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Switching RA Medicines – Don’t Wait Too Long or Try Too Many

I’ve been on seven – count them – seven different biologic medicines since being diagnosed with rheumatoid arthritis. I started with several anti-TNF biologics and then moved to several others even bouncing back to try another anti-TNF before eventually trying Rituxan. I’ve self-injected with auto-inject pens, self-injected with needles, and seems like I’ve had every type of infusion possible. This is probably something of a record although similar stories emerge on discussion boards from time to time. With some of the biologics, I would respond for a period of time and then it would stop working. With others, there was never a response. With yet others, there would be some adverse side-effect causing cessation. This is not all to unusual as it is widely know in the rheumatology community that upwards of 30% of RA patients do not positively respond to anti-TNF biologic medicines.1 It is important to know that there is no perfect RA treatment and every patient responds differently to medicines probably due to genetics.

A therapeutic strategy for switching RA treatments?

Switching medicines when one doesn’t work is an important therapeutic strategy that rheumatologist and patients can use in an attempt to keep the disease at bay. In an earlier post, I discussed strategies for knowing when it may be time to switch RA treatments. In 2012, the American College of Rheumatology (ACR) published guidelines developed by an expert panel for using disease modifying (DMARD) and biologic medicines for RA.[2] These guidelines represent a revision of ones published in 2008. Revisions after only four years reflect the rapidly changing landscape of treatment options and research on treatment effectiveness. The guidelines are constructed around disease activity, disease duration, and prognosis.

What does the RA treatment algorithm recommend?

The guidelines recommend starting with one DMARD upon diagnosis. If after three months of monotherapy with a DMARD, the patient is still showing disease activity, then it is recommended to move to multiple DMARDs. One option mentioned in the ACR guidelines is to try multiple DMARD therapy without biologics. This is sometimes called “triple therapy” and includes methotrexate, hydroxychloroquine (Plaquenil), and sulfasalazine. Researchers demonstrated that this triple therapy approach has been shown to be as effective as biologic treatments[3] and is certainly much cheaper. If after three months the patient still does not show improvement on multiple DMARD therapy, then the addition of a biologic is recommended starting with an anti-TNF such as Enbrel, Humira, Cimzia, Remicade, or Simponi. If after three months on the first anti-TNF biologic the patient still does not show improvement, then it is recommended to switch to another anti-TNF or a non anti-TNF. These non anti-TNFs include Orencia, Actemra, and Rituxan. If after six months there is not a positive response, then the patient can try another non anti-TNF biologic. Xeljanz has recently been approved as another treatment option. The protocol is fairly straightforward except for other factors to consider including side effects and life threatening events.

One of the important factors to be considered is to only wait three months before making an assessment about the effectiveness of each treatment. This is a fairly tight timeline and I wonder how closely this recommendation is followed. Part of this could be related to the difficultly in determining treatment effectiveness as blood tests are not always perfect predictors and patient opinions can be subjective. In my own personal experience, there were times when we would go 6 to 12 months before making a change in medications. Part of this was due to my own stubbornness and lack of willingness to admit that medicines were not working. There were times when my rheumatologist would look me in the eye and insist that it was time to make a change. There were other times when we just couldn’t be sure. The medicine might have been doing some good but probably not enough.

Another issue that researchers have found is that patients who try many anti-TNF biologics have less of a response to additional anti-TNFs and non anti-TNFs. A review of research on switching anti-TNF biologics demonstrated that patients showed a dramatic decline in response from two to three anti-TNFs. The message is that patients are more likely to fail in responding to the use of more anti-TNF biologics.[4]In a study just published in the Journal of Rheumatology, researchers found that patients who had failed a fewer number of biologic medicines did better on Rituxan (Rituxamab) than patients who had been through multiple biologics.[5] Rituxan is considered a second-line biologic to be used for patients who don’t respond to anti-TNF biologics (e.g. Enbrel, Humira, Remicade). Such results make a case for moving right into second-line treatments like Rituxan if a couple of anti-TNFs don’t work.

