1. A NEW LOOK AT RA Interactive Hot Topics Series
Managing GI Adverse Events Due To Oral MTX: What Are the Options?
I’m going to spend the next 15 minutes discussing gastrointestinal (GI) adverse events that occur in patients receiving MTX, what we know about why they occur, and approaches to decreasing their occurrence.
MP-RA-0283

2. How Frequent Are Gastrointestinal (GI) Adverse Events (AEs) in RA Patients Taking Oral Methotrexate (MTX)?
The first questions to address are: How common are GI adverse events in patients receiving oral MTX; and what is their impact on adherence to therapy?

3. GI Toxicity of Oral Methotrexate: Clinical Trial Results
24-month ULTRA trial, of patients with rheumatoid arthritis (RA) years of age with active disease for ≥6 months
Treatment:
Leflunomide (LEF; mean dose 19.7 mg/day during year 1 and 19.6 mg/day in year 2)
Oral MTX (mean dose 11.7 mg/day during year 1 and 12.6 mg/day in year 2)
Placebo
First 12 Months
24 Months
LEF (n=190)
PL (n=128)
Oral MTX (n=190)
All serious AEs
16.3
8.6
7.4
18.9
9.4
Treatment-related AEs
1.1
1.6
2.6
3.7
AEs leading to withdrawal
3.2
4.2
6.3
Treatment-related AEs leading to withdrawal
0.5
0.8
Specific AEs
Diarrhea
32.6
18.8
19.5
36.8
20.3
21.6
URI
28.9
21.1
31.6
37.4
25.0
38.4
Headache
18.4
16.4
20.5
20.0
17.2
23.2
Nausea
18.0
17.9
Dyspepsia
14.8
13.2
14.2
Rash
8.9
17.4
11.1
Hypertension
11.6
4.7
New onset
2.1
0.0
Alopecia
10.0
5.8
10.5
Abdominal pain
3.1
7.9
3.9
Dizziness
7.0
UTI
6.8
7.8
8.4
Vomiting
Mouth ulcer
5.5
9.5
Pruritis
Information about GI events in patients taking oral MTX can be obtained from three sources: clinical trials, surveys of patient records, and you own experience. The next few slides summarize information about the tolerability of oral MTX from the first two of these sources.
This slide shows safety results from the ULTRA trial, a comparison of leflunomide and oral MTX in RA patients carried out 15 years ago. The results show that diarrhea, nausea, and dyspepsia occurred in 15 to 20 percent of patients taking relatively low doses of oral MTX (12-13 mg/week) and that they did not appear to decline in frequency over 2 years of follow-up.
*Values are the percentage of patients. URI, upper respiratory tract infection; UTI, urinary tract infection.
Cohen S, et al. Arthritis & Rheumatism. 2001;44:

4. GI Toxicity of Oral Methotrexate: Clinical Trial Results
958 RA patients randomized to receive 5 mg or 10 mg of tofacitinib twice daily or oral MTX at a dose that was incrementally increased to 20 mg/week (mean dose = 18.5 mg/week)
Preferred Term
Patients with Adverse Event, n (%)
Tofacitinib 5 mg Twice Daily (N=373)
Tofacitinib 10 mg Twice Daily (N=397)
Oral Methotrexate (N=186)
Adverse events
1097
1435
561
Abdominal pain
8 (2.1)†
16 (4.0)†
2 (1.1)
Abdominal pain upper
12 (3.2)
13 (3.3)
5 (2.7)
Constipation
7 (1.9)
10 (2.5)
7 (3.8)‡
Diarrhea
15 (4.0)
24 (6.0)
15 (8.1)‡
Dyspepsia
13 (3.5)
18 (4.5)
9 (4.8)‡
Gastritis
13 (3.5)†
9 (2.3)
4 (2.2)
Gastroesophageal reflux disease
6 (1.6)
6 (1.5)
Nausea
27 (7.2)
30 (7.6)
40 (21.5)‡
Vomiting
11 (2.9)
11 (5.9)‡
This slide shows safety data from a more recent study that compared oral MTX, dosed up to 20 mg/week, and tofacitinib in the ORAL Start study.
Safety data recorded over 6 months of follow-up indicated that 8.1% of patients who received oral MTX had diarrhea, 21.5% had nausea, and 5.9% had vomiting. In addition, 4.8% of patients treated with oral MTX had dyspepsia and 3.8% had constipation.
†Event occurred more frequently in patients receiving tofacitinib 5 or 10 mg twice daily compared with MTX. ‡event occurred more frequently in patients receiving methotrexate compared with tofacitinib 5 or 10 mg twice daily.
Lee EB, et al. N Engl J Med. 2014;370: (suppl).

