control treatment arm of the CAMERA study
Switch data were evaluated post-hoc
N=151
Bakker MF, et al. Ann Rheum Dis. 2010;69:

19. SC MTX Can Improve Efficacy Without Increasing Risk for Adverse Events: Meta-analysis
Data from direct comparisons between oral and parenteral MTX were pooled and quantitatively analyzed using maximum likelihood random effects meta-analysis
Relative treatment effects were generated as odds ratios (ORs) (OR >1 indicated a higher probability of achieving the outcome in question for parenteral therapy)
Speaker Notes
This meta-analysis involved a direct comparison of oral MTX and SC MTX.
In terms of efficacy, parenteral MTX was more likely to achieve ACR20 across the studies included. ACR scoring is not used in many offices, but it is critical in evaluating efficacy vs other treatments. Evaluation of the risk for adverse events in the same studies was also examined. With an odds ratio of 1, this means that there is an equal opportunity for side effects with oral and SC MTX. For HCPs, this means they get increased efficacy without increased risk of side effects with SC MTX.
These 2 factors clearly demonstrate the potential for optimizing MTX with SC MTX before considering other therapies.
Reference
Janjua S, et al. Arthritis Rheumatol. 2017;69 (suppl 10). Accessed November 30, 2017.
ACR20, 20% improvement in ACR response criteria; CI, Confidence Interval; MTX, methotrexate; OR, odds ratio; SC, subcutaneous
Janjua S, et al. Arthritis Rheumatol. 2017;69 (suppl 10). meta-analysis/. Accessed November 30, 2017.

20. Lower Rates of All Common Adverse Events With SC vs Oral MTX
Speaker Notes
This prospective study was conducted to asses the efficacy, safety and compliance of subcutaneous methotrexate in patients with active RA.
A total of 92 patients were included; mean duration of the disease was months in the SC group and 49 months in the oral group.
At week 24, ACR 20/50 response rates were significantly higher in the SC MTX than oral MTX group.
The results of the study demonstrated that subcutaneous MTX was significantly more effective than oral MTX at the same dosage in patients with active RA, with no increase in side effects.
Reference
Islam MS, Haq SA, Islam MN, et al. Comparative efficacy of subcutaneous versus oral methotrexate in active rheumatoid arthritis. Mymensingh Med J. 2013;22:
MTX, methotrexate; SC, subcutaneous
Islam MS, et al. Mymensingh Med J. 2013;22:

21. SC MTX: Vial and Syringe or Autoinjector?
Speaker Notes
Generally I will go to the autoinjector, unless, in rare cases, the local commercial carriers will only approve the syringe and vial.
There is sort of an inherited fear or aversion to needles, let’s say. I think the presentation is key. For example, in the autoinjectors where they don’t really see the needle, that is a tremendous help. For some reason, the aversion to needles is put aside when they are not able to see the needle. They know that the needle’s in there and it’s going to do its job, but as long as they don’t see it, they are okay.
That’s a bigger challenge with the vial and syringe where they are not only seeing the needle, they see it several times. And if we manage to convince them to do it, those are the patients that are more likely to be nonadherent, and we have a harder time trying to control their disease. Those are the patients in whom I will typically see low MTX polyglutamate levels.
This choice has a lot to do with practicality. Many of these patients with RA have issues with hand dexterity and fine motor movements, and it’s difficult for them to draw medication and then inject the medication. Those added steps are challenging for many of these patients because of their hand deformities. So I stick with the autoinjector.
We spend a lot of time in adjusting our patient education with regard to initiation of SC MTX. A lot depends on the patient.
I have a patient, for example, who is a diabetic injecting insulin. That individual is not going to need a lot of training with their subcutaneous methotrexate, so I may show them what the methotrexate looks like, and just walk them through it. Sometimes we have them take the first dose in the office, so we can see that they are injecting it correctly. When you show them the autoinjector pen, they often say “I’m very familiar with that.” It’s another color, another look, but they’re very familiar with it. There’s a much greater level of comfort in those individuals.
Then there’s the other type of patient who has never self-injected. That patient, we tend to hold their hand. We ask them to come in so we can see them inject. Either myself or a nurse will supervise it and make sure it is being done correctly. They have access to us as many times as they like. I have some patients want to come and inject in our office for the first three or four times. They will do it themselves but, for some reason, it gives them some level of comfort to be in the office.
All patients get a verbal training and a written instruction pamphlet or handout. 

