Rob Volansky , 2025-05-15 09:30:00
Careful examination of clinical trial data and a better understanding of risk factors can help rheumatologists determine if a patient is truly at risk for an adverse event, according to a presenter at the Biologic Therapies Summit.
“There are no solutions in rheumatology,” Michael Putman, MD, MSci, of the Medical College of Wisconsin, told attendees. “When it comes to safety, there are really only trade-offs.”
Although the drug development process of phase 1, 2 and 3 trials can be useful for sorting out broad patterns of safety signals and adverse events, phase 4 post-marketing studies conducted years after the approval of a medication can yield “small but real” signals that are not so easily described, according to Putman.
“These are the signals that plague us,” he said.
One instance pertains to the black box warning for lymphoma in patients treated with TNF inhibitors. Although some of the pre-approval studies demonstrated significant risk, others did not.
“Is this a signal or is this noise?” Putman said. “It is kind of hard to adjudicate that.”
Prospective, observational and meta-analysis data taken as a whole ultimately demonstrate hazard ratios for lymphoma associated with TNF inhibition ranging between 1 and 1.1, according to Putman.
“It is not the kind of data that would make me tell my patient, ‘It is better to be stiff than to take a TNF inhibitor,” he said.
Putman encouraged deep investigation into the data to determine where the risks lie. Although patients with risk factors such as older age or smoking history may, in fact, be at risk for lymphoma after treatment with TNF inhibition, younger nonsmokers may not.
However, Putman added that many clinicians do not have the time to drill down into these findings.
“Trying to get rid of irregular safety signals is incredibly complicated,” he said.
A similar phenomenon has been seen with Janus kinase inhibitors and their black box warnings for major adverse cardiovascular events and malignancy, according to Putman.
“We over-generalize safety signals,” he said. “There is probably a group of people for whom JAK inhibitors are safe. We have to have nuanced conversations about safety signals.”
The final example Putman offered pertained to the risk for blindness and retinopathy in patients treated with hydroxychloroquine. Data have shown that reduced dosing can minimize this risk, he said.
“If you start cutting down everyone’s hydroxychloroquine and tell people they will go blind with this drug, there will be consequences,” Putman said.
Those consequences may include hospitalizations, organ damage and flares, he added.
Although Putman acknowledged that a subset of patients may experience vision-related events with hydroxychloroquine, he stated it does not mean that this drug should be removed from the armamentarium.
“This is a problem we can solve with screening,” he said.
However, this type of solution is not always employed.
“Often, when we have a safety signal, we over-generalize it,” Putman said. “Then we solve it by over-reacting. On balance, this may not be great for patient care.”
To this point, Putman offered a broader point for attendees to consider.
“We need to take a holistic view of safety,” he said. “We need to counsel patients about tradeoffs.”
Sources/Disclosures
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Putman, M. Signal and the Noise: Safety in Rheumatology. Presented at: Biologic Therapies Summit XI; May 9-10, 2025 (hybrid meeting).
Disclosures:
Putman reports research funding from AbbVie and Amgen, research and other compensation from AstraZeneca and Novartis, and being on the advisory or review panel for GlaxoSmithKline.