5. GI AEs with Oral Methotrexate: Survey Results
Adverse event
Nausea
Headache
Mouth ulcers
Light-headedness
Diarrhea
Stomach pains
Skin rashes
Heart palpitations
Vomiting
Others
No effects
No answer 10 20 30 40 50
% of patients
AEs reported by patients with RA taking oral MTX (n=1,034)
Occurrence of AEs was not correlated with oral MTX dose
Event experienced ever
Event experienced regularly
Of the patients who experience the event regularly, event experienced continuously
Results from patient surveys also indicate high frequencies of GI adverse events in patients with RA taking oral MTX. The slide shows results from a survey that included 1,313 patients with RA of whom 1,034 were taking oral MTX. Of these patients, 28% experienced nausea at least once and 15% had this adverse event regularly. The respective values for diarrhea were 20% and 9%.
Nash P, Nicholls D. Int J Rheumatic Dis. 2013; 16:

6. Percentage of all oral MTX users
GI-related AEs Common Reason for Safety-related Oral MTX Discontinuation
Drug adverse reaction
Frequency (93 patients)
Percentage of all oral MTX users
Hepatic 18
2.2
Liver biopsy 4
Gastrointestinal 37
4.7
Nausea 26
Mouth ulcers 7
Abdominal pain 1
Diarrhea 2
Pancreatitis
Central nervous system
3.3
Headache 9
Short-term memory loss 3
Fatigue 6
Drowsiness
Dizziness
Irritability
Pulmonary 10
1.1
Cough
Pneumonitis
Dyspnea
Bronchiolitis obliterans
Fibrosis
Bronchiectasis
Hematology
0.2
Neutropenia
Thrombocytopenia
Other
2.3
Rash/pruritus
Hair loss
Hot flushes
Increased arthralgia
Chest pain
Mastalgia
Recurrent infections
Weight loss
Retrospective, case review of patients seen in a private rheumatology practice attached to a major teaching hospital was undertaken over an 18-year period
Records for 790 patients were reviewed and toxicity- related discontinuation occurred in 93 patients (11.8%)
A retrospective, case review of patients seen in a private rheumatology practice attached to a major teaching hospital in Sydney, Australia showed that GI adverse events were the most frequent reason for discontinuation of oral MTX due to intolerability. This study included 790 patients (518 with RA) treated over an 18-year period. Of these, 93 (11.8%) stopped oral MTX due to adverse events and 4.7% discontinued due to GI events.
Varatharajan N, et al. Internal Medicine Journal. 2009;39:

7. Over 25% of Oral MTX Intolerance Is Due to GI Events
Reasons for oral MTX withdrawal in patients with RA
Retrospective electronic database review was undertaken to identify all patients who had received oral MTX for RA or psoriatic arthritis (PsA)
Patients who had discontinued oral MTX were then identified, and the reasons for this were categorized
A total of 1,257 patients who had received oral MTX were included [762 (61%) RA and 193 (15%) PsA]
Oral MTX had been stopped in 260 (34%) patients with RA and 71 (36%) patients with PsA, most commonly due to GI intolerability
An audit of the electronic database at Addenbrooke’s Hospital in Cambridge, UK, identified 1,257 patients with RA or psoriatic arthritis who discontinued treatment with oral MTX. The most common reason for stopping treatment was GI adverse events, which accounted for 28.6% of all discontinuations.
Nikiphorou E, et al. Clin Rheumatol. 2014;33: © Clinical Rheumatology 2014.

