The Great Debate 2023

Panelists at ACR Convergence 2023 Debate the Merits of IL-6 Inhibitors vs. Glucocorticoids for the Initial Treatment of GCA & PMR

SAN DIEGO—At a scientific session of ACR Convergence on Monday, Nov. 13, two panelists discussed treatment approaches for giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), debating the use of anti-IL-6 therapies at disease onset.

PMR and GCA are closely linked, overlapping syndromes occurring almost exclusively in people aged 50 or older. Both are highly responsive to glucocorticoids, which have been the treatment approach for many years.

Dr. Robert Spiera

Robert Spiera, MD, a rheumatologist and director of the Scleroderma, Vasculitis and Myositis Center at the Hospital for Special Surgery, New York City, pointed out that research in the past decade has convincingly demonstrated the effectiveness of anti-interleukin (IL) 6 therapies for both conditions via well-designed clinical trials. He also underscored that the rheumatology community agrees on the major need for glucocorticoid-sparing therapies in both disorders to reduce side effects and toxicities.

“What remains unclear, however, is whether anti-IL-6 therapies should be first-line in all patients and whether they should be first-line in specific populations,” Dr. Spiera said.

Differences in current treatment guidelines reflect this current equipoise in understanding. Whereas the recent ACR guideline conditionally recommends using oral glucocorticoids with the IL-6 inhibitor tocilizumab over oral glucocorticoids alone in newly diagnosed patients with GCA, EULAR guidelines recommend tocilizumab only for a subset of patients (e.g., those with refractory disease or those at high risk of complications from glucocorticoids). Note: The current ACR guideline on PMR was completed before the most recent clinical trials of these agents.^1,2

Dr. Spiera debated whether anti-IL-6 treatments should be initiated at disease outset, coming down against the premise.

Dr. Philip Seo

Philip Seo, MD, MHS, an associate professor in the Division of Rheumatology at Johns Hopkins University, Baltimore, and former physician editor of The Rheumatologist, presented arguments in favor of initiating treatment at disease outset.

Although, Dr. Spiera noted that each panelist could have argued for the other position.

Using IL-6 Inhibitors at Disease Onset: Con

Dr. Spiera explained that, unlike the biologics used in conditions like rheumatoid arthritis, evidence has not convincingly demonstrated that anti-IL-6 therapies are truly disease modifying in GCA. For example, scientists haven’t shown that anti-IL-6 therapies help prevent aneurysms or cranial ischemic complications.

One potential disadvantage of using anti-IL-6 therapies is that they lower inflammatory markers, such as the erythrocyte sedimentation rate and C-reactive protein, explained Dr. Spiera, which means they are no longer available as reliable biomarkers of disease activity. In some cases, he argued, it can be helpful to have that information, especially in patients presenting with monocular blindness.

Dr. Spiera highlighted some technical aspects of the phase 3 GIACTA trial of tocilizumab in GCA, which demonstrated improved glucocorticoid-free remission with use of the anti-IL-6 therapy.³ However, Dr. Spiera also argued that evidence from that or other studies hasn’t clearly demonstrated that IL-6 inhibitors reduce major complications related to glucocorticoid use. He acknowledged, however, that one analysis suggested a benefit in patient-reported outcomes of quality of life and function with early use of tocilizumab.⁴

Dr. Spiera shared that one approach to managing an initial presentation of GCA is to start with glucocorticoids alone, with a target of tapering within six months. In this scenario, he recommends not necessarily escalating steroid therapy to try to get inflammatory markers within a normal range (in the absence of clinical signs or symptoms of active disease), thus reducing overtreatment and glucocorticoid toxicities. (Patients with vision loss early in their disease course are an important possible exception.)

In discussing PMR, Dr. Spiera noted the efficacy and low cost of corticosteroids. He explained that because PMR doesn’t show clear evidence of disease-related damage, the concept of disease modification may not apply to the condition, so the advantage of using a biologic isn’t convincing from that angle. He also underscored that not all patients require a long course of therapy, and corticosteroids are potentially dangerous or poorly tolerated in some patients with PMR, but not all.