22. Needle Phobia Is Common
Fear
of Needles
No Fear
Total*
Gender, n (%)
Male
8 (20.5)
40 (31.3)
50 (28.2)
Female
28 (71.8)
68 (53.1)
101 (57.1)
Not specified
3 (7.7)
20 (15.6)
26 (14.7)
Age range in years, %
18-29
30.8
20.3
22.6
30-39
21.9
24.3
40-49
7.7
14.1
12.4
50-59
15.4
18.0
17.5
>60
12.8
22.7
19.8
2.6
3.1
3.4
Speaker Notes
This study investigated the prevalence of fear of needles in a southeast Queensland community, described associated symptoms, and highlighted health care avoidance tendencies of affected individuals.
One hundred and seventy-seven participants attending an outer urban general practice responded to a questionnaire on fear of needles, symptoms associated with needles and its influence on their use of medical care.
Twenty-two percent of participants reported a fear of needles. Affected participants were more likely than participants with no fear to report vasovagal symptoms, have had a previous traumatic needle experience (46.2 vs 16.4%, P<0.001) and avoid medical treatment involving needles (20.5 vs 2.3%, P<0.001).
Reference Wright S, Yelland M, Heathcote K, Ng SK, Wright G. Fear of needles--nature and prevalence in general practice. Aust Fam Physician. 2009;38:
*Total number includes nonrespondents to the question regarding fear of needles.
Wright S, et al. Aust Fam Physician. 2009;38:

23. Overcoming Barriers to SC Delivery of Medication: Impaired Dexterity1
Duration of RA
Speaker Notes
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.
Reference
Horsten NC, Ursum J, Roorda LD, van Schaardenburg D, Dekker J, Hoeksma AF. Prevalence of hand symptoms, impairments and activity limitations in rheumatoid arthritis in relation to disease duration. J Rehabil Med. 2010;42:
~25% of patients with RA on biologics relied on caregivers or HCPs to administer medication injection2
pROM, passive range of motion.
1. Adapted from Horsten NCA, et al. J Rehabil Med. 2010;42: McInnes IB, et al. Clin Exp Rheumatol. 2013;31:

24. RA Patients Can Manage MTX Self-Treatment With an Autoinjector
“The self-injection is easy to perform using few steps”
“I feel comfortable to perform the self-injection correctly without help”
“The injection system lies comfortably and secure in the hand during the injection”
81 (73.0%)
82 (73.9%)
84 (75.7%)
95% CI:
95% CI:
95% CI:
“I am not scared of being hurt before the injection is done”
“I am not scared of being hurt after the injection is done”
“It does not take much effort to overcome self-injection”
82 (73.9%)
84 (75.7%)
74 (66.7%)
Speaker Notes
This multicenter, randomized, crossover study 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 MTX via a prefilled pen or a prefilled syringe at doses of 15, 17.5, or 20 mg per week for 3 weeks. They were then crossed over to the alternative treatment.
Overall patient preference for the MTX prefilled pen was 75.7% (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.
Reference
Demary W, Schwenke H, Rockwitz K, et al. Subcutaneously administered methotrexate for rheumatoid arthritis, by prefilled syringes versus prefilled pens: patient preference and comparison of the self-injection experience. Patient Prefer Adherence. 2014;8:
95% CI:
95% CI:
95% CI:
Preference for MTX autoinjector
In addition, 76.1% of patients preferred an autoinjector to a prefilled syringe
CI, confidence interval.
Demary W, et al. Patient Prefer Adherence. 2014;8:

25. The Value of Measuring Polyglutmates
Speaker Notes
We often monitor patients to ensure that the switch to subcutaneous methotrexate is being adequately absorbed, and often to check on patient adherence.
I use the methotrexate polyglutamate labs that are offered by both AVISE in one of our commercial labs.
In patients who seem to be responding to subcutaneous methotrexate, I will continue to check their methotrexate polyglutamates. As the methotrexate concentration increases over time, there is a clinical response that correlates to methotrexate polyglutamate levels.
There are quite a lot of data on MTX polyglutamtes.

