Side Effects and Genes: More Evidence for Listening to Patients | Rheumatoid Arthritis Warrior

Side Effects and Genes: More Evidence for Listening to Patients

Some readers say medical terms bug them. Wait! Don’t let the weird words in an abstract make your eyes glaze over. Sometimes there’s important stuff there!  You might still get the general idea if you just read “the whatever” when you get to a word you can’t pronounce. Then look up significant words if you want to know more.

Biological reason found for side effects to leflunomide / Arava

directions signsThis recent abstract might sound obscure at first, but let’s look closer “Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis.” The conclusion in Arthritis Research & Therapy made me read further: “CYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolisers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.”

Leflunomide, Arava in the U.S., is a DMARD that’s frequently used to treat RA. Patients who take it realized it may have side effects, and this new study explains why. Certain people (such as those above called CYP2C19 phenotype) were more likely to stop the drug because their system does not metabolize it well. For them, the side effects for leflunomide outweigh any benefits.

Two important points about side effects

1) Perceived versus actual side effects

First, side effects are real whether a doctor has a way to measure them or not. Patients know this already, but they may not realize the way such things are discussed in medical circles.

Generally, when I read medical literature, the discussion is with regard to “perceived side effects,” not side effects themselves. To the medical community, perceived side effects must be minimized in order to increase compliance with medications (also sometimes called adherence). It seems this new study validates that actual side effects with an actual biological explanation are likely to be a reason many discontinue leflunomide.

Perceptions can be real, of course. People who can’t tolerate Arava probably do also perceive it. And hopefully, when they communicate it to their doctors, it’s accepted as what it is: their system does not tolerate this medication. Not that they just perceive it’s a harsh medication or complain about feeling sick because someone suggested it could happen. This is the main reason patients are not warned about dangerous side effects, because clinicians fear the power of suggestion will produce perceived side effects.

By the way, I’ve read one study showing that perceived side effects had only a weak association with non-adherence to Rheumatoid Arthritis medications (not taking prescribed DMARDs).

2) There are biological explanations for varying responses to treatment.

Numerous patients have written to us saying their rheumatologist tells them they must have been misdiagnosed with Rheumatoid Arthritis because they do not respond to treatment. Treatment response rates with RA are rather dismal. Large studies show real world remission rates are low. And even best-care clinical trials show only 20% of patients have a great response (70% improvement).

Patients who report treatment responses, side effects, or disease activity should be believed. Someday, blood tests that “prove” poorly metabolized medications could be widely available. Just as we know there will be a diagnosis test or a test to show which medications will help which patients.

Meanwhile, what works already? Listening to patients.

Important related reading

Evidenced-based Medicine or Easy-bake Oven: Tension Between Evidence and Reality

Kelly O'Neill

Kelly O'Neill (formerly Kelly Young) has worked about 12 years as an advocate helping patients to be better informed and have a greater voice in their healthcare. She is the author of the best-selling book Rheumatoid Arthritis Unmasked: 10 Dangers of Rheumatoid Disease. Kelly received national acknowledgement with the 2011 WebMD Health Hero award. She is the president of the Rheumatoid Patient Foundation. Through her writing and speaking, she builds a more accurate awareness of rheumatoid disease (RD) aka rheumatoid arthritis (RA) geared toward the public and medical community; creates ways to empower patients to advocate for improved diagnosis and treatment; and brings recognition and visibility to the RA patient journey. In addition to RA Warrior, she writes periodically for newsletters, magazines, and websites. There are over 60,000 connections of her highly interactive Facebook page. You can also connect with Kelly on Twitter or YouTube, or LinkedIn. She created the hashtag: #rheum. Kelly is a mother of five, longtime home-schooler, NASA enthusiast, and NFL fan. She has lived over fourteen years with unrelenting RD. See also https:/

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14 thoughts on “Side Effects and Genes: More Evidence for Listening to Patients

  • July 13, 2012 at 3:20 pm

    Interesting and irksome. I do realize there is a real association for some people with hearing about something and then thinking you are experiencing it. For example, if you just TALK about being dizzy, or having a stomach flu, my head and tummy will hurt. I have such an aversion motion sickness that I can get it just thinking about it. It is kinda funny except for the part where it makes me feel sick. I am ok right now though – just in case you are worried about me! LOL.