Dr. Spiera suggested that clinicians consider that PMR is not organ or life threatening, and its disease flares are manageable. He also noted that a relatively rapid glucocorticoid taper is possible in a substantial proportion of patients, even without the introduction of glucocorticoid-sparing therapies. Thus, he advised clinicians to plan a rapid glucocorticoid taper (to zero by month four).

Dr. Spiera underscored that for both disorders, it’s not yet clear that initial treatment with IL-6 inhibition results in fewer disease-related symptoms or overall toxicities. He also noted the value in selecting out the potentially easy to treat patients, who may be less well represented in trials, particularly trials currently available for PMR.⁵ A subset of patients may be effectively treated with glucocorticoids, using rapid tapers to reduce toxicities.

But for both conditions, he added, “You should also be attentive to risks of glucocorticoid complications and have a low threshold to introduce IL-6 inhibitors for a flare or for glucocorticoid intolerance.”

Using IL-6 Inhibitors at Disease Onset: Pro

Dr. Seo responded from the other perspective. “Simply put, this is the structure of my argument,” he said. “Biologics work, and glucocorticoids are bad.”

Dr. Seo discussed some data which followed up on GIACTA trial participants after initial study completion. The results demonstrated that patients who were originally randomized to receive treatment with tocilizumab had a longer time to first relapse and had higher rates of treatment-free remission, indicating a potential prolonged benefit to tocilizumab treatment in GCA.⁵

Dr. Seo also acknowledged that many rheumatologists might be more skeptical about IL-6 inhibition as initial treatment in patients with PMR compared to GCA. He drew attention to the trial of the IL-6 inhibitor sarilumab in PMR, led by Dr. Spiera. He noted that in addition to demonstrating efficacy of the drug, it also demonstrated how frequently glucocorticoids fail at keeping patients in sustained remission.⁶ “Every time a patient flares, they go back on higher doses of glucocorticoids for a prolonged period, leading to other glucocorticoid side effects,” Dr. Seo said.

Citing some additional studies, Dr. Seo argued that the current data indicate that IL-6 inhibition is an overall effective approach for PMR, with an increase in glucocorticoid-free remission periods in patients treated with IL-6 at disease onset.^7,8

Dr. Seo acknowledged that clinicians may be reluctant to initially employ IL-6 inhibitors in older patients due to concerns about infection or the very rare but potentially devastating possibility of colonic perforation. Dr. Seo shared that the rate of serious infections with IL-6 blockade is between four to six per 100 patient-years.⁹ But he noted that that rate is similar to that of adalimumab, which clinicians are usually comfortable prescribing in rheumatoid arthritis.

Clinicians may also be hesitant about starting with IL-6 inhibition because they don’t think of PMR as requiring high prednisone doses. However, Dr. Seo shared data indicating that patients are often treated with at least 15 milligrams of prednisone daily, with many patients treated at 25 mg or higher.¹⁰ And he noted that even though PMR patients should ideally be tapered off steroids within a year, a meta-analysis found that about half of patients remain on at least some glucocorticoids two years after initiating therapy.¹¹

Dr. Seo also argued that clinicians may tend to underestimate the risks of glucocorticoid therapy, even at lower doses. He cited an analysis showing that patients taking very low-dose glucocorticoids had increased risks of myocardial infarction and other cardiac events.¹² Moreover, low-dose glucocorticoids can induce white matter changes in the brain that correlate with decreased cognitive function, as well as contribute to such risks as increased HbA1C, cataracts, weight gain and osteoporosis.

Bottom Line

Although they debated some of the finer points of interpretation of current studies, the two panelists agreed much more than they disagreed. Starting IL-6 inhibition in patients with new-onset GCA or PMR is a reasonable approach for many patients, especially for those at higher risk of serious glucocorticoid toxicities.

On the other hand, initial steroid-only therapy is also a valid approach, depending on the medical context. If they do opt for initial steroid-only treatment, clinicians should be vigilant about prescribing the lowest effective dose of glucocorticoids for the minimal time needed, escalating to anti IL-6 therapies promptly at signs of refractory or relapsed disease.

Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.

References

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2. Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020 Jan;79(1):19–30.
3. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017 Jul;377(4):317–328.
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