8. Mechanisms Underlying GI Toxicity of Methotrexate
Surprisingly little research has been directed toward elucidating the mechanisms underlying GI adverse events in RA patients being treated with MTX. However, as you surely know MTX is also employed in oncology and potential mechanisms underlying often serious GI adverse events observed in cancer patients taking MTX have been studied extensively.

9. GI Toxicity of MTX: Inhibition of Dihydrofolate Reductase Synthesis
MTX-associated GI toxicity is not considered to be a result of direct action on gastrointestinal tract tissues, but rather to inhibition in dihydrofolate reductase synthesis:
This enzyme is required to maintain the intracellular pool of tetrahydrofolate during purine and thymidine synthesis
This adversely affects all rapidly dividing cells, including those in the GI mucosa
MTX-associated GI toxicity is not considered to be a result of direct action on gastrointestinal tract tissues, but rather to inhibition in dihydrofolate reductase synthesis. Dihydrofolate reductase is required to maintain the intracellular pool of tetrahydrofolate during purine and thymidine synthesis. When it is inhibited, this adversely affects all rapidly dividing cells, including those in the GI mucosa.
Horie T, et al. J Nutr. 2006;136 (3 Suppl):861S-863S.

10. Methotrexate Increases Oxidative Stress
MTX increases levels of reactive oxygen species (ROS) and this may be involved in the beneficial effects of the drug.1
MTX is toxic to cultured intestinal epithelial cells (IECs) and this toxicity is correlated with production of ROS2,3
Administration of an anti-oxidant, α-lipoic acid, decreases MTX-induced intestinal damage in a rabbit model:3
Antioxidant enzyme activities, lipid peroxidation level, and intestinal tissue injury in the intestine of rabbits
Control
Methotrexate
Methotrexate + Alpha-lipoic Acid
Glutathione peroxidase (U/mg wet weight of tissue)
1.69 ( )
0.80 ( )
1.30 ( )
Superoxide dismutase (U/mg wet weight of tissue)
1.93 ( )
1.10 ( )
1.50 ( )
Malondialdehyde (U/mL)
0.95 ( )
3.70 ( )
2.20 ( )
Intestinal tissue injury index
1.0 ( )
10.0 ( )
7.0 ( )
Values are as median (range). The differences among all three groups were significant (P<0.05)
Another mechanism by which MTX may adversely effect the GI tract is elevation of oxidative stress. Results from in vitro studies have shown that exposure of intestinal epithelial cells to MTX increases levels of reactive oxygen species (ROS) and decreases those of antioxidants, such as glutathione peroxidase and superoxide disumutase. These effects are injurious to intestinal epithelial cells.
Reduction of oxidative stress with the anti-oxidant, α-lipoic acid decreases MTX-induced intestinal damage in a rabbit model.
Phillips DC, et al. Br J Pharmacol. 2003;138:
Chang CJ, et al. PLoS One. 2013;8:e72553.
Somi MH, et al. Indian J Gastroenterol. 2011;30:38-40.

11. Reducing GI Toxicity: Folate Administration
Treatment guidelines for patients with RA recommend folate supplementation in those receiving MTX and this has been shown to decrease GI adverse events and to reduce the risk for discontinuation of the drug.

12. Efficacy of Folate/Folinic Acid for Decreasing GI Toxicity of Oral Methotrexate: Studies Analyzed
409 records identified through database searching
326 records after duplicates removed
326 records screened
15 full-text articles assessed for eligibility
6 studies included in quantitative synthesis (meta-analysis)
12 additional records identified through other sources
The Cochrane group has assessed the potential benefits of folate supplementation in decreasing GI events in a meta-analysis that included double-blind, randomized, placebo-controlled clinical trials in which adult patients with RA were treated with oral MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation (a starting dose of ≤7 mg weekly). Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. Six trials with 624 patients were eligible for inclusion.
311 records excluded
9 full-text articles excluded, with reasons
Shea B, et al. Cochrane Database Syst Rev. 2013;5:CD

