Making a SELECT-CHOICE in refractory RA
In patients whose RA has proved refractory to one or more biologics, opting for the oral Janus kinase inhibitor upadacitinib as next-line therapy is significantly more effective than turning to the T-cell costimulation modulator abatacept, but at the cost of a doubled risk of severe adverse events, according to the findings of the phase 3, double-blind, 24-week, randomized SELECT-CHOICE trial.
In this 612-patient study, the week-12 clinical remission rate as defined by a C-reactive protein (CRP)-based DAS28 below 2.6 was 30% in the upadacitinib arm, compared to 13.3% with abatacept. At week 24, the remission rates were 46% and 31%, respectively. However, the severe adverse event rate was 6.3% in the upadacitinib group, including one death, one stroke, and two cases of VTE, compared to 3.2% with abatacept.
“Maybe this is a win for upadacitinib, but abatacept is a win when it comes to safety,” Dr. Cush said. “So the question is, when you’re making your second or third change in a biologic DMARD, are you going for safety or are you going for efficacy?”
Make way for machine learning
Studies of machine learning and artificial intelligence aimed at developing a more individualized treatment approach are popping up with increasing frequency at the major rheumatology meetings.
“This is really, I think, the future because for most of us, in most of our choices, as great as all of us are in managing RA, it is a crystal ball and a coin toss as to whether our next therapy is going to work,” Dr. Cush said.
He highlighted a study presented at the 2020 ACR annual meeting as an example of how machine learning can generate better evidence for selecting therapies. An international team of investigators used artificial intelligence to develop a simple rule to predict an RA patient’s likely response to the interleukin-6 receptor inhibitor sarilumab (Kevzara). The researchers developed a list of 42 candidate predictors of an ACR20 response, including demographics, biomarkers, and disease activity scores, then applied machine learning to data from the 1,197-patient, phase 3 MOBILITY trial of sarilumab versus placebo in order to generate a predictive rule of better outcomes.
Out of the 42 candidate predictive values, the best predictive rule turned out to be the combination of the presence of anti-citrullinated protein antibodies and a baseline CRP level greater than 12.3 mg/L. This rule was then put to the test using data from four phase 3 clinical trials in which 34%-51% of RA patients randomized to sarilumab were rule-positive. The rule-positive patients had worse baseline prognostic factors and more severe RA. Yet rule-positive patients had a better outcome than that of those who were rule-negative. For example, a week-24 ACR70 response was achieved in 34% of rule-positive patients, nearly fivefold greater than the 7% rate in the rule-negative group.
Treat-to-target strategies don’t tame excess mortality in RA
At a mean of 17 years of follow-up in the Dutch BeST study – a pioneering treat-to-target study in RA – patients with early RA who were assigned to one of four treat-to-target strategies for 10 years showed excess mortality compared to the general age- and sex-matched Dutch population, Johanna M. Maassen, MD, reported at the 2020 annual meeting of the European Alliance of Associations for Rheumatology (EULAR). Indeed, mortality was 37% higher in the RA patients than in the comparator population, with no significant differences in survival curves evident between the four tight-control strategies.
“This raises the question of whether survival in patients not strictly treated to target would have been even lower. Are we not doing as well as we think we’re doing?” Dr. Kavanaugh said.
“This is very sobering. It tells us we really do need to be better at managing RA. And I would say based on this data we need to be better at managing RA really early to get better outcomes really late,” said Dr. Cush. “The damage that led to cardiovascular risk could have been incurred earlier on and then carried forward when you look out to 15-20 years.”
More trouble for tofacitinib
Tofacitinib faces an uncertain future following Pfizer’s late-January press release announcing that the JAK inhibitor failed to meet noninferiority compared to anti-TNF therapy in terms of adjudicated major adverse cardiovascular events (MACE) and adjudicated malignancies in an FDA-mandated postmarketing safety study. The study, known as ORAL Surveillance, or Study A3921133 – ‘1133’ for short – randomized 4,362 RA patients aged 50 years or older with at least one additional cardiovascular risk factor to tofacitinib at 5 or 10 mg twice daily or to a TNF inhibitor.
The Pfizer press release was soon followed by an FDA safety warning and announcement that the agency is reviewing the full study data before making any final recommendations. The FDA already requires black box warnings for tofacitinib regarding increased risks of blood clots and death, but only at the 10-mg twice-daily dose. In the ORAL Surveillance study, however, the primary endpoint was noninferiority of the combined tofacitinib doses, and there was no evidence of a difference in endpoints between the 5- and 10-mg twice-daily doses.
Only the topline results released in the Pfizer press release are publicly available so far. The combined tofacitinib doses were associated with a 1.33-fold greater risk of adjudicated MACE and a 1.48-fold increase in adjudicated malignancies other than nonmelanoma skin cancer, compared to adalimumab or etanercept.
The jury is still out pending release of the full study data, in Dr. Kavanaugh’s view.
“When I get to look at the data, I want to see who are the people who had the events, their characteristics,” he said.
Alexis R. Ogdie-Beatty, MD, said the study’s topline results “make me a little nervous.
“The effect size is pretty large. It’s in the 1.4 range, which means there might be something there for real,” said Dr. Ogdie-Beatty, a rheumatologist and epidemiologist at the University of Pennsylvania, Philadelphia.
Dr. Alexis R. Ogdie-Beatty
In contrast, Eric M. Ruderman, MD, said he’s not concerned “just yet” about the results.
“Frankly, the FDA was just plain wrong in their press release because the confidence intervals for the MACE events crossed 1.0 meaningfully [0.91, 1.94], so there’s nothing there. And the confidence intervals hit 1.0 for the malignancies,” observed Dr. Ruderman, professor of medicine at Northwestern University, Chicago.
This was a nearly 4,400-patient study, and given that it couldn’t convincingly show a safety risk, such risk – if it even exists – would seem to be tiny, he added.
Bruce Jancin/MDedge News
Dr. Eric M. Ruderman
“It’s probably not going to change the way we prescribe these drugs. So I don’t see that trial taking away from the big run for JAK inhibitors we’re going to see in the next year,” the rheumatologist said.
The speakers reported having financial relationships with numerous pharmaceutical companies.