26. MTX-PGs Predict Clinical Response in RA
Intracellular MTX polyglutamate levels in patients receiving weekly doses of 2.5 to 37.5 mg for rheumatoid arthritis. The blood was taken at the time each patient was seen and classified according to his/her response to treatment with methotrexate
Response category
E-MTX (μg/L RBC)
MNC-MTX (pmol/109 cells)
PMN-MTX (pmol/109 cells)
Responders
27.69 ± 8.68 (n = 59)
± (n = 47)
± (n = 43)
Partial responders
23.15 ± (n = 29)
± (n = 17)
± (n = 20)
Non-responders
9.76 ± 4.85 (n = 11)
85.14 ± (n = 7)
31.16 ± (n = 7)
Speaker Notes
Sixty-five patients with RA who had been on weekly pulse MTX ( mg) for at least 2 months were entered into this study, and MTX-polyglutamates were measured using an enzymatic assay.
Polyglutamates in circulating erythrocytes in responders and partial responders were significantly higher (P< 0.001) than in non-responders.
The results suggest that circulating intracellular levels of MTX polyglutamates in RBC and PMN correlate with clinical efficacy but not with toxicity in patients with RA.
Reference
Angelis-Stoforidis P, Vajda FJ, Christophidis N. et al. Clin Exp Rheumatol. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis.1999;17:
1μg/L = 2.2 nmol/L
Angelis-Stoforidis P, et al Clin Exp Rheumatol. 1999;17:

27. Levels of MTX-PG Correlate With Clinical Response
71 patients with RA diagnosed according to 2010 ACR/EULAR criteria, who had never been treated with MTX or a biologic agent
MTX was started at a dosage of mg/wk and was increased by 4 mg every 4 weeks until it reached 16 mg/wk (unless adverse events occurred)
Blood samples were obtained at baseline; weeks 4, 8, and 12; and every 12 weeks thereafter
Clinical responses correlated with MTX-PG1-5 levels
180
160
140
120
100 80 60 40
Total MTX-PG (nmol/L)
-15
-10 -5 5 10 15 20 25 30
∆SDAI (12w SFAI-0w SDAI)
R=0.433, P=0.044
Speaker Notes
This slide shows results for 71 patients with RA, diagnosed according to 2010 ACR- EULAR criteria. The patients had never been treated with MTX or biologic agents.
MTX was started at a dosage of 8 mg per week and increased by 4 mg by every 4 weeks until it reached 16 mg per week unless adverse events occurred.
Blood samples were obtained at baseline, week 4, 8, and 12, and every 12 weeks thereafter.
Clinical responses were correlated with MTX PG1-5 levels.
Reference
Takahashi C, Kaneko Y, Okano Y, et al. Methotrexate polyglutamates in erythrocytes correlates with clinical response in Japanese patients with rheumatoid arthritis. Ann Rheum Dis. 2014;73:
Takahashi C, et al. Ann Rheum Dis. 2014;73:

28. Switching From Oral to SC MTX Increases Long-chain MTX PGs and Decreases DAS28
Results for 10 patients who were switched from oral to SC MTX
Speaker Notes
This study evaluated methotrexate pharmacokinetics 47 methotrexate-naïve patients enrolled in an dose-escalation study for an average of 20 weeks, and patients enrolled in a cross-sectional study under long-term methotrexate therapy. 
In 10 patients shown here, a switch from oral to parenteral methotrexate was associated with a 37% increase in long-chain MTX-PGs, a 132% increase in very long-chain MTXPGs and a concomitant 31% reduction in disease activity (P<0.02).
Switching from oral to parenteral MTX produces a selective accumulation of longer chain MTX-PGs, resulting in decreased DAS28 scores in these patients.
Reference
Dervieux T, Zablocki R, Kremer J. Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology (Oxford). 2010;49:
CI, Confidence Interval; MTX, methotrexate; PG, polyglutamate; SC, subcutaneous
Dervieux T, et al. Rheumatology (Oxford) ;49:

29. Poor Adherence to MTX Treatment Is Associated with Inferior Treatment Outcomes
Comparison of DAS28 values between patients with ≥80% adherence and patients with <80% adherence to DMARDs (81% taking MTX)
<80% Adherence to Correct DMARD Dose
4.95 (n=68)
≥80% Adherence to Correct DMARD Dose
5.00
4.10 (n=68)
4.50
P=0.002
4.09 (n=68)
DAS28 Score
4.00
P=0.08
P=0.02
3.80 (n=22)
3.50
Speaker Notes
The objective of this study was to quantify adherence to oral therapies in ethnically diverse and economically disadvantaged patients with RA.
A total of 107 patients with RA enrolled in a 2-year prospective cohort study agreed to have their oral RA drug therapy intake electronically monitored using the Medication Event Monitoring System.
Adherence to DMARDs and prednisone was determined as the percentage of days (or weeks for MTX) on which the patient took the correct dose as prescribed by the physician.
Patient outcomes were assessed, including function measured by the modified Health Assessment Questionnaire, disease activity measured by DAS28, health-related quality of life, and radiographic damage measured using the modified Sharp/van der Heijde scoring method.
Adherence to the treatment regimen as determined by the percentage of correct doses was 64% for DMARDs and 70% for prednisone.
Only 23 of the patients (21%) had an average adherence to DMARDs ≥80%. These patients showed significantly better mean DAS28 values across 2 years of followup than those who were less adherent (3.28 versus 4.09, P=0.02). Radiographic scores were also worse in nonadherent patients at baseline and at 12 months.
Reference
Waimann CA, Marengo MF, de Achaval S, et al. Electronic monitoring of oral therapies in ethnically diverse and economically disadvantaged patients with rheumatoid arthritis: consequences of low adherence. Arthritis Rheum. 2013;65:
3.28 (n=18)
3.45 (n=16)
3.00
Baseline
12 months
24 months
Waimann CA, et al. Arthritis Rheum. 2013;65:

30. SC MTX: How long is long enough?
Speaker Notes
One of the important points about the use of methotrexate is duration of therapy.
We re-evaluate patients on subcutaneous methotrexate at about 8 weeks. It generally takes up to 12 weeks to see a full response, at the appropriate dose.
We check to see if we are reaching our goal: clinical improvement - measuring and counting tender/ swollen joints, and following acute phase reactants. This may be through our regular monitoring routines or use of VECTRA, in some challenging cases.
Let’s take a look at some of the data to support a 12 week trial.

31. Percentage Achieving Remission or LDAS
Achievement of Remission or LDAS at 0-6 Weeks and 6-12 Weeks of Treatment: CATCH Cohort
Percentage Achieving Remission or LDAS
Speaker Notes
One hundred three patients were included from a single site between 2008 and All received MTX (98% received subcutaneous MTX; 98% dosed with 25 mg/week).
Results from this analysis also showed that continuing MTX treatment for up to a total of 12 weeks increased the percentages of patients achieving low disease activity as determined by Clinical disease Activity Index (CDAI), Simple Disease Activity Index (SDAI), or DAS28 criteria.1,2
References
O'Connor A, Thorne JC, Pope JE. The Rapid Kinetics of Optimal Treatment with Subcutaneous Methotrexate in Early Inflammatory Arthritis. Arthritis Rheumatol. 2015; 67(suppl 10). Abstract 611.
O’Connor A, Thorne C, Kang H, Tin D, Pope JE. The rapid kinetics of optimal treatment with subcutaneous methotrexate in early inflammatory arthritis: an observational study. BMC Musculoskeletal Disord. 2016;17:364.
Measure
O'Connor A, et al. Arthritis Rheumatol. 2015;67(suppl 10). Abstract O’Connor A, et al. BMC Musculoskeletal Disord. 2016;17:364.