13. Risk Ratio M-H, Fixed, 95% CI
Efficacy of Folate/Folinic Acid for Decreasing GI Toxicity of Oral Methotrexate: Results
Study or subgroup
Treatment (n/N)
Control (n/N)
Risk Ratio M-H, Fixed, 95% CI
Weight
Buckley 1990
6/20
9/20
8.0%
0.67 (0.29, 1.52)
Morgan 1990
6/16
9/16
0.67 (0.31, 1.43)
Morgan 1994
2/25
7/28
5.9%
0.32 (0.07, 1.40)
Shiroky 1993
4/44
14/48
11.9%
0.31 (0.11, 0.88)
Van Ede 2001
95/274
55/137
65.3%
0.86 (0.67, 1.12)
Weinblatt 1993
1/8
0.9%
1.00 (0.07, 13.37)
Total (95% CI)
387
257
100.0%
0.74 (0.59, 0.92)
Total events: 114 (Treatment), 95 (Control)
Heterogeneity: Chi2 = 5.50, df = 5 (P = 0.36); I2 = 9%
Test for overall effect: Z = 2.64 (P = )
Test for subgroup differences: Not applicable
This slide shows the results of the Cochrane meta-analysis. Addition of folate or folinic acid to treatment in RA patients receiving oral MTX decreased the risk for GI adverse events by 26%. This decrease was significant with a P-value of
0.05
0.2 1 5 20
Shea B, et al. Cochrane Database Syst Rev. 2013;5:CD

14. Folate Treatment Decreases Oral MTX Discontinuation Due to AEs
48-week study of the effect of folates on discontinuation of oral MTX due to toxicity
Patients with active RA (n= 434) were randomly assigned to receive oral MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week)
The initial oral MTX dosage was mg/week; dosage increases were allowed up to a maximum of 25 mg/week
Folate dosages were doubled once the dosage of oral MTX reached 15 mg/week
The primary end point was oral MTX withdrawal because of AEs
Percentages of patients who did not permanently discontinue oral MTX
treatment during the study period, by supplement group
P<0.001 for folate or folinic acid vs placebo
350
300
250
200
150
100 50
Days After Start of Oral MTX Treatment 90 80 70 60
Percent
Folic Acid
Folinic Acid
Placebo
Results from one of the studies included in the Cochrane meta-analysis also determined whether administration of folate or folinic acid decreased the risk for treatment discontinuation in RA patients receiving oral MTX. In this 48-week study, 434 patients with with RA were randomly assigned to receive oral MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial oral MTX dosage was 7.5 mg/week; and increases up to a maximum of 25 mg/week were permitted. Folate dosages were doubled once the dose of oral MTX reached 15 mg/week. Treatment with either folate or folinic acid significantly decreased the risk for treatment discontinuation versus placebo with a P-value less that
van Ede AE, et al. Arthritis & Rheumatism. 2001;44:

15. Reducing GI Toxicity: Changing Route of MTX Administration
Changing the route of administration for MTX has also been shown to decrease the risk for GI adverse events in RA patients receiving this drug.

16. Safety of SC vs Oral MTX: Single-dose Crossover Study
Single-center, open-label, randomized, 2-period, 2-sequence, single-dose, crossover study
Enrolled healthy subjects aged years into 1 of 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg), where they received a single dose of SC MTX and of the oral MTX tablets
TEAEs
SC MTX Pen (n=59)
Oral MTX Tablet (n=57) # n %
Gastrointestinal disorders 9
15.3 19 16
28.1
Diarrhea 5
8.5 8 14
Nausea 3
5.1
5.3
Abdominal pain upper —
Results from healthy patients who received single doses of oral or subcutaneous (SC) methotrexate demonstrated much better GI tolerability with the latter route of administration. In this single-center, open-label, randomized, 2-period, 2-sequence, single-dose, crossover study, adult subjects were randomly assigned to 1 of the 2 treatment sequences within each dose group (7.5 mg, 15 mg, 22.5 mg, and 30 mg). Each subject participated in only 1 of the 4 dose groups and received a single dose of MTX administered either with an SC MTX pen (in the abdominal wall) or orally in tablet form. After a washout phase of at least 1 week, MTX was then administered in the same dose, by the alternative route.
As can be seen in the table, all GI events, diarrhea, and abdominal pain occurred about twice as often with oral versus SC drug delivery. There was no difference between routes of administration for nausea.
Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014;32:

