Differences in Oral, Subq MTX Bioavailability Linked to RA Outcomes

Methotrexate parenterally administered was associated with less treatment failure and lower disease activity scores in patients with early rheumatoid arthritis (ERA) as compared to oral dosing.

The clinical relevance of differences in bioavailability between orally and subcutaneously administered methotrexate (MTX) for the treatment of early rheumatoid arthritis (RA) was examined by researchers in an observational study and recently reported in the Annals of the Rheumatic Diseases.1 Pharmacokinetic studies have suggested that MTX bioavailability differs widely according to route of administration, with improved MTX absorption after parenteral administration especially at doses >15 mg/week.2 The effects of these differences in bioavailability on specific measures of RA disease activity had not been previously examined.

Glen Hazlewood, MD, from the University of Toronto, Ontario, Canada and colleagues sought to compare the effectiveness of initial MTX treatment administered either orally or subcutaneously for the treatment of early RA (ERA).  They also evaluated whether route of administration influenced the need to change treatment course over the year. 

Data was collected from the Canadian Early Arthritis Cohort,  an ongoing prospective observational study of patients with ERA in Canada between January 2007 and January 2014. All patients had ERA diagnosed according to 2010 American College of Rheumatology/European League Against Rheumatism criteria, with symptom duration of ≤1 year, and no or minimal prior exposure to MTX. 

Initial treatment dose and route was left to the treating rheumatologists’ discretion. Treatment effectiveness, quantified by disease activity score (DAS)-28-erythrocyte sedimentation rate (ESR), DAS-28 remission (DAS-28 <2.6), DAS-28 sustained remission (DAS-28 <2.6 on two consecutive visits), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) was determined after the first year of treatment.

High Yield Data Summary

  • Parenterally administered MTX was associated with less treatment failure and DAS-28 scores in patients with early ERA as compared to oral dosing

Treatment failure was defined as the need for treatment escalation with another disease-modifying antirheumatic drug (DMARD) or necessity for changing dose or route of MTX administration secondary to side effects of inefficacy after the first three months of therapy. 

A total of 666 patients were included in the data analysis, 417 were prescribed oral MTX and 249 were prescribed subcutaneous MTX. After 1 year of treatment, 49% of those patients receiving MTX subcutaneously switched treatments as compared to 77% of those patients receiving MTX orally.   

After adjusting analysis for potential confounders, researchers found the subcutaneously administered MTX was associated with lower rates of treatment failure (hazard ratio [HR] 95% confidence interval [CI]: 0.55 [0.39 to 0.79]). 

The majority of treatment failures were classified as due to medication inefficacy, with no difference between groups in toxicity measures alone. Moreover, MTX administered subcutaneously was associated with decreased average DAS-28 scores (mean difference −0.38 [95% CI: −0.64 to −0.10]).

No significant differences were found in sustained remission scores or HAQ-DI (P=.43, P=0.75 respectively).

It is important to note that the majority of cohort patients received MTX at doses ≥15 mg/week.  “In this range, the bioavailability of oral MTX plateaus, whereas the bioavailability of subcutaneous MTX continues to increase… our findings may relate to the expected difference in bioavailable MTX with subcutaneous administration compared with oral administration at higher MTX doses,” the authors noted.

Summary and Clinical Applicability

In patients with ERA, initial treatment with subcutaneous MTX was associated with decreased treatment regimen changes and improvements in some measures of RA disease activity as compared to oral MTX during the first year of treatment. There was no statistically significant changes in toxicity between the two routes of MTX administration.

Limitations and Disclosures

The observational nature of the study has several limitations, including inability to account for additional potential confounders such as corticosteroid treatment and medication adherence. 

“While our findings suggest subcutaneous MTX is more effective than oral MTX as initial therapy, it is not possible to establish definitive causation given the observational nature of the study,” the authors cautioned.

The Canadian Early Arthritis Cohort Study analyzed was funded by Amgen, Pfizer Canada, Hoffmann-La Roche, UCB Canada, Bristol-Myers Squibb Canada, AbbVie Corporation, and Janssen Biotech.


1.  Hazlewood GS, Thorne JC, Pope JE, et al. The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis. 2016;75(6):1003-8.

2.  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(8):1549-51.

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