May 19, 2017
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Giant Cell Arteritis: What a Long Strange Trip It Has Been

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Leonard H. Calabrese

In this issue of Healio Rheumatology, we feature an update on giant cell arteritis as provided by a panel of experts, which charges me with excitement about a disease that continues to challenge us. I thought for some time about what to say about giant cell arteritis in this Editorial, and all I could do was mull over the twisting and turning history of this form of vasculitis that continues to fascinate us.

Aside from the ancients, who no doubt encountered and described the condition, giant cell arteritis (GCA) was first well-described by the medical polymath Sir Jonathan Hutchinson, who in 1890 encountered and described a classic case in an 80-year-old man named Rumbold. No pathology accompanied the case, but there was no doubt that this was GCA.

The modern era of GCA begins in 1934 when Horton and colleagues at the Mayo Clinic elegantly described two patients who exhibited the characteristic vascular pathology we now recognize as classic GCA. From there, through fits and starts, the rest of the puzzle surrounding GCA began to fill in: its signs and symptoms, especially the visual component; its relationship to polymyalgia rheumatica (PMR); and its propensity for large vessel involvement that became part of our expanding understanding of the disorder. For rheumatologists, these classical descriptions have warmed our hearts and provided us, on occasion, with increasingly rare moments of a bedside diagnosis.

Defining the Cause

The journey has not been smooth for defining the cause of GCA. We remain as in the dark about it today as when old Rumbold stumbled into St. Bartholomew’s, challenging Hutchinson to figure out what he had. Giant cell arteritis is a disorder like no other in rheumatology in its enticement for us to find an infectious pathogen. I will qualify this in that if you consider sarcoidosis a rheumatic disease, then the sarcoid people win the contest; but GCA is still close behind. The granulomatous pathology begs for some sort of infectious agent to be discovered, and the relationship to increasing age and its implied surrogate of immunosenescence make the infection hypothesis even stronger. Despite these facts, we have seen theories come and go for agents such as mycoplasma, B19, Burkholderia and more recently varicella zoster virus, all of which have failed the tests of rigor and method and I can tell you personally this has been painful.

© 2017 Shutterstock.com/orthfoto

Finally, there is the road of therapy. The amazing and rapid efficacy of glucocorticoids in GCA, as well as PMR, continues to gratify us. What rheumatologist does not like becoming the new PMR patient’s best friend overnight? A more cool and reflective view of glucocorticoids in GCA, however, reminds us these are good at controlling disease activity (if you want to call relapse rates from 40% to 75% “good”), but do not cure the condition – and at what a price. I will not bore you with the data for long-term glucocorticoid toxicity, knowledge of which is encoded in the rheumatologist’s germ line. Until now, I have frankly been bored with the hand-wringing about the question of whether methotrexate is truly steroid-sparing. Maybe it is, but not in a clinically meaningful way and chronic refractory GCA on prednisone doses of more than 10 mg per day remain a formidable challenge. Add to this fact that relapse rates are high and many patients have numerous relapses.

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Promises of a ‘Game Changer’

This brings us to the present – the era of interleukin-6 (IL-6) inhibition. As the sources in the Feature Story describe, the inhibition of IL-6 in GCA promises to be a “game changer.” Tocilizumab has been granted breakthrough therapy designation by the FDA and is being fast-tracked through the regulatory pathway. Tocilizumab is poised to be the first drug approved for GCA in more than 50 years, yet as of this moment, we do not know what the label will say and we have questions. How will we, our patients, the regulators and third parties weigh in on how and where the current therapy of glucocorticoids, which are associated with the direct costs of a cheap lunch, compete with a new drug that will cost as much as new Land Rover.

Don’t get me wrong. I am only writing an Editorial and trying to ask tough questions. I am hopeful that with the dramatic steroid-sparing effects that future and mandatory economic impact studies may show us that this therapy will pay off in indirect cost savings. We will have to wait and see. For steroid refractory/dependent patients, it will be a no-brainer and if I had GCA, I would want access to the treatment knowing what I now know. Unfortunately, IL-6 inhibition, at least with tocilizumab, will not cure GCA and so the long strange trip will continue.

So, here we are after 80 years. Jerry Garcia is gone, three of the remaining members of the Grateful Dead are still touring and GCA is still a conundrum. We now have a comprehensive clinical picture of GCA and recognize more atypical, especially large vessel disease, forms. While we understand immunopathogenesis better, we are no closer to finding a cause. Finally, we will have a new and impressive therapy, but we do not know at the moment exactly how we will use it. As the Grateful Dead song Truckin’ goes, “Takes time, you pick a place to go, and just keep truckin’ on.”

Thanks for reading this issue of Healio Rheumatology. Please email me your comments at calabrl@ccf.org or follow me on Twitter @LCalabreseDO and @HealioRheum.

Disclosure: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi, Janssen and AbbVie; and is on the speakers bureau for Genentech, AbbVie and Bristol-Myers Squibb and Crescendo Bioscience.