17. Trial Design
6-month, multicenter, randomized, double-blind, controlled clinical trial evaluating the efficacy of SC administration of MTX compared with oral administration of MTX in the treatment of patients with active RA
MTX naive
MTX oral 15 mg (2 7.5-mg tablets + dummy syringe
MTX SC 15 mg (10-mg/ml prefilled syringe + dummy syringe
MTX SC 15 mg
MTX SC 20 mg R A N D O M I Z T
ACR20 nonresponder
Weeks 16 24
The largest direct comparison of oral and SC MTX carried out to date was a 6-month, multicenter, randomized, double-blind, controlled, 2-arm phase IV trial that included 375 adult, MTX-naïve RA patients who received 15 mg/week MTX, either orally or SC. After 16 weeks of treatment, patients who did not achieve at least a 20% improvement in the American College of Rheumatology Composite response criteria had their treatment changed. Those on oral MTX were switched to SC delivery of the same dose and those receiving SC MTX had their dose increased to 20 mg/week.
Braun J, et al. Arthritis & Rheumatism. 2008;58:73-81.

18. Safety of SC vs Oral MTX No. (%) of patients receiving SC MTX (n=193)
No. (%) of patients receiving Oral MTX (n=193)
Adverse events
Any adverse event
128 (66)
116 (62)
At least a moderate adverse event
79 (41)
77 (41)
Adverse event possibly related to study drug
102 (53)
90 (48)
Serious adverse event
11 (5.7)
8 (4.3)
Adverse event leading to withdrawal
18 (9.3)
At least moderate adverse events reported at a ≥3% incidence
Gastrointestinal
Abdominal pain
17 (8.8)
20 (10.6)
Diarrhea
5 (2.6)
13 (6.9)
Dyspepsia
13 (6.7)
11 (5.9)
Loss of appetite
14 (7.3)
6 (3.2)
Nausea
32 (16.6)
23 (12.2)
Stomatitis
6 (3.1)
7 (3.7)
Vomiting
7 (3.6)
Increased alanine aminotransferase
3 (1.6)
Bronchitis
4 (2.1)
Headache
Nasopharyngitis
9 (4.7)
10 (5.3)
Safety data collected over the entire 24-week treatment period indicated that abdominal pain and diarrhea occurred more frequently with oral MTX, but that nausea was more common with SC delivery.
Braun J, et al. Arthritis & Rheumatism. 2008;58:73-81.

19. GI Tolerability in Patients Switched from Oral to SC MTX
VAS Score (0-100)
P=0.053
Decreased risk for GI adverse events with SC vs oral MTX has been documented by results from a small-scale, retrospective postal survey completed by 37 patients who had changed from oral MTX to SC MTX. These patients rated the frequency and intensity of GI adverse events using a visual analogue scale. Results from this analysis indicated significant reductions in visual analog scale scores for three of four primary outcome measures for GI adverse events. Only frequency of vomiting was not significantly reduced.
SC, subcutaneous; VAS, visual analog scale
Adapted from Kromann CB, et al. J Dermatolog Treat. 2014;17:1-3.

20. Retrospective Analysis of Switching Patients from Oral to SC MTX
Retrospective analysis of 80 patients with RA who were switched from oral MTX (mean dose = 15.1 mg/week) to SC MTX (mean dose = 16.5 mg/week) due to GI side effects
After switching:
30 patients (37.5%) experienced GI side effects in the first month
27 patients (33.7%) experienced GI side effects during the second month
No patients discontinued SC MTX due to intolerability over 3 months of follow-up
A retrospective analysis of 80 patients with RA who were switched from oral MTX (mean dose = 15.1 mg/week) to SC MTX (mean dose = 16.5 mg/week) due to GI side effects indicated that most patients were able to tolerate the drug with parenteral administration. After switching, 30 patients (37.5%) experienced GI side effects in the first month; 27 patients (33.7%) experienced GI side effects during the second month; and no patients discontinued SC MTX due to intolerability over 3 months of follow-up.
Borman P, et al. Open Rheumatology J. 2014;8:18-19.

