What are my choices when methotrexate fails?


In rheumatoid arthritis there is an ongoing debate about what to do when methotrexate fails. Physicians typically have two choices.

In rheumatoid arthritis there is an ongoing debate about treatment options when methotrexate fails. Physicians typically have two choices:  triple therapy with methotrexate, hydroxychloroquine and sulfasalazine as one treatment, or adding or switching to the tumor necrosis factor inhibitors - biologics such as adalimumab, etanercept or infliximab. Research has shown that the effectiveness of triple therapy and biologics is roughly the same, but triple therapy can cost about $200 a month, while biologics can cost about $2 to $3,000 a month.


  • When methotrexate alone fails to control rheumatoid arthritis, triple therapy with the conventional drugs methotrexate, hydroxychloroquine and sulfasalazine is a reasonable approach.
  • Another reasonable approach is to replace methotrexate or add to it with biological drugs such as adalimumab, etanercept or infliximab.
  • Well-designed, randomized, controlled trials have found the two approaches to be equivalent. 
  • Some rheumatologists say that, in their experience, the biological drugs work better than triple therapy, despite the trials. 



Annals of Internal Medicine



study published in the March 13 issue of


 shows that outcomes improved more rapidly for patients treated with biologics as compared to patients prescribed disease modifying drugs.  The study, led by David L. Scott of King's College London School of Medicine in England, reported as follows:  432 patients were enrolled at baseline with 101 patients prescribed TNF inhibitors and 104 prescribed combined drug therapy. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity and 42 discontinued the intervention. Disability and quality of life were better with DMARDs than with TNF inhibitors. [[{"type":"media","view_mode":"media_crop","fid":"40707","attributes":{"alt":"","class":"media-image media-image-left","id":"media_crop_7727116574533","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4209","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.0080003738403px; line-height: 1.538em; float: left;","title":" ","typeof":"foaf:Image"}}]]In a review published in the August 18 issue of the

Annals of Internal Medicine

, B.D. McLeod, MD, of the UBC Southern Medical Program in British Columbia, states that the results “add perspective to the ongoing debate regarding optimal choices in the management of RA.” However, he highlights some weaknesses in the findings. “The National Institutes for Health and Care Excellence and the European League Against Rheumatism recommend starting biological therapy after failure of methotrexate plus 1 other DMARD. The RCT by Scott and colleagues compared this strategy with administration of DMARD combinations of patients with established RA,” he wrote.   “The study report did not indicate whether other outcomes had similar temporal responses. The TNF inhibitor group had more remissions overall and more early remissions than the DMARD group, but the final analysis did not show that this resulted in better outcomes. It is unclear what proportion of patients in the biologics group received concurrent methotrexate. EULAR recommends concurrent use of methotrexate with TNF inhibitors; lower use of methotrexate in the TNF inhibitor group could have biased the study against the anti-TNF agents,” McLeod wrote. 

The non-inferiority controversy

As previously reported in

Rheumatology Network

, the

equivalence of triple therapy and biologics is controversial among rheumatologists

. A review published in The Medical Letter in December 2014 also found that the two therapies were equivalent. But off the record, two of The Medical Letter’s consultants disagreed. The Medical Letter’s conclusions depended on a

randomized trial by the Veterans Affairs researchers

published in the

New England Journal of Medicine

which compared triple therapy to methotrexate plus etanercept. But the consultants said that in their experience, that was “not so,” etanercept was superior.  Around that time, the Annals of Internal Medicine published another editorial arguing that the two approaches were equivalent. They based their conclusions on the Swedish SWEFOT study, which was

previously reported in Rheumatology Network


Related coverage on Rheumatology Network



B.D. McLeod, ACP Journal Club:

Combination intensive DMARD therapy is noninferior to TNF inhibitors for reducing disability in active RA.Annals of Internal Medicine.

2015;163(4):JC9. August 18, 2015. DOI:10.7326/ACPJC-2015-163-4-009  Scott DL, Ibrahim F, Farewell F, et al.

Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ

2015; 350. March 13, 2015. DOI: 10.1136/bmj.h1046 

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