EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM

SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS) – The sustained remission rate in patients with giant cell arteritis was three times better with subcutaneous tocilizumab than with long-term prednisone in the landmark GiACTA trial, John H. Stone, MD, reported at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Moreover, the serious adverse event rate was significantly lower with the interleukin-6 receptor inhibitor tocilizumab (Actemra). This finding serves to underscore the pronounced, yet sometimes stealthy, toxicity of long-term, high-dose prednisone. Many rheumatologists have underplayed these side effects for lack of a better treatment option, because until the randomized, double-blind GiACTA trial, corticosteroids were the standard of care and only known effective therapy for giant cell arteritis (GCA), observed Dr. Stone, professor of medicine at Harvard Medical School, Boston.

“There’s finally something new in giant cell arteritis,” the rheumatologist declared. “The era of unending steroid therapy with no viable alternative is over.”

GiACTA , by far the largest-ever clinical trial in GCA, also highlighted the need for reconsideration of the American College of Rheumatology diagnostic criteria for GCA, now more than a quarter century old. Several common and distinctive baseline clinical features among GiACTA participants aren’t mentioned in the diagnostic criteria. And some features that are played up in the diagnostic criteria turned out to be not so common among GiACTA participants, all of whom had temporal artery biopsy-proven disease or definitive imaging evidence of large vessel vasculitis.

Dr. Stone was global principal investigator in GiACTA, a 14-country study including 251 GCA patients, roughly evenly divided between newly diagnosed patients and those with previously treated relapsing disease. GiACTA, he noted, was a study of several firsts: the first-ever clinical trial in any disease to utilize a blinded variable-dose steroid regimen, the first to feature a double-blind steroid-tapering regimen, and the first prospective study of 1 full year of tapered-dose prednisone.

The primary outcome was sustained remission as defined by absence of flare during study weeks 12-52 coupled with normalization of the C-reactive protein level to less than 1 mg/dL. This sustained remission endpoint was achieved in 14% of patients on 26 weeks of prednisone plus placebo and 17.6% of those on 52 weeks of prednisone and placebo.

“The results in the two steroid arms are lousy,” the rheumatologist pointed out. “This is I think one of the most astounding things about the trial.”

In sharp contrast, the sustained remission rate was 56% with 162 mg of subcutaneous tocilizumab once weekly plus 26 weeks of prednisone, and 53.1% with 162 mg of the humanized monoclonal antibody every 2 weeks plus 26 weeks of prednisone.

Tocilizumab’s steroid-sparing capability was impressive. The mean cumulative prednisone dose was 4,199 mg in patients on a 52-week prednisone taper plus placebo – a steroid regimen that most closely mimics what most rheumatologists have until now considered standard practice – versus only 2,098 mg in patients on once-weekly tocilizumab plus a 26-week prednisone taper.

Serious adverse events occurred in 24% of patients on prednisone-only, compared with less than 15% of those on tocilizumab. Quality of life scores as measured on the physical component score of the Short Form–36 were significantly better in the tocilizumab recipients.

“I think this speaks again to corticosteroid toxicity,” Dr. Stone said.

Another corticosteroid toxicity underscored in GiACTA was weight gain. At enrollment, patients with newly diagnosed GCA weighed significantly less than did those with previously diagnosed, relapsing disease for which they’d already been on long-term steroids. This body weight disparity was particularly pronounced in men. Men with relapsing GCA weighed a mean of 18.6 pounds more at baseline – nearly three additional body mass index points – than did newly diagnosed men who hadn’t been on aggressive steroid therapy.

“This is a steroid toxicity that I think sneaks up on us,” Dr. Stone observed.

The ongoing GiACTA study is continuing for an additional 2 years of open-label tocilizumab restricted to participants who flared during the initial double-blind phase or thereafter.

Joel M. Kremer, MD, rose from the audience to pronounce GiACTA “a home run.”

“I thought this was the most important study presented at the 2016 ACR annual meeting,” added Dr. Kremer, professor of medicine at the University of Albany (N.Y.) and president and founder of CORRONA, the Consortium of Rheumatology Researchers of North America.

The Snowmass symposium afforded Dr. Stone the opportunity to delve into aspects of GiACTA that time didn’t permit him to address at the 2016 ACR annual meeting:

• What’s the best dose of tocilizumab?

Weekly therapy appears to be preferable, although that’s a decision for the regulatory agencies. Time to first relapse post steroid taper was significantly longer with weekly than with biweekly tocilizumab, a result driven primarily by a markedly better result in the baseline relapser group. The pharmacokinetic data also support weekly dosing: Although patients randomized to weekly tocilizumab got twice as much of the biologic over the course of 52 weeks, their serum trough levels were actually six times higher than in those on biweekly therapy.

“This has implications for control of acute phase reactants,” the rheumatologist noted.

• Which patients with GCA should receive tocilizumab, and for how long?

The GiACTA finding that patients on 52 weeks of prednisone were only one-third as likely to be in continuous remission at 1 year is a deal breaker for the traditional therapy so far as Dr. Stone is concerned, he said in response to an audience question.

“I would treat almost everyone with tocilizumab right out of the gate, and I think the goal is to get them off concomitant prednisone fast. I think we can probably achieve that in less than the 6 months we used in GiACTA,” he said.

The ongoing second, open-label phase of the study will be informative regarding optimal treatment duration. In the meantime, the rheumatologist said, “I would treat patients for 12 months and then follow them to see what they need. We treat ANCA-associated vasculitis with rituximab and steroids, and some of them go into remission that lasts 5 years. I think some giant cell arteritis patients will be the same way, and others will flare right after you stop tocilizumab or maybe even while they’re still on it. Tocilizumab is not a cure, and these patients will still need to be followed closely.”

• What about intravenous tocilizumab, the far less costly option under Medicare?

The Food and Drug Administration will consider approval only for subcutaneous tocilizumab in GCA, since that what was used in GiACTA, although Dr. Stone is convinced based upon personal experience that the subcutaneous and intravenous formulations act identically. Roche/Genentech officials have told him they will pursue a separate approval process for the intravenous formulation.

• How about Takayasu’s arteritis?

It looks like a separate approval process, including a new study, will be required for this form of large-vessel vasculitis, Dr. Stone said.

• Intriguing baseline clinical features in GiACTA:

Mouth pain/jaw claudication was present in 34% of the GCA patients at enrollment.

“Jaw claudication is, I think, vastly underestimated as a very important symptom in giant cell arteritis. Of course, patients don’t say, ‘I have jaw claudication today, doc.’ You have to ask about it specifically. It’s not part of the ACR criteria, and I think it should be,” Dr. Stone said.

Also, cranial symptoms were present in only 79% of patients at enrollment.

“I think that’s important for physicians to know: One-fifth of patients had no cranial symptoms when they were enrolled in the study,” he continued.

Another key finding: Only 67% of GCA patients had a new-onset headache at enrollment.

“We think of headache as being so crucial in this disease, and it is important, but only two-thirds of patients in this trial had it,” the rheumatologist said.

Also, 62% of GCA patients had polymyalgia rheumatica at enrollment. More interestingly, 21% of patients with confirmed GCA had only polymyalgia rheumatica, with no cranial symptoms at all.

Dr. Stone reported receiving research grants from and serving as a consultant to Roche/Genentech, which sponsored GiACTA and markets tocilizumab for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis.

bjancin@frontlinemedcom.com

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