1. The Role of Methotrexate in RA
UPDATES from EULAR 2017
Hello. I’m Dr. Grace Wright from the NYU Langone Medical Center in New York and I’m going to spend the next minutes discussing recent research concerned with the use of methotrexate in the treatment of patients with rheumatoid arthritis – RA – and polyarticular juvenile idiopathic arthritis – pJIA – that was presented at the European League Against Rheumatism – EULAR – annual congress that took place this June in Madrid.
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2. Scope of Review
We have reviewed studies concerned with the use of methotrexate (MTX) in rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA)
The presentations reviewed fall into several categories:
Efficacy
Safety
Effectiveness in “real-world” studies
Dosing
Subcutaneous administration
Response prediction
Adherence to therapy
Comorbidities
This slide provides a summary of the different areas in which there were interesting posters or oral presentations concerned with methotrexate and I have organized the studies that I will review as shown here.

3. Efficacy
The efficacy of methotrexate is, of course, very well established. However, information about it still accruing, which we will examine in this section.

4. Long-term Efficacy of MTX
RA patients with 10 years of follow-up from the BeSt study were analyzed
Patients were treated to target aiming at DAS28 ≤2.4
Percent of Patients Achieving Target at 10 years
We learned more about the long-term efficacy of methotrexate based on a report of 10-results from the BeSt study. Results for 247 patients followed for 10 years indicated that 11% achieved remission on methotrexate monotherapy. Combination of methotrexate with either sulfasalazine plus prednisone or infliximab, resulted in a substantially higher 10-year remission rate.
BeSt, Behandel Strategieen; DAS, Disease Activity Index; MTX, methotrexate
Bergstra SA, et al. Presented at EULAR, 2017:OP0252.

5. MTX Significantly Improves Response to Biologic Treatment
Observational study from a prospective cohort treated at the Biological Unit of the University Hospital La Paz, Madrid, Spain
293 RA patients treated with IFX (n=112 patients), ADA (n=71), or ETN (n=110 patients)
Patients were grouped according to MTX dose: no MTX, low dose (≤12.5 mg/week), intermediate dose ( mg/week) and high dose (≥20 mg/week)
Clinical responses were assessed by DAS28-ESR at 1 year
P=0.01
P=0.03
P=0.007
Change from Baseline in DAS28-ESR
One presentation of results from an observational study verified a concept already supported by a large body of data: adding a tumor necrosis factor – TNF – inhibitor to methotrexate is more effective than switching to TNF inhibitor monotherapy in RA patients who have failed methotrexate treatment.
This observational study from a university hospital in Madrid showed further that low and high doses of oral methotrexate are equally effective for lowering the Disease Activity Score – DAS – when added to a TNF inhibitor.
P values vs TNF inhibitor only
ADA, adalimumab; DAS, Disease Activity Index; ETN, etanercept; ESR, erythrocyte sedimentation rate; IFX, infliximab; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor
Martinez-Feito A, et al. Presented at EULAR, 2017:AB0375.

6. MTX Is More Effective Than Other Synthetic DMARDs When Combined with Adalimumab
Evaluation of whether ADA in combination with non-MTX conventional DMARDs has similar effectiveness as MTX combination therapy on clinical outcomes and PROs
The study included 519 patients on ADA + MTX and 235 patients on ADA + non-MTX synthetic DMARDs
In this real world study, patients on ADA + MTX had significantly greater improvements in disease activity compared to patients on ADA + non-MTX synthetic DMARDs therapy
Adjusted OR = 0.58, 95% CI
Adjusted OR = 0.59, 95% CI
Percent of Patients
While it is generally acknowledged that continuing methotrexate when a patient is started on a biologic results in better efficacy than switching to biologic monotherapy, less is known about the relative efficacy of different conventional disease-modifying anti-rheumatic drugs – DMARDs – when they are combined with a biologic.
This uncontrolled study compared results for patients with RA treated with adalimumab and methotrexate vs adalimumab and other DMARDs, such as sulfasalazine or hydroxychloroquine.
Results from this analysis indicated a significantly higher percentage of patients receiving adalimumab plus methotrexate achieved low disease activity vs those who received methotrexate and another conventional DMARD.
ADA, adalimumab; CDAI, Clinical Disease Activity Index; CI, confidence interval; DMARD, disease-modifying anti-rheumatic drug; LDA, low disease activity; PRO, patient reported outcome; RA, rheumatoid arthritis
Pappas D, et al. Presented at EULAR, 2017:FRI0188.

