All Hail the Negotiator | Seronegative Rheumatoid Arthritis (RA)

I first met JY 2 weeks ago. A 35-year-old, tall, lanky male with a 2-year history of seronegative rheumatoid arthritis (RA), JY initially presented to a rheumatologist in my area with only a handful of troubling issues. His labs were all negative with the exception of an elevated C-reactive protein (50 mg/dL) and increased eosinophilia count (45%). Hepatitis and QuantiFERON-TB panels were negative. Physical exam demonstrated 3 swollen proximal interphalangeal joints but no tender joints. JY also reported regular morning stiffness of approximately 2 hours.

In essence, nothing truly remarkable.

What has made the initial management of JY unique is unraveling his convoluted treatment history and parsing the truth from the, well, untruth.

As we began discussing his medication history, we started at the beginning when JY was prescribed methotrexate 2 years ago. He recalled his initial reaction when reading through the potential side effects. “I remember seeing that it causes alopecia no matter how small the dose,” he told me. A bit of an exaggeration, but I didn’t push it.

I then asked JY if he was prescribed daily folic acid in addition to the methotrexate and was told, “That’s just a vitamin—there wasn’t any reason for me to take it.” I calmly explained to him that the reality was just the contrary and that folic acid can help to reduce the toxicity of methotrexate and mitigate the risk of some side effects.1

As our conversation continued, I learned about some of the other reasons why methotrexate was “not for me,” include the fear of liver, pulmonary, and blood toxicities. While it is true that methotrexate can cause side effects such as hepatotoxicity, asymptomatic radiographic lung damage, impairment of glomerular filtration, diminished vaccine responses, and alopecia, frequent monitoring can often identify any of these adverse events before they become significantly damaging.2

JY had lasted only 4 months on methotrexate before he voluntarily discontinued the medication due to all of his (exaggerated) concerns.

We kept going.

JY’s medical chart stated that he was a “non-drinker.” When I asked for verbal confirmation of this fact, JY admitted that it wasn’t really true. He then proceeded to ask me how much daily alcohol he could drink and still be “safe” if he decided to restart methotrexate. This had the uncomfortable feel of a negotiation, as if there was some magic number of drinks I would agree was OK so that he could restart methotrexate. To JY’s dismay, I assured him that no amount of daily drinking was safe or recommended while taking methotrexate.

It was starting to become clear why JY had stopped taking methotrexate—despite reporting that he had almost no morning stiffness and limited synovitis while on the drug—and had switched to cyclosporine 100 mg BID. I asked him if cyclosporine had been effective, but was told “not too much.” Apparently, despite cyclosporine’s possible side effects of renal toxicity and hypertension,3 it was a lack of efficacy and not safety fears that were the overriding factor behind its discontinuance.

There was, of course, more to be said. “I couldn’t take (cyclosporine) and drink or eat grapefruit, which was a nonstarter for me,” JY said. On this, at least, JY’s knowledge was sound. There are a group of active compounds in grapefruit known as furanocoumarins that are inhibitors of the cytochrome P-450 3A enzyme, which can increase the exposure to cyclosporine.4 Consequently, unless specifically cleared by a clinician, patients taking cyclosporine are instructed to avoid grapefruit and grapefruit juice.
Sulfasalazine had also been a no-go. “It made my urine too yellow,” JY told me.

Somehow, JY’s previous rheumatologist had convinced him to give an injectable a try to better match his active lifestyle, and adalimumab was initiated. As with methotrexate, JY saw his symptoms improve quickly as his tender and swollen joint count reduced from 10/8 to 4/2, respectively. His C-reactive protein level also dipped to <5 mg/dL.

Again, though, success was short-lived. After 6 months of twice-monthly injections of adalimumab, JY decided that too much damage was occurring at the injection site and that he wanted to stop all medications to give a holistic approach to care a try. Fresh fruits, fresh vegetables, no meat, and no gluten, but still a “safe” amount of alcohol as determined by JY. How alcohol fits into a “holistic” diet remains a mystery a me, but again, I bit my tongue as best as I could.

Three months after the holistic diet began, JY first showed up in my office with badly progressing problems. His CRP was back up to 60 mg/dL, he had 12 tender and 10 swollen joints, 2 hours of daily morning stiffness, and was barely able to walk without pain.

It was obvious—at least to me—that JY needed an immediate steroid taper followed by an NSAID and then likely a second try at a biologic therapy. At the same time, I knew that JY would likely put up roadblocks to any medications involving a needle and perhaps would simply find potential danger with anything I suggested. Let’s face it—a biologic has more potential side effects than a carrot stick, and I was likely going to hear about it if I failed to tread extremely carefully.

I started with a positive—there was no presence of erosive disease on a recent X-ray. However, I noted that, on the current road JY was on, this wasn’t going to last long. No treatment—and fruits and vegetables don’t count as treatment!—would eventually lead to disfiguring joint damage and disability.

I then reviewed with JY the side effect profiles and mechanisms of action of his more viable treatment options. Because it was an “unjection” in pill form, JY opted to start with tofacitinib after a brief indomethacin boost for joint pain. The fact that tofacitinib has shown efficacy as monotherapy was an added bonus—JY is a patient where I definitely felt that the less drugs he needed to take, the better.5

JY is an Internet-savvy young adult. It is clear that empowering him in our office with information about his disease and the treatment options available to him is vital, but it’s also clear that his education isn’t going to stop once he leaves our office. Giving him the tools to help differentiate fact from fantasy isn’t easy—so many of our patients want to believe what they read online regarding things such as a holistic diet. It’s my job to reinforce information and encourage JY to continue to be an active participant in the control of his disease at every step.

There is nothing enjoyable about those “gotcha” moments when we find out that what is in our patient’s medical record doesn’t necessarily reflect the truth, or that there are important details that are missing when we first meet a new patient. I have been sure to document these new details so that others who eventually will be responsible for treating JY have a better idea of what they may be up against. In the meantime, I’ll continue to serve as a negotiator to get past whatever roadblocks JY throws up in the future so that we’re able to quiet the impact of his disease and maintain his busy lifestyle.

Jacqueline Fritz, RN, MSN, CNS, RN-BC, is Owner and Coordinator of Education at the Medical Advancement Center in Cypress, CA. Her primary responsibility is working as an advanced practice nurse for a large rheumatology practice where she is involved in patient visits, research programs, and infusion center coordination. In addition, she enjoys speaking, teaching, and learning about immunology



1. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol. 1998;25(1):36-43.
2. Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med. 1983;75(6A):69-73.
3. Ishida Y, Matsuda H, Kida K. Effect of cyclosporin A on human bone marrow granulocyte-macrophage progenitors with anti-cancer agents. Acta Paediatr Jpn. 1995;37(5):610.
4. Hollander AA, van Rooij J, Lentjes GW, et al. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther. 1995;57(3):318-24.
5. Fleischmann R, Mysler E, Hall S, et al; ORAL Strategy investigators. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet. 2017;390(10093):457-468.