    So because of the above, I get it – some docs don’t tell you every thing because then you’ll be looking for it. Heck I have to play mind games with myself like that about certain things, too. On the other hand, I had a doc leave out a particularly detrimental side effect (to a non ra drug) that caused me undue harm and suffering in my opinion. I am still over a year later dealing with the imbalance that drug caused, even though I haven’t taken it for so long. I got desperate and googled it and then I got a new doctor. I may be 40, fat, and female, but I am not an idiot. Give it to me straight, and let the rest fall where it must.

  • July 13, 2012 at 3:40 pm

    This is very interesting. I tend to get unusual side effects from meds. For the past 14 yrs I’ve had a doc that believes me when I say it is happening.

    On the other hand, I tend to metabolize the biologics faster than average. I’m currently doing OK on Simponi, and it is supposed to be a once per 28 day injection. At exactly 19 days I start to flare. I’m managing every 3 week injections thanks to 1) my dr. understanding my response is real and how to get something through the FDA they pick an average for treatment times (he told me this) and 2) him giving me the occasional patient sample he gets from reps, since my insurance won’t give it out more frequently.

    I also metabolize things like Novacaine or anesthesia more quickly. I’m sure at some point there with be physical evidence to show why. Right now I’m only managing because I have a doc who understands that just because we don’t know about something yet doesn’t mean it doesn’t exist.

    • July 13, 2012 at 3:51 pm

      It’s so good you have a dr who listens! And that’s great he helps you get a few extra syringes!
      Must be about the most important thing a dr could learn in school. How to listen. Yet a well-known dr / author gave a speech recently where we were and he said drs are taught to “minimize verbalizations” from patients. Not good.

  • July 13, 2012 at 5:57 pm

    Thanks everyone!! I am 68 and I was diagnosed with RA when I was 31. Until this very minute I did not know my throat/voice/neck problems were in any way connected with The Disease. All of the symptoms mentioned have been my experience too. I did complain this week about neck pain and it is being investigated now. Xrays of my cervical spine, throat and neck have been taken. I don’t know it this will show anything or not but at least now I can talk intellegently and confidently to my doctors without feeling alone.. thank you..I don’t know how serious the situation could be but there have been many times when I am unable to open my mouth wide enough to even stuff pills past my teeth because of jaw pain and inflamation. My meds have been doubled this week so hopefully some of these issues will fade into the past in the next few months..Thanks again.. for all the information.

  • July 13, 2012 at 8:24 pm

    So essentially, the people with the poorest response to the medication also had the worst side effect profile because they weren’t metabolizing the medication? I do read some of these research papers but, yes, they can be really dense and difficult to understand. Thanks for sorting this one for us! And, that makes perfect sense too.
    On the other subject, I have had doctors minimize reported side effects, even good, caring doctors are, I think, taught to expect people to have a perceived response and try to minimize it. It’s hard sometimes to separate that even for yourself since many of the drugs we take are enough to make anyone anxious! I was considerably worked up when my rheumatologist first prescribed MTX but surprised even myself by having absolutely no side effects until I hit maximum dosage at 20mg. Then I had to split it to two days instead of just one to minimize the intestinal effects but I have recently noticed an increase in heart palipitations and didn’t know if that might be related.
    On the other hand, when my family doctor several years ago prescibed a statin, I never gave it a second thought and as I began experiencing muscle pain and weakness and leg cramps it took a long time before I made the association. This was before I was diagnosed with RA. I reached the point of being unable to lift my groceries before my doctor went oh lord, it’s the statins! No more of those for me! But shortly after my recovery, I became ill with RA – it’s like it set it off. Talk about side effects!

  • July 13, 2012 at 9:30 pm

    It is interesting that some doctors are taught to “minimize verbalizations” from patients. My mother is an RN and even when she went to school(early ’80s) she was repetedly told to ‘always suspect the medication’ when the patients became sicker. I have personally been through a drug-trial (phase three open-lable) and I found the nurse and administrator to be far more willing to act upon symptoms I had versus the doctor overseeing the study.
    I also think having lots of other patients be a little too easy to treat can tend to make a doctor less-likely to believe that Medication Sensitive Jane Doe cannot tolerate even a little of drug ‘X’ because Non-Sensitive (to medications) Jane Doe takes twice that amount and is just fabulous. Just my two cents.