7. Safety
Some new data about the safety of methotrexate was also presented at the EULAR meeting, which I will cover in this section.

8. Recent Analysis Regarding MTX and Risk for Malignancy
Investigation of the association between the occurrence of malignancies (overall and malignant lymphoma) and drug use (MTX and biological agents) in a large observational cohort of Japanese patients with RA over a long-term period
Among 11,106 Japanese patients with RA representing 68,483 person-years of follow- up, 507 malignancies, including 68 malignant lymphomas, were confirmed. Neither MTX nor biological agent use was a significant risk factor for overall malignancy, with HRs (95% CI) of 1.18 ( ) and 1.01 ( ), respectively, or for malignant lymphoma, with HRs (95% CI) of 1.17 ( ) and ( ), respectively
Hazard Ratio
This slide show results from an investigation into the association between the occurrence of malignancies (both overall and malignant lymphoma, specifically). This included a large observational cohort of 11,106 Japanese patients with RA representing 68,483 person-years of treatment, and documented the occurrence of 507 malignancies, including 68 cases of malignant lymphoma. Neither methotrexate nor biological agent use was determined to be a significant risk factor for either of these events.
Note: Malignancy is an identified risk in the labeling information for MTX
CI, confidence interval; HR, hazard ratio; MTX, methotrexate; RA, rheumatoid arthritis
Sugimoto N, et al. Presented at EULAR, 2017:SAT0120.

9. Long-term Safety of Oral MTX
Evaluation of the safety of long-term MTX safety in patients with RA
RA patients on MTX therapy at recommended doses ( mg/week) as monotherapy or in combination with other conventional DMARDs or biologics for over 4 years were enrolled
The cumulative exposure to MTX was 926 patient years. Of 228 patients, 218 continued methotrexate through 4 years, either as monotherapy or part of combination treatment
Adverse Events on MTX Therapy
Number of Adverse Events
Serious/Severe AE’s
Skin, hair, mucosa
Infections
GI AE’s
AE’s 50
100
150
200
250
300
Year 1
Year 2
Year 3
Year 4
This slide shows results from an observational study of patients taking methotrexate, either as monotherapy or in combination with other conventional DMARDs or a biologic, with 4 years of follow-up.
The graph also indicates that adverse events declined over the course of the study period.
It is also worth noting that only 218 of 228 patients continued methotrexate as monotherapy or part of combination treatment over 4 years of follow-up.
AE, adverse event; GI, gastrointestinal; MTX, methotrexate; RA, rheumatoid arthritis
Nalawade AB, et al. Presented at EULAR, 2017:THU0178.

10. Effectiveness in “Real-world” Studies
Increasing attention is being paid to the effectiveness of all medications in real-world clinical practice and results from such studies are an important complement to data from controlled clinical trials.

11. Optimizing MTX Dosing in a Treat-to-Target Strategy
STRATEGE was a prospective, observational, multicenter study that included evaluable RA patients who received initial MTX monotherapy
After the inclusion visit:
Initial MTX treatment was maintained (dose and route) for 28.1% of patients, interrupted for 1.9%, and modified for %:
Dose increase for 50.2%
Dose taper for 1.8%
Route modification for 21.4% (88.2% oral to parenteral)
Biologic treatment was added in 14.6%
Other conventional DMARDs were added in 4.8%
All approaches resulted in significant reductions in DAS28 scores N
DAS28 Baseline
DAS28 (M6)
D DAS28 P
MTX unchanged (Ref.)
126
3.4 (1.3)
2.5 (1.0)*
-0.8 (,.2) —
MTX optimization
519
4.0 (1.0)
2.9 (1.2)*
-1.1 (1.3)
0.10
bDMARDs
117
4.6 (1.1)
3.2 (1.1)*
-1.4 (1.3)
0.22
csDMARDs 39
4.3 (1.2)
3.1 (1.3)*
-1.3 (1.4)
0.37
This slide shows results from STRATEGE and they demonstrate the effectiveness of methotrexate, used in a variety of different approaches in a treat-to-target strategy, to decrease disease activity in patients with RA.
Results from this analysis also showed that most patients require some modification of their initial methotrexate regimen, and that switching from oral to subcutaneous – SC – delivery is employed frequently in an effort to improve efficacy.
bDMARD, biologic disease-modifying anti-rheumatic drug; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; D, delta; DAS, Disease Activity Index; M6, 6 months; MTX, methotrexate; RA, rheumatoid arthritis; Ref, reference
Flipo R-M, et al. Presented at EULAR, 2017:SAT0057.