21. Intramuscular MTX Also Has Better Tolerability than Oral Drug
143 patients were switched from intramuscular (IM) to oral MTX
A multiple choice questionnaire was sent by mail to evaluate clinical and biological criteria of efficacy and tolerance
Effects of a switch from IM to oral MTX in 143 patients
Percent of Patients with Changes in GI Events
Another retrospective study compared the clinical efficacy and safety of MTX in 143 RA patients who were switched from intramuscular to oral administration because of a shortage of the intramuscular preparation. Results from questionnaires sent to these patients indicated that 48% of patients experienced an increase in GI adverse events after switching from intramuscular to oral delivery of MTX.
Adapted from Wegrzyn J, et al. Ann Rheum Dis. 2004;63:

22. Why Is GI Toxicity of MTX Decreased with Parenteral Administration?
While there is evidence that GI tolerability is improved by SC administration of MTX, the reason for this is not clear.

23. Some Facts and Considerations
Rapidly proliferating cells have a very high demand for folic acid and are greatly affected by folic acid deficiency1
A primary sign of folic acid deficiency is intestinal mucosa deterioration1
Uptake of folic acid by intestinal cells is mediated by the human protein- coupled folate transporter (hPCFT/SLC46A1)1
MTX is also taken up by hPCFT2,3
Uptake of both folic acid and MTX by hPCFT is concentration dependent and folic acid uptake by this transporter is competitively reduced by MTX1-3
Oral delivery of MTX may result in higher intestinal drug concentrations vs parenteral administration leading to:
Greater inhibition of hPCFT
Greater folate deficiency
Increased risk for GI AEs
While the reason for decreased GI adverse events with parenteral delivery of MTX is by no means clear, available information does permit some reasonable speculation. Rapidly proliferating cells have a very high demand for folic acid and are greatly affected by folic acid deficiency. A primary sign of folic acid deficiency is intestinal mucosa deterioration and this may result in clinical adverse events.
Uptake of folic acid by intestinal cells is mediated by the human protein-coupled folate transporter (hPCFT) and MTX is also taken up by this transporter. Uptake of both folic acid and MTX by hPCFT is concentration dependent and folic acid uptake by this transporter is competitively reduced by MTX. Thus, oral delivery of MTX may result in higher intestinal drug concentrations vs parenteral administration leading to greater inhibition of hPCFT, more pronounced folate deficiency, and increased risk for GI adverse events.
Urquhart BL, et al. Am J Physiol Gastrointest Liver Physiol. 2010;298:G
Inoue K, et al. Am J Physiol Gastrointest Liver Physiol. 2008;294:G
Yokooji T, et al. J Pharm Pharmacol. 2009;61:

24. Summary

25. Summary
GI AEs occur often in patients receiving oral MTX and are the most common reason for intolerance-associated discontinuation of the drug in patients with RA
These events may be mediated, at least in part, by adverse effects of oral MTX on the metabolism of intestinal epithelial cells
Administration of folate significantly decreases the risk for GI AEs in patients with RA receiving oral MTX
SC or IM administration of MTX also decreases the risk for GI events
The decreased risk for for GI AEs with parenteral MTX may be due, at least in part, to lower levels of drug in the intestine and reduced competition with folate for hPCFT
In summary, GI adverse events occur often in patients receiving oral MTX and are the most common reason for intolerance-associated discontinuation of the drug in patients with RA. These events may be mediated, at least in part, by adverse effects of oral MTX on the metabolism of intestinal epithelial cells. Administration of folate significantly decreases the risk for GI adverse events in patients with RA receiving oral MTX, and SC or intramuscular administration of MTX also decreases the risk for GI events. The decreased risk for for gastrointestinal AEs with parenteral MTX may be due, at least in part, to lower levels of drug in the intestine and reduced competition with folate for hPCFT. Thanks very much for your attention.