  • July 14, 2012 at 12:37 pm

    Gotta say, I have no clue as to what “CYP2C19 phenotype” means, but the people who wrote the article do know. While genetic testing is expensive, it HAS to be less than the cost of giving these hugely expensive biologic drugs to someone who won’t benefit and may become seriously ill from them. Any chance of testing becoming routine?

    Ms. M, you’re lucky to have a doctor who first of all believes that you metabolize drugs quickly, and secondly, will adjust your dosage schedule. It makes me worry when I see my 86-year-old, 85 lb. friend given the same “adult” dose of something my 200 lb husband takes.

    I have had a hard time getting doctors to believe that Tylenol makes me quickly and dramatically sick. (Would you like me to vomit in your office?) I knew my current family practice doc was a keeper when I she didn’t even raise her eyebrows, just said that yes, that is a problem sometimes.

  • July 15, 2012 at 8:50 am

    I just recently started getting average blood work back so the PA thonls I’m in remission. I have got to find me a new rheumy that treats me not just the numbers. I loved my rheumy because he diagnosed me without any blood work. He saw how red, swollen, and after manually moving them, diagnosed me. Then I was told from then on I would be seeing one of his NP. Didn’t have a problem at all with her because she has lupus and understood. Then she had to stop working and I was shuffled to this PA that treats you like a drug addict if your numbers are fine. Have tried & tried to explain to her that I have been having huge falls & will take an extra dose of liquid hydrocodone to help. I’ve shown her the bruises & pictures of more scraps & bruises but she says that they do not warrant an extra dose. I feel like she views all the RA patients as whine bags who are addicted to meds. Heck, I was on 45mg of morphine a day that didn’t do anything at all for me. Never has. And she said that I should be having withdrawal s because of the dosage. Quit it all in 1 day & never suffered anything. I guess that could make her think that I’m a dope head because the morphine didn’t do anything & then no withdrawals. I have had numerous surgeries were they hooked me up to the morphine pump but never used it because it didn’t help….lol guess I metabolize morphine differently.
    Sorry for running on & on, just get frustrated. My Counselor is making me look into a pain management dr so I don’t have to suffer the humiliation of asking her for a little more hydrocodone & being treated as a junky. Thanks all for just letting me rant. xxx to all
    look into a pain management dr so I don’t have to sufder the humiliation

  • July 15, 2012 at 2:30 pm

    When I read this article it was if there is FINALLY VALADATION for those who cannot tolerate some treatments!!! I have ALWAYS had problems tolerating medication and I am SO BLESSED to have an internest, pulmonologist, and rheumatologist that accept the fact my body is very picky when it comes to medication. I am going to share this article with a rheummy friend. I was SO disappointed and annoyed when I could not tolerate Metho; it “seems like” the majority of people take it and do well. When I saw the Rheummy last week she said, “Thanks for trying it one more time and I am sorry it made you ill. It helped your pain so much, but it just makes you too sick. We just keep moving forward from here. Meds are not a one-size-fits-all. The only way to find what will work for you is to keep trying meds until we find the one that your body likes and will tolerate. I am sorry that the only way is through trial and error. We WILL find something to help with your pain. It helps that you are your own advocate.” I thanked her as docs from the past have not been as open and acted like med side affects were all in my head; now there is proof its not in my head but in my genes!! I hope you are all as blessed as I am by my medical team. If not, KEEP LOOKING, they are out there!!

  • July 17, 2012 at 4:45 am

    My son did some research years ago (on his own) when I was having so many horrific med allergies. What he found actually clarified why I personally was having so many problems. He researched on the med sites and elsewhere and found that different meds are used by our bodies through different pathways. Now I am horrific allergic to sulfur and whatever med used the same pathway caused me an allergic reaction. Weird but for me it was soooo true. So for my next med and before I agreed to take it, he researched the pathway…I took it and had no reaction. That med did not use the same pathway as sulfur would. We have so much to learn in this world and meds are not a one size fits all by any means.