12. What Rheumatologists Tell Their Patients About MTX
An online survey was designed and subsequently refined based on interviews with rheumatologists in the UK
The survey asked rheumatologists about their clinical setting and their views and practices with respect to treating RA with MTX
Rheumatologists were asked how often specific pieces of MTX-related information were discussed during a consultation to commence the drug (5=Always to 1=never)
The specific pieces of MTX-related information rheumatologists in the UK report they often/always discuss in clinic (%)
The benefits of MTX
Common side effects of MTX
Blood monitoring
How to use MTX
Alcohol use
Serious side effects
RA prognosis
Patient concerns about MTX
Synovitis
Patient adherence
Smoking & response to MTX
Autoimmunity
Drug mechanism
Obesity & response to MTX
100 90 80 70 60 50 40 30 20 10
Results presented at EULAR also provided insight into how physicians discuss methotrexate with their patients. Most physicians cover a wide range of relevant topics, but there is little consideration about how the drug works to control the symptoms of RA.
MTX, methotrexate; RA, rheumatoid arthritis; UK, United Kingdom
Hope HF, et al. Presented at EULAR, 2017:THU0192.

13. Factors That Hinder Treating to Target in Patients with RA
Assessment 388 patients with RA who were observed between January and October 2016 and who had not received new DMARDs for >3 months before the assessment
P<0.001
P=0.09
P<0.01
P<0.001
Odds Ratio for Not Treating to Target
Information was also presented about factors that interfere with achievement of treatment goals in RA.
This slide shows results from 388 patients with RA and their risk (odds ratio) for failing to achieve treatment goals (remission or low disease activity). Lack of methotrexate in the treatment regimen more than doubled the odds of not achieving treatment goals.
DMARD, disease-modifying anti-rheumatic drug; GC, glucocorticoid; MTX, methotrexate; RA, rheumatoid arthritis
Hagiwara T, et al. Presented at EULAR, 2017:SAT0068.

14. Dosing
Achieving optimal dosing is important for RA patients receiving methotrexate and one study presented at EULAR provided information on this topic.

15. Higher Dose MTX Is Associated with a Better Response to Therapy
Comparison of 6-month responses to MTX in RA patients starting at 7.5 mg/week (n=171) vs those starting at 15 mg/week (n=639)
P=0.004
Percent of Patients
Results from a 6-month study of 810 patients who initiated methotrexate treatment at a dose of either 7.5 or 15 mg/week indicated that the higher dose resulted in a significantly higher percentage of patients achieving a “good” response to treatment based on EULAR criteria.
EULAR Response Category
EULAR, European League Against Rheumatism; MTX, methotrexate; RA, rheumatoid arthritis
Davies R, et al. Presented at EULAR, 2017:OPP0025.

16. Subcutaneous Administration
Increasing attention is being paid to SC vs oral administration of methotrexate in patients with RA and five EULAR presentations were focused on this issue.

