Friday, 27 Mar 2020

You are here

The Born Again Rheumatoid

The treatment of rheumatoid arthritis has gone through several key paradigm change eras, beginning with the introduction of gold, followed by methotrexate in the mid-1980s, and more recently with the introduction of biologic therapies.

While there are currently 9 biologic agents approved and marketed for the treatment of RA, and although each has a valued place in our arsenal, I would propose that none has been as influential or dramatic as the inhibitors of tumor necrosis factor (TNFi).

The TNFi appeared in 1998 as new class of “cytokine inhibitors” that has since yielded impressive results in many domains: clinical, radiographic, quality of life, patient-reported outcomes, work/disability, fatigue, etc. But the one advantage (not generally seen with the other biologics or novel therapies) is the ability to induce the “born again” RA patient.

I can only describe this “born again” feeling as a surprised joyful feeling or belief that with this new drug they can go bungee-jumping or join the Marines. Although TNF inhibitors work rapidly, many patients report feeling significantly improved after the first or second injection, hence the sudden and surprising “born again” thing. This almost always appears even before objective improvement in synovitis. Such improvements are often accompanied by marked reductions in stiffness, pain, with an increase in mobility and energy, and many people return to activities they’ve long avoided because of the severity of their arthritis. In the early days of reviewing the data from lenercept (a p55 receptor for TNF), I remember the investigators talking about an amazing and immediate “steroid like CNS effect” with this new subcutaneous cytokine inhibitor.

The “born again” rheumatoid feeling is not well captured by any of the usual metrics or measures. It’s not found in the HAQ, DAS28, SF36 (either mental or physical), fatigue score (e.g., FACIT), or any lab parameter. I believe it’s best described by my patient RH who wrote me this letter soon after starting etanercept.

August 03, 2000
Dr. Cush;
I am writing to express my warmest thanks for suggesting Enbrel as a therapy for my rheumatoid arthritis. As you know, I’m a new patient, recently moving to Dallas from Tennessee. My records show that I have been through a laundry list of medications for my RA, but the only thing that gave any semblance or relief was prednisone IV therapy 500 mg. Relief lasted for 2 days during which I could not sleep and resulted in a very painful period immediately following.
You suggested Enbrel at our first office visit. The morning after my first injection was the start of a new chapter in my life. The pain was gone! Now, in my third month I am still pain free and am gradually weaning off prednisone.
Before this treatment, it was all I could do to go for a walk with my kids. The pain affected literally every aspect of my life, and I’m only 37. Now I feel so good, I bought a pair of roller blades. I fell and broke my arm the next day, but it was worth it.
I hope you can turn everybody on to this stuff that can afford it. I would further urge you to make the first line of treatment, not the last resort. In my opinion, to drag a new RA patient though all the other therapies with all their side effects, while knowing that this silver bullet exists, borders on malpractice.

These born-again rheumatoids almost always report a surprising resumption of physical or pleasurable activities long past forfeited due to the debility and malaise associated with their disease. Like the patient above, they often feel so good they go on to injure themselves (thus my line about bungee-jumping). The direct inhibition of TNF appears to be responsible for this functional improvement and is often associated with the cessation of fatigue, malaise, anorexia, weight loss, anhedonia, and other constitutional features that have been linked an excess of systemic proinflammatory cytokines.

The famed Dr. Charles Dinarello has often stated that “these patients live under a cloud of TNF or IL-1” and that the inhibition of proinflammatory cytokines is akin to relieving them of the monstrous ball and chain they’ve been carrying for months or years.

While I have repeatedly noted this phenomenon with all the TNF inhibitors (in RA and other disorders), I have occasionally seen it with anakinra (the IL-1 inhibitor) and tocilizumab (the IL-6 inhibitor); rarely with the other targeted biologics or oral DMARDs.

The goal of therapy should be the return of health, improvement in pain and swelling, prevention of damage and the avoidance of drug side effects. This fortunate drug benefit, the “born again” feeling is worth noting as it becomes a strong motivator for adherence, compliance and the need for specialty care by a rheumatologist. Once experienced, that “born again” feeling easily out-weighs any of inconveniences, hazards, unknown risks associated with new aggressive therapy.


The author has received research/grant financial support on this subject
The author has received compensation as an advisor or consultant on this subject
Dr. Cush is the Director of Clinical Rheumatology at the Baylor Research Institute and a Professor of Medicine and Rheumatology at Baylor University Medical Center in Dallas, TX. He a Professor of Clinical Medicine at the University of Texas Southwestern Medical School.
Dr. Cush is the Executive Editor of and also Co-Edits the online textbook 
Dr. Cush's research and interests include novel drug development, rheumatoid arthritis, spondyloarthritis, drug safety, pregnancy and Still's disease/autoinflammatory syndromes. He has published over 140 articles and 2 books in rheumatology.
He can be followed on twitter: @RheumNow.

Rheumatologists' Comments

When I was doing the original clinical trials on D2E7 (now known as Humira) I recall an investigators meeting where I said "The only way I could be blinded in these trials is if the subjects wore a bag over their heads. Those on active drug were just beaming at every visit!"
Cal, Thats story is a blast from the past and one that lead to a major redesign in how we do RA trials. The born again thing caused unblinding that since resulted in the need for 2 MD's to run the trial - the "blinded" doc who would come in and do the exam and global assessment based on the exam ("DONT TALK TO THE PATIENT!!") and what we at UT Southwestern called the "Toxic" doc - the one who saw all the data and assessed the labs and safety issues. Nevertheless; as you point out this phenomenon lead to the need for a blinded assessor - a practice still in evidence today, although if its not a TNF inhibitor, Im not sure how the doctor would be unblinded. Great recall!