A study of 217 people afflicted with an eye disease called uveitis tried to determine just how well adalimumab, a pricy “biologic” drug, could stave off frustrating symptoms like inflammation inside the eye, floaters, cloudy vision, and blurred vision. Every patient received standard daily injections of a corticostroid called prednisone, but half were also given a placebo injection, and half were given injections of adalimumab, which is FDA-approved to treat other diseases. Adalimumab held uveitis at bay for 24 weeks, or nearly twice as long as the control group at 13 weeks. But that extra uveitis symptom control came with two costs: a significant uptick in “severe adverse events” and a treatment that costs 50 times more than the one it supplemented.
The study published in the NEJM was one of two that supported FDA approval of the drug for uveitis. As this news release clearly points out, the study was sponsored by the company that sells the drug and many of the authors served as paid consultants to the company.
The Duke Medicine-issued release about the study also grasped the benefits and quality of the evidence very well.
Uveitis, or inflammation of and damage to important structures in the eye, is a relatively rare disease that affects about 43,000 new people a year in the United States, according to the Ocular Immunology and Uveitis Foundation. While treatable, left untreated it was once a leading cause of blindness worldwide.
Most people are treated with daily injections of a corticosteroid called prednisone. However, steroids like prednisone, used long-term or sometimes only briefly, can lead to diabetes, osteoporosis, and even psychological changes, since they not only only dial back inflammation, but also affect the body’s metabolism. So any drug that can more specifically target the inflammation seen in the eyes of uveitis patients could cut back these risks and improve treatment efficacy.
Adalimumab (marketed as Humira) is approved for several other immune system diseases including psoriasis, arthritis and Crohn’s disease. Although adalimumabit is not a cure for those diseases or for uveitis, it is an alternative to steroids. That said, the drug comes with side effects, many of which have to do with its action in suppressing the immune system which increases the risk of infections and cancer.
No dollar signs here, which — as we discovered — is quite an oversight, given the steep costs of adalimumab.
Prednisone costs about $0.33 per mg, and chronic uveitis patients take anywhere from 10 mg to 60 mg per day. Looking at the minimum number (which patients are usually tapered to 6 months into their treatment), that’s a cost of more than $1,190 a year.
In comparison, the name-brand of adalimumab, Humira, costs about $54.49 per mg. In the study, patients received adalimumab on a bi-weekly basis, receiving some 1,640 mg of the drug over 80 weeks if they didn’t drop out. That adds up to a total of $89,400 — an average of $58,000 per year or $1,120 per week.
The benefits are well-represented in the release, and so is their context. By working adalimumab into the standard treatment, most of the key measurements of uveitis are held in check for nearly twice as long in a typical patient — 24 weeks instead of 13 weeks.
This represents improvement — but not a cure — for a chronic disease.
The harms covered in the study were glossed over in the release, in particular by this sentence: “[P]atients in the adalimumab group reported serious adverse effects, such as respiratory tract infections and allergic reactions, more frequently than those in the placebo group.”
Given what was left out, we’ll mark this one unsatisfactory.
What’s not mentioned is that 16% patients in the adalimumab group dropped out compared to less than 7% in the placebo group. We also learned that some of the adverse events that triggered dropout weren’t included in the release: “Adverse events leading to discontinuation of participation in the trial were more common in the adalimumab group and included choroidal neovascularization, blurred vision, reduced visual acuity, fatigue, malaise, and suicidal ideation.”
Something simple that the release could have characterized about the adalimumab treatment’s harms, but didn’t: it had three times the rate of “adverse events” and twice as many serious adverse events.
Including any of these numbers — and some