32. Mean Number of Days to Achieve DAS28, LDAS, or Remission After Initiation of SC MTX
Speaker Notes
Patients with RA who were naïve at baseline to both conventional and biologic disease- modifying antirheumatic drugs, fulfilled the ACR/EULAR 2010 criteria, and had one or more follow-up visits were selected through sequential chart review for analysis of retrospective data.
Patients received SC MTX at varying doses (10-25 mg per week). The primary end point was a change in the DAS28.
Thirty-seven patients who initiated treatment with subcutaneous MTX and remained on it as monotherapy for 1.8 years are included in this analysis.
The mean number of days to low disease activity as measured by DAS28 for patients this goal was and that for achievement of remission for those who achieved this target was
Reference
Müller RB, von Kempis J, Haile SR, Schiff MH. Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real- world data from the St. Gallen cohort. Semin Arthritis Rheum. 2015;45:28-34.
Müller RB, et al. Semin Arthritis Rheum. 2015;45:28-34.

33. Moving to a Biologic: Continuing MTX Optimizes Outcomes
Speaker Notes
After 8 to12 weeks of methotrexate monotherapy, optimized with the use of subcutaneous administration, we evaluate the patient.
If I am not seeing clinical improvement, I generally add to the subcutaneous methotrexate (usually with a biologic). We maintain the subcutaneous methotrexate with the selected therapy. Methotrexate continues to be our foundation, and we build on it.
Methotrexate is good to have on board because it is contributing to the clinical response. Once I’ve reached what I consider a clinically stable patient, either a low disease activity or remission, I sometimes titrate their methotrexate to a lower dose, but always keep it on board.

34. Adding/switching TNF inhibitor, Non–TNF inhibitor, or Tofacitinib
Probability of ACR20/50/70 response with 95% CrI for different classes of biologic treatment, with and without MTX
ACR20
ACR50
ACR70
Non–TNF
Non–TNF
Non–TNF
Non–TNF
Inhibitor
Inhibitor
Inhibitor
Inhibitor
100
74.1
77.1
63.7
71.0
74.3
72.9
55.4
50.1
52.2
55.9 90
37.2
44.3
50.5
28.7 80
58.3
27.9
49.7
19.0 70
19.5
28.8
17.0
12.5
24.7 60
Percentage
30.5 50 40
15.5
Speaker Notes
These results are from a systematic review of the literature, which identified 28 randomized controlled trials (published between January 1990 and April 2013) that assessed approved novel DMARDs used as monotherapy or as combination therapy with MTX in DMARD-IR RA patients.
Results suggest that in combination with MTX most of the available novel DMARDs have similar levels of efficacy in DMARD-IR patients.
Reference
Buckley F, Finckh A, Huizinga TW, et al. J Manag Care Spec Pharm. Comparative Efficacy of Novel DMARDs as Monotherapy and in Combination with Methotrexate in Rheumatoid Arthritis Patients with Inadequate Response to Conventional DMARDs: A Network Meta-Analysis. 2015;21: 30
17.3
4.1
4.6 20
6.2 10
1.3
Placebo
Placebo
TNF
TOF 5 mg
TCZ
ABT
ANA
TNF
TOF 5 mg
TCZ + + + + + +
MTX
MTX
MTX
MTX
MTX
MTX
ABT, abatacept; ACR, American College of Rheumatology; ANA, anakinra; CrI, credibility interval; MTX, methotrexate; TNF, tumor necrosis factor; TOF, tofacitinib; TCZ, tocilizumab
Buckley F, et al. J Manag Care Spec Pharm. 2015;21:

35. PRACTICE INSIGHTS: BUILDING ON THE FOUNDATION FOR RA TREATMENT IN THE CLINIC
Speaker Notes
Thank you for taking time to listen to this program.
Brought to you by