  • July 19, 2012 at 10:03 am

    Patricia R. would you be willing to go into detail more about your throat neck and voice problems? I’m having some issues with mine as well and wondered if it was related to RA. I’ve also experienced some hearing loss. My GP told me to take and allergy med, maybe it’s the little bit of fluid in my ear. Does any of your throat issuses involve swallowing while eating? And sometimes my head feels to heavy for my neck. Like the muscles can’t hold it up. Even when I lie down the feeling doesn’t always go away. I know RA affects other organs and such not just joints but I wondered if it involves muscles and such. Thank you Patricia for mentioning it. I never know where I will learn something about RA. Not so much from Drs. anymore!

  • July 19, 2012 at 10:07 am

    I always felt bad telling my Rhuemy that a med made me sick for so many reasons. IT meant another med was now going to have to be tried. BUt I felt like maybe the dr. doesn’t believe me. As if I didn’t try it long enough. Let the Dr try sulphasalozine and try to stay on that evil crap for more than 2 weeks. SO this article makes me feel better. I know my mother who had RA had the same reactions to meds. so it must be the way everyones body is different at processing these meds.

  • July 23, 2012 at 1:30 pm

    I am very fortunate that my previous rheumy, my pain doc, the NP at my pain doc’s office and the docs I dealt with at the nursing home during my stay have ALL believed me when I said I reacted badly to a certain medication. Only one time did my rheumy ask me to go back on a med to see if I could tolerate it at a lower dose than the previous rheumy had me on. Since it was a much lower dose (1/4 of the prior dose I believe) I was open to it. We gave it 6-12 wks but when it was clear the side effects were not going to let up as some do when you get past an initial adjustment period and it was clear I was not being helped, he said “Never take this again!”. I agreed that it was worth a shot to see if a lower dose would work. But since it didn’t help, the side effects were not worth it. Had it helped, we likely would have treated the side effects and kept me on the med. I was then switched to Arava. I’d been dealing with problems that seemed to be IBS and it had increased after taking Arava. So since my rheumy had started me at the highest dose (20mg) he said we could cut it in half and see if that helped. When it didn’t, we tried Imuran. I began to worsen within a month. And the IBS like problems didn’t go away so he decided they were NOT side effects from Arava and we restarted me at the 20mg dose and added treatment for IBS. He determined I had IBS-D which meant I spent a LOT of time in the restroom. If we were out anywhere, I knew where the bathrooms were within minutes just in case, Even with me taking narcotics for pain treatment, I didn’t have the typical constipation from the narcotics. I’d have been glad for that side effect because it would have evened things out. It wasn’t until after the infection problems and being hospitalized and then acquiring C-Diff because my immune system was so depressed by Remicaide that I had multiple infections and they got rid of the C-Diff and other infections that the IBS-D calmed down and I seemed to be relatively normal. Then my doc at the nursing home more than doubled my methadone dose and that changed things more and Miralax became a med I frequently told the nurses I needed or was brought to me by some nurses.

    None of my healthcare providers except my new NP who does both my general care and rheumatology care. The pain doc and NP there do not give me side effects of meds but that is only because they know I am going to go look it up online. My former rheumy never gave me side effects either because he knew the same. The only reason the new NP does tell me things is because she doesn’t know my habit of reading the FDA monographs of a med and reading other things on it as well. She’ll eventually learn that I do these things.

    I seem to be in the minority of people who does well on Arava. Most people have trouble it seems.

  • October 29, 2014 at 11:17 pm

    I also had a severe reaction to Arava- Horrible oral ulcers and throat; am allergic to so many meds and foods. The worse case was a Steven-Johnson Syndrome and almost intubated, from Azithromycin. Due to this, I always carry an Epi-Pen and Benadryl.
    I really appreciate your rawarrior website and all that you have done to increase awareness in this field of Rheumatoid Disease. It has not been a easy journey and just diagnosed three years ago~ of which I was pretty much home/bed bound about 1.5yrs of this time. Everyday that I am moving is a good day.


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