Methotrexate Use in RA Suboptimal Prior to Biologic Therapy

Physicians treating patients with rheumatoid arthritis (RA) are failing to optimize the use of methotrexate (MTX) prior to initiating biologic therapies, according to a recent analysis of prescribing practices in the US.1 The study, published ahead of print November 18 in Arthritis Care & Research, found that MTX is frequently underdosed, prescribed for an insufficient duration, and rarely used subcutaneously, a route which facilitates higher bioavailability than oral administration.2

MTX is considered to be the “anchor drug” in RA by several clinical guidelines.3,4 “Rheumatologists in the US have been convinced that essentially all [patients with RA] should be on biologics,” said study co-author James O’Dell, MD, chief of the Section of Rheumatology at the University of Nebraska Medical Center (UNMC) in Omaha1 in an email interview with Rheumatology Advisor.

The study by Dr O’Dell and colleagues used a database comprising medical, hospital, and prescription healthcare claims from 274 million patients, representing more than 85% of the US population. The investigators analyzed records from 2 cohorts:  patients diagnosed with RA in 2008 or 2009 with an RA claim submitted every year from 2009 to 2014, and patients newly diagnosed with RA in 2012 with an RA claim submitted every year from 2012 to 2014.

Patients in both cohorts were required to be MTX-naïve, as defined by a 1-year look-back period. The researchers also recorded the first drug prescription for all patients with a new diagnosis of RA in 2009.

Results showed that in the 2009 cohort the most common first-line therapies employed were oral (PO)MTX  (68% of patients), a biologic drug (25% of patients), and subcutaneous (SC) MTX (7%). Less than half of the patients started on PO MTX (44%) and remained on the medication for the full 5-year follow-up.

Eighty-seven percent of patients who changed therapy during the study period either switched to a biologic, or had a biologic added to their regimen, while 13% were switched to SC MTX. The mean dose of PO MTX prior to the start of biologic therapy was 15.3 mg/week (± 5 mg).

Patients newly diagnosed with RA in 2012 who were switched to biologic therapy had a mean dose of PO MTX of 15.9 mg/week (European League Against Rheumatism [EULAR] guidelines recommend that MTX should be used in doses of 25-30 mg/week4).

Additionally, patients in the 2012 cohort were more likely to receive SC MTX after failure of PO MTX (16% in 2012 versus 13% in 2009, P <.0001).

Summary and Clinical Applicability

“Given the cost of biologic therapy and required route of administration of either intravenous or subcutaneous, change from PO to SC MTX prior to initiating a biologic seems to be the most appropriate and logical next step for patients in whom PO MTX is not completely effective,” concluded the research team. “Efforts should be made to change MTX prescription practices to improve utilization of our anchor RA treatment, MTX.”



  • The retrospective study design did not allow the researchers insight into the reasons why therapies were changed in some patients, which also includes an understanding of the disease activity at the time of change.
  • There is an incomplete understanding of how MTX should be optimally dosed and administered at the individual patient level.
  • There were several prescribing biases: the researchers noted that study physicians were more likely to change to SC MTX rather than biologic treatments in patients with heart failure, malignancy, or a history of malignancy.


Funding for data extraction from the Symphony Health Solutions Integrated Dataverse was provided by Medac. Drs O’Dell and Cohen have received personal fees from Medac for their work as consultants and advisory board members. Dr Thorne received personal fees from Medac for his work as a consultant, speaker, and advisory board member.

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  1. Rohr MK, Mikuls TR, Cohen SB, Thorne CJ, O’Dell JR. The Underuse of methotrexate in the treatment of RA: a national analysis of prescribing practices in the U.S. Arthrit Care Res. November 2016. doi:10.1002/acr.23152 [Epub ahead of print]
  2. Bianchi G, Caporali R, Todoerti M, Mattana P. Methotrexate and rheumatoid arthritis: current evidence regarding subcutaneous versus oral routes of administration. Adv Ther. 2016;33(3):369-378. doi:10.1007/s12325-016-0295-8
  3. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis: ACR RA treatment recommendations. Arthrit Care Res. 2016;68(1):1-25. doi:10.1002/acr.22783
  4. Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492-509. doi:10.1136/annrheumdis-2013-204573