17. Efficacy of SC MTX in Elderly RA Patients
Assessment of the results of 12 months of therapy with SC MTX in 32 RA patients aged >60 years
All patients were administered SC MTX monotherapy starting at mg/week, with subsequent up-titration by 5 mg every 1-2 weeks to a maximum of 30 mg/week
Number of Patients
This slide shows assessment of the results of 12 months of therapy with SC methotrexate in a cohort of 32 RA patients. These patients were greater than 60 years of age, and started treatment at mg/week, with subsequent 5 mg up-titration every 1-2 weeks to a maximum dose of 30 mg/week.
The results showed that 22 patients achieved remission or low disease activity with SC MTX monotherapy and that the remaining 10 patients required addition of a biologic to achieve this goal.
DAS, Disease Activity Score; LDA, low disease activity; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Muraviev Y, et al. Presented at EULAR, 2017:AB0441.

18. Use of SC MTX in Patients with RA in Poland
The aim of this study was to evaluate use of SC MTX as initial therapy and after failure of oral MTX in a cohort of Polish patients with RA; 144 patients started on oral MTX and 50 started on SC MTX
74.3%
88.0%
Number of Patients
A study carried out in Poland included 144 patients who were started on oral methotrexate and 50 who started on SC. Both were followed for 3 months.
88% of those started SC methotrexate monotherapy were maintained on this treatment for the entire study period. This was also the case for 74% of patients started on oral methotrexate.
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Przygodzka M, et al. Presented at EULAR, 2017:AB1211-HPR.

19. Time to Remission in Patients Treated with Oral or SC MTX: Results from the CATCH Cohort
1,749 participants from 13 centers with mean age 54 years, 73% female, mean DAS28 = 4.9, and mean CDAI = 25.6 were included
The initial therapeutic strategies:
At 6 months, patients on SC MTX were more than twice as likely to have achieved disease remission vs those on oral drug (OR=2.04, 95% CI= )
Percent of Patients
Results from a study of 1,749 RA patients in the CATCH cohort were used to compare the efficacy of different treatment approaches for achieving remission by 6 months.
The analysis indicated that patients on SC methotrexate were more than twice as likely to achieve disease remission versus those on oral drug.
CDAI, Clinical Disease Activity Index; CI, confidence interval; DAS, Disease Activity Index; DMARD, disease-modifying anti-rheumatic drug; MTX, methotrexate; OR, odds ratio; RA, rheumatoid arthritis; SC, subcutaneous
Barnabe C, et al. Presented at EULAR, 2017:THU0085.

20. Visits Required to Train RA Patients in SC DMARD Injection
109 patients treated with SC MTX or a biologic
Number of Patients
Number of Training Visits Required
Results presented at EULAR also suggested that training patients to self inject either methotrexate or a biologic may be difficult. While about 25% of patients require only one clinic visit for training, most require two or more visits.
DMARD, disease-modifying anti-rheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous
Erra A, et al. Presented at EULAR, 2017:AB1183.

21. Response Prediction
The largest group of EULAR presentations concerned with methotrexate in the treatment of RA were focused on response prediction.

22. Remission at 6 Months Predicts Better Long-term Response to MTX20 15 10 5
Clinical Disease Activity Index 60 48 36 24 12 6 3
Months
SDAI remission at six months
SDAI LDA at six months 5 4 3 2 1
Clinical Activity Score 28 Joints 60 48 36 24 12 6
Months
SDAI remission at six months
SDAI LDA at six months 6 4 2 1
Modified Health Assessment Questionnaire Score 60 48 36 24 12 3
Months
SDAI remission at six months
SDAI LDA at six months
Of 1,148 eligible RA patients in the NOR-DMARD study, 867 (75.5%) started with MTX monotherapy and 281 (24.5%) started with another sDMARD or sDMARD combination
Patients in SDAI remission (n=145; 16.6%) rather than LDA (n=454; 39.5%) 6 months after initiating therapy had better physical function (mHAQ, P<0.02), higher SF-36 PCS (P<0.003), and SF-6D (P<0.0001), and lower disease activity (SDAI, P<0.05) for all visits during 5 years of follow-up. 50 45 40 35 30
SF-36 Physical Component Summary Score 60 48 36 24 12 6 3
Months 46
SF-36 Manual Component Summary Score 60 48 36 24 12 6 3
Months 50 52 54 56
.60
SF-6D 60 48 36 24 12 6 3
Months
.65
.70
.75
.80
.85
Results from the NOR-DMARD cohort of 1,148 RA patients (75.5% treated with methotrexate) indicated that achievement of remission at 6 months according to the Simplified Disease Activity Index was associated with significantly better 5-year results for physical function, physical quality of life, and disease activity.
LDA, low disease activity; MTX, methotrexate; mHAQ, modified Health Assessment Questionnaire; PCS, Physical Component Score; RA, rheumatoid arthritis; SDAI, Simplified Disease Activity Index; sDMARD, synthetic disease-modifying anti-rheumatic drug; SF-36, Medical Outcomes Study Short-form 36; SF-6D; Medical Outcomes Study Short-form 6D
Norvang V, et al. Presented at EULAR, 2017:SAT0075.

