Monday, 18 Feb 2019

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RA Guidelines Shouldn't Ignore the Power of Methotrexate Combo Therapy

The updated ACR guidelines for the treatment of RA were recently published. They include newer drugs, and treatment philosophies such as treating to a target and reducing medications have been incorporated. I will applaud the group for all their work.

However, when are we going to actually follow the data that is proven in every single trial?  Iinitial therapy with combination methotrexate (MTX) is always far superior to methotrexate monotherapy.

In every randomized clinical trial (RCT) in early, active, poor prognosis RA, MTX monotherapy is a failure 70% of the time, whereas MTX in combination with another conventional (or biologic) DMARD(s) is sufficient 70% of the time.

Over and over, triple therapy has been found to be superior to methotrexate monotherapy and some other traditional DMARD combinations at onset have not be studied as well. The first O’Dell triple DMARD trial from years ago, and the more recent TEAR and RACAT trials, have all shown triple therapy is superior to methotrexate monotherapy. Also any combination of MTX with biologics is better than MTX alone in those not exposed to methotrexate (such as TNFi’s, and some other advanced therapeutics).

So when I study the new treatment guidelines for early RA, those in low disease activity should be considered to be treated with DMARD monotherapy and surprisingly those with moderate or high disease activity are also recommended to have DMARD monotherapy.  Why such recommendations despite all the data that always show MTX in combination is superior to MTX monotherapy in ERA with the odds of improvement (i.e. getting an ACR target response) are approximately 2 to 1 (combination vs. monotherapy)?

The only consideration of combination therapy is short-term corticosteroids for flare. Only after treatment failure with MTX monotherapy is there a suggestion of use of MTX combinations with traditional DMARD(s) or a biologic with or without methotrexate.

Where is the rationale that empowers such weak evidence while avoiding the strong? I am sure that some day treatment guidelines will reflect consistent RCT data and improve good clinical practice.

The author has no conflicts of interest to disclose related to this subject

Dr. Janet Pope is a Professor of Medicine in the Division of Rheumatology at the University of Western Ontario (UWO), Schulich School of Medicine, London, Ontario, Canada.  She is the Division Head in Rheumatology at St. Joseph's Health Centre, London. Her research includes studies in scleroderma, SLE and RA, including outcome measurements, clinical trials and disease manifestations. She has published over 450 peer-reviewed articles, 15 chapters, 500 abstracts and several Cochrane meta-analysis reviews. Mentoring of research students and trainees numbers more than 125. She has received the Distinguished Investigator Award from the Canadian Rheumatology Association, Rheumatologist of the Year from the Ontario Rheumatology Association, Department of Medicine Research Achievement Award, and the Dean’s Award of Excellence in Research. She has been inducted into the Canadian Academy of Health Sciences.


Rheumatologists' Comments

In patients for whom pill burden limits compliance with oral triple therapy, I've had good experience with the addition of leflunomide to methotrexate in the case of inadequate response to methotrexate monotherapy. See, e.g.:
Agreed. In Ontario, until recently we HAD to use leflunomide prior to access to biologics and had to use high dose Mtx and had to use at least one combination so many Ontario rheumatologists used triple and then Mtx + Leflunomide or even sometimes triple + leflunomide. Sometimes it was a home run, sometimes diarrhea or other side effects (oral ulcers, cytopenias, transaminitis). However, there is a lot of experience out there with it and we can't forget about it but have to observe carefully for side effects that may occur in the lab monitoring (as the symptoms patients may get from it are obvious, but the labs can be affected). Thanks, Janet
Good Critique. In a recent talk I developed on RA therapy to describe the ACR criteria I borrowed from Antoni Scalia the term "applesauce". By the way the ACR guidelines in Table 1 say one of the criteria for remission is the Simplified DAS of < 3.3. New Criteria? At least they got in right in table 2.
Wonder if the <3.3 was for CDAI, SDAI?