Trying different RA treatments based on their mechanism of action


Based on the ACR guidelines and research on the use of multiple RA treatments, the rule of thumb appears to be to try DMARDs first, multiple DMARDs next, then one or two anti-TNFs, and finally non anti-TNFs. Cycling through more than two anti-TNFs seems to be counter productive and moving onto new treatments quickly is the best approach. In other words, don’t wait too long or try too many different treatments. The longer one waits, the more the chance of permanent damage from disease activity.

Please remember that treatment decisions should be made between a patient and doctor. Don’t stop taking any medication without talking to your doctor.

This article represents the opinions, thoughts, and experiences of the author; none of this content has been paid for by any advertiser. The team does not recommend or endorse any products or treatments discussed herein. Learn more about how we maintain editorial integrity here.



  • aslan1178
    6 months ago

    I have been on Plaquenil for a year now. Stiffness and pain began gradually in late October and after Christmas it had nearly returned completely so I went back to the doctor. I just completed a 10 day regiment of Prednisone which helped tremendously but as I tapered my dosage down and completed it, the stiffness and aching has come back. My doctor now wants me to switch to Methotrexate and stop Plaquenil. So frustrating.

  • Moonbeam
    5 years ago

    Doesn’t it take 3 months for DMARD results to show up based on the cycle of white blood cell production?

  • Andrew Lumpe, PhD moderator author
    4 years ago

    I don’t know if it’s connected to the cycle of blood cell production but it can take several months to feel the impact of most DMARDS.

  • rmancini
    5 years ago

    I have failed many biologics, But with all of them it has taken 4 to 6 months to even see if they are going to work at all. If I gave up at 3 months I wouldn’t have received the sometimes temporary relief I did receive. Now on month 4 of Actemra waiting to see if it will work.

  • Andrew Lumpe, PhD moderator author
    5 years ago

    That’s an excellent point. Maybe the guidelines should be changed. It took over 4 months to tell if Rituxan was working. I hope Actemra works wonders for you!

  • jaide winn
    5 years ago

    This is a really good article. I am on Plaquenil and Methotrexate. We tried Enbrel for a year, then had to switch to Remicade. Still not working well, we have increased the dosage twice. I am on Prednisone 5mg just as a temporary measure until I go back next week. It is time to move on, but I couldn’t decide between Rituxin, Acterma, or Orencia. Your article has help show me that we need to move on to Rituxin. When moving on to higher level of medications, do you need to stay on Plaquenil and Methotrexate? The Prednisone really helps, I wish I could stay on it, but I know the bad long-term side effects. Thank you for the help.

  • jaide winn
    5 years ago

    So are you saying that Acterma or Orencia would be a better choice to start out with, and leave Rituxin to a last resort? Do you have to come off Plaquenil and MTX with any or all of these meds? I think my Plaquenil helps, not sure my MTX does much. I know there are some serious risk with Rituxin. Do you have any comparative info for these 3 meds (Rituxin, Acterma, Orencia) that would be helpful for those of us that are needing to change to one of them. Thank you so much for you help and information.

  • Andrew Lumpe, PhD moderator author
    5 years ago

    Jaide, glad you liked the article. Remicade does have that luxury of being able to increase dose. I suspect many docs would want to try Orencia or Actermra before Rituxan but make sure you discuss all options with your doc. In terms of staying on DMARDs, that depends on the biologic and your doctor recommendations.

  • Kelly Mack moderator
    5 years ago

    Thanks Andrew–really good info to consider. I’m on a biologic and DMARD now for six months and not sure of efficacy so was planning on discussing with my rheumy when I see him in a couple weeks. Very good food for thought on next steps.

  • Andrew Lumpe, PhD moderator author
    5 years ago

    Jaide, there are no comparison studies between those three drugs that I’m aware of. I can’t say anything about better choices as that’s between you and your doctor (we really can’t give medical advice here). If you read the ACR guidelines, they also don’t give details about 2nd line choices. Everyone responds differently to different drugs.

  • Carla Kienast
    5 years ago

    Hi Andrew: Thanks for a great post. Getting a treatment plan is a momentous occasion and making the decision that it’s time to change can be equally daunting. But it’s important to be realistic if drugs aren’t working. You can slow or stop joint damage with a viable drug, but you can’t reverse the damage done while one isn’t working.

  • Andrew Lumpe, PhD moderator author
    5 years ago

    You’re in the midst of switch meds again Carla. I was thinking of you while writing this article.

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