23. Clinical and Laboratory Factors Predicting Response to MTX in a Case-control Study
Case-control study aimed at assessment of clinical and demographic characteristics related to response to MTX in DMARD-naïve RA patients
Compared patients with sustained CRP-DAS28 <3.2 vs patients who discontinued MTX due to ineffectiveness or toxicity
Characteristics
Responders
n=125
Nonresponders
n=99
P-value
Age at onset, y (mean, SD)
53.48 (13.0)
46.65 (11.5)
0.0006
Female n (%)
80 (65.0)
72 (72.7)
Current smokers n (%)
23 (18.7)
40 (40.4)
<0.01
Alcohol consumers n (%)
35(28.5)
28 (28.3)
Comorbidity n (%)
92 (74.8)
61 (61.6)
<0.05
CV risk factors n (%)
81 (81.8)
Polyarticular onset of RA n (%)
61 (49.6)
Extra-articular involvement n (%)
17 (13.8)
21 (21.2)
Positive RF n (%)
89 (72.4)
79 (79.8)
Positive ACPA n (%)
70 (60.3)
64 (68.1)
Duration of RA, m (mean, SD)
96.1 (63.1)
96.0 (73.9)
MTX toxicity n (%)
47 (38.2)
59 (59.6)
MTX dose, mg (mean, SD)
15.6 (0.32)
17.8 (0.37)
0.0001
A case-control study carried out in 224 patients with RA who were treated with methotrexate indicated that younger age at onset of disease, not smoking, a higher frequency of comorbidities, less methotrexate toxicity, and a slightly lower drug dose were all associated with significantly increased probability of responding to treatment.
ACPA, anti-citrullinated protein antibodies; CV, cardiovascular; CRP, C-reactive protein; DAS, Disease Activity Score; DMARD, disease-modifying anti-rheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; SD, standard deviation
Chamizo-Carmona E, et al. Presented at EULAR, 2017:AB0212.

24. Predictors of Poor Response to MTX
Time-averaged DAS28
Time-averaged PGA
Time-averaged HAQ
Time-averaged CRP
HAQ at Baseline
TJC at Baseline
Weight (kg)
Male:Female
Age (Years) 1 10
3.718 (2.488, 5.557)
1.025 (1.004, 1.047)
2.198 (1.079, 4.477)
0.982 (0.970, 0.995)
0.536 (0.313, 0.920)
0.982 (0.963, 1.001)
1.013 (1.000, 1.026)
0.553 (0.323, 0.943)
1.014 (0.998, 1.031)
Odds ratio (95% CI)
MTX Insufficient Response
Identification of predictors of MTX insufficient response and rapid radiographic progression among patients with early RA receiving 6 months of MTX therapy in the OPTIMA and PREMIER trials
Time-averaged DAS28
Time-averaged HAQ
Time-averaged Pt Pain
Time-averaged CRP
Time-averaged TJC
HAQ at Baseline
Prior corticosteroid use
mTSS
BMI 1 10
Odds ratio (95% CI)
Rapid Radiographic Progression
RF (IU/mL)
3.382 (2.096, 5.457)
2.572 (1.266, 5.224)
0.973 (0.957, 0.989)
1.016 (1.004, 1.027)
0.952 (0.926, 0.980)
0.437 (0.251, 0.762)
0.571 (0.372, 0.877)
1.013 (1.003, 1.022)
0.965 (0.933, 0.997)
1.001 (1.000, 1.001)
Results from the PREMIER and OPTIMA clinical trials were used to identify baseline and on-treatment predictors of insufficient methotrexate response and rapid radiographic progression among patients with early RA receiving 6 months of therapy.
Significant risk factors for an insufficient clinical response and rapid radiographic progression included higher on-treatment scores for the Health Assessment Questionnaire and DAS28.
BMI, body mass index; CI, confidence interval; CRP-C-reactive protein; DAS, Disease Activity Score; HAQ, Health Assessment Questionnaire; MTX, methotrexate; mTSS, modified Total Sharp Score; PGA, Physician Global Assessment; Pt, patient; RA, rheumatoid arthritis; RF, rheumatoid factor; TJC, tender joint count
Kavanaugh A, et al. Presented at EULAR, 2017:SAT0142.

25. Predictors of Poor Response to MTX in the MARI Study
Case-control analysis including 186 RA patients who did not achieve a DAS28 LDA score (≤3.2) and 558 age- and gender-frequency- matched (1:3), randomly selected controls who achieved a DAS28 LDA from the original cohort investigated in the MARI study
Factors significantly associated with failure to achieve LDA (logistic regression analysis:
Polyarticular disease (OR = 4.0, 95% CI , P<0.001)
Erosive arthritis (OR = 2.2, 95% CI , P<0.001)
Increased CRP (OR = 7.4, 95% CI , P<0.001)
A similar analysis of patients in the MARI cohort indicated that polyarticular disease, erosive arthritis, and elevated C-reactive protein were all significantly associated with higher probability of not achieving low disease activity with methotrexate treatment.
CI, confidence interval; CRP, C-reactive protein; DAS, Disease Activity Score; LDA, low disease activity; MTX, methotrexate; RA, rheumatoid arthritis
Giusti A, et al. Presented at EULAR, 2017:THU0181.

26. Elevated RF Predicts a Poor Response to MTX
Investigation of whether RF impacts response to therapy in ACPA-positive early RA patients treated with MTX
574 early RA patients consecutively enrolled in Early Arthritis Clinic between 2005 and and treated with incremental doses of MTX according to a treat-to-target strategy aiming at LDA (DAS28 ≤3.2)
High levels of RF were associated with a poorer response to MTX (achievement of LDA or remission):
Percent of Patients Achieving Goal
DAS28 ≤3.2
100 80 60 40 20 6 4 2
Months
Percent of Patients Achieving Goal
DAS28 <2.6
100 80 60 40 20 6 4 2
Months
ACP-pos RF-neg
ACPA-pos RF <3 ULN
ACP-pos RF >3 ULN
Results from a cohort of 574 early RA patients were used to determine whether the presence of rheumatoid factor influenced the response to methotrexate in patients who were also positive for anti-citrullinated protein antibodies. Results indicated that the presence and level of rheumatoid factor were significantly associated with failure to achieve low disease activity or remission with methotrexate.
ACPA, anti-citrullinated protein antibodies; DAS, Disease Activity Score; LDA, low disease activity; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; ULN, upper limit of normal
Bugatti S, et al. Presented at EULAR, 2017:SAT0060.

27. Anti-RA33 Predicts Poorer Response to MTX and TNF Inhibitors
The anti-RA 33 antibodies can be found in tumor necrosis factor-transgenic mice that develop spontaneous arthritis and these antibodies (which are directed to the nuclear antigen hnRNP-A2) could be of prognostic value in patients with RA 1,2
The aim of this study to measure the prevalence of anti-RA33 IgG, IgM, and IgA antibodies in patients with RA and to determine their potential prognostic value regarding prediction of response to treatment with MTX or TNF inhibitors2
50% improvement in SDAI with TNF Inhibitor
50% improvement in SDAI with MTX
P=0.0117
P<0.0001
P<0.0001
Percent of Patients
Percent of Patients
The anti-RA 33 antibodies can be found in tumor necrosis factor-transgenic mice that develop spontaneous arthritis, and these antibodies (which are directed to the nuclear antigen hnRNP-A2) could be of prognostic value in patients with RA .
The aim of this study was to measure the prevalence of anti-RA33 immunoglobulins in patients with RA and to determine their potential prognostic value regarding prediction of response to treatment with methotrexate or a TNF inhibitor.
Study results indicated that anti-RA33 antibodies were associated with poorer responses to both methotrexate and TNF inhibitors.
MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous; SDAI, Simplified Disease Activity Index; TNF, tumor necrosis factor
1. Lashkari M, et al.  Global Journal of Health Science. 2014;6:   2. Steiner G, et al. Presented at EULAR, 2017:THU0103.

28. Prediction of Requirement for Biologic Treatment in Patients Receiving SC MTX
Determination of whether polymorphisms of immune response genes are associated with early prescribing of biological treatment in early RA patients, refractory to SC MTX monotherapy
45 patient started SC MTX monotherapy with rapid up-titration of the dose from 10 to mg/week
Therapy was assessed every 3 months using DAS28, SDAI, and CDAI indices; and polymorphisms for multiple inflammatory genes were evaluated
By the end of 3 months of SC MTX therapy:
23 patients (51.1%) adequately responded to SC MTX (EULAR criteria) and continued on SC MTX monotherapy
22 patients (48.9%) failed SC MTX monotherapy and were switched to SC MTX + adalimumab
CTLA-4 gene polymorphism (+49A/G) was the only predictor for the requirement of administration of biological therapy
A small study of 30 patients with RA addressed the importance of polymorphisms in immune response genes for predicting the need for biologic treatment in early RA patients receiving SC methotrexate monotherapy.
Study results indicated that a CTLA-4 gene polymorphism (+49A/G) was the only predictor for the requirement of administration of biologic therapy in this group of patients. Study results also indicated that 51% of patients could be maintained on SC methotrexate monotherapy.
CDAI, Clinical Disease Activity Index; CTLA-4, cytotoxic T-lymphocyte-associated protein 4 DAS, Disease Activity Score; EULAR, European League Against Rheumatism; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous; SDAI, Simplified Disease Activity Index
Guseva I, et al. Presented at EULAR, 2017:AB0230.

29. Adherence to Therapy
Adherence to therapy is an important determinant of treatment outcomes and several studies presented at EULAR addressed this issue for patients receiving methotrexate.

30. Persistence with MTX Monotherapy in Patients with Early RA
This study compared persistence with MTX treatment in 219 patients with very early RA (4 weeks after symptom onset) and 155 patients with early RA (24 weeks after symptom onset)
There was no difference between persistence in the two groups
300.00
250.00
200.00
150.00
100.00
50.00
.00
Time (weeks)
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Survival
VEA EA
An analysis of persistence with methotrexate monotherapy in patients with early or very early RA indicated no difference between the two groups of patients.
Study results also indicated that about 40% of patients in each group persisted with treatment for at least 2 years. In early RA patients, predictors of shorter methotrexate persistence were younger age at diagnosis (P=0.004), lower dose of methotrexate (P=0.032), earlier diagnosis from symptom onset (P=0.0001), higher titer of rheumatoid factor (P=0.037) and female gender (P=0.019).
EA, early RA; MTX, methotrexate; RA, rheumatoid arthritis; VEA very early RA
Anelli MG, et al. Presented at EULAR, 2017:FRI0110.

31. Specific Behaviors and Attitudes in Patients Adherent and Non-adherent to MTX
Analysis of Result from the FORGET study with adherence measured by the Compliance Questionnaire for Rheumatology (Self-assessment questionnaires returned by 214 patients)
Non-adherent
Adherent
P-value %
34.0
66.0
Behaviors
Skipped doses
54.2
14.8
<0.01
Temporarily stopped treatment in accord with physician’s recommendation
22.2
2.8
Temporarily stopped treatment in accord without physician’s recommendation
37.5
4.2
Attitudes
Taking my medication is constraining
29.4
23.9
0.013
I feel less well with a change in dosage
30.9
24.3
0.016
My treatment does more harm than good
18.7
9.2
0.0001
I think every day about my arthritis
22.0
16.9
0.012
Results from the FORGET study that included 214 RA patients indicated that adherent patients were significantly less likely than non-adherent patients to believe that taking methotrexate was constraining, that changing the dose made them fell less well, and that treatment did more harm than good. Adherent patients were also significantly less likely than non-adherent patients to think about their arthritis every day.
MTX, methotrexate
Beauvais C, et al. Presented at EULAR, 2017:THU0169.

32. Support from Physician and Family Improves Adherence to MTX
Analysis of Result from the FORGET with adherence measured by the Compliance Questionnaire for Rheumatology (Self-assessment questionnaires returned by 214 patients)
Non-adherent
Adherent
P-value
High Impact of Disease
Low Impact of Disease % 14 19 33 34
Follow-up in private practice 16 21 39 40
0.015
Follow-up in hospital 66 47 43
0.028
Distance from hospital >30 minute ride 63 52 73
0.005
Live in a city with >100,000 people 27 8 28
0.004
Physician to time to explain treatment and answer questions
100 85 97 99
Physician made me participate in treatment choice 48 60 54 71
0.248
I had good support from my rheumatologist about my treatment 93 88 96
I had good support from my relatives about my treatment 55 82
0.000
Living alone 31 32 22 11
0.020
Another analysis of results from the FORGET study indicated that support from the treating physician and family members both contributed to better adherence to therapy.
MTX, methotrexate
Beauvais C, et al. Presented at EULAR, 2017:THU0184.

33. Comorbidities
Comorbidities are very common in patients with RA and two important studies addressed the impact of methotrexate treatment on cardiovascular disease and diabetes.

34. Early Treatment with MTX Improves Cardiovascular Outcomes
Study of RA patients enrolled in the population- based Ontario Rheumatoid Arthritis Database (ORAD) who were diagnosed after reaching 65 years of age
28,172 incident RA patients were followed for 141,072 person years. During follow-up, 8,848 (31%) patients died with 1,419 (5%) deaths due to CVD
Hazard Ratio
A study of 28,172 RA patients in the population-based Ontario Rheumatoid Arthritis Database who were diagnosed after reaching 65 years of age and followed for 141,072 person years indicated that methotrexate treatment significantly decreased both all-cause and cardiovascular mortality.
CVD, cardiovascular disease; MTX, methotrexate; RA, rheumatoid arthritis
Widdifield J, et al. Presented at EULAR, 2017:FRI0684.

35. MTX Improves Glucose Tolerance in Patients with RA
Newly registered 20 RA patients with glucose intolerance (A1C ≥5.6%) treated with MTX alone (n=8), TNF inhibitor + MTX (n=6) or other DMARDs (n=6)
Only the patients treated with MTX monotherapy experienced reductions in baseline in A1C
A small study of 20 RA patients with mild glucose intolerance indicated that treatment with methotrexate lowered glycosylated hemoglobin.
A1C, glycosylated hemoglobin; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis
Fujioka K, et al. Presented at EULAR, 2017:FRI0148.

36. Polyarticular Juvenile Idiopathic Arthritis
One poster presentation at EULAR addressed the efficacy of methotrexate in the treatment of pJIA.

37. Methotrexate in Non-systemic Juvenile Idiopathic Arthritis
The German BIKER registry was used to compare the efficacy of oral and SC MTX in MTX-naïve patients (410 oral, 384 SC)
Study results indicated no significant differences between treatments at 1 year
ACR50
ACR90
JADAS-ACC
JADAS-MDA
JADAS-REM
100 80 60 40 20
Oral MTX
SC MTX
Results from the German BIKER registry were used to compare the efficacy of oral and SC methotrexate in 794 methotrexate-naïve patients with polyarticular juvenile idiopathic arthritis. Study results indicated no significant differences in efficacy between the two approaches to drug delivery after 1 year of treatment.
ACC, acceptable disease activity; ACR, American College of Rheumatology; JADAS, Juvenile Arthritis Disease Activity Score; MDA, minimal disease activity; REM, remission
Bakry R, Horneff G. Presented at EULAR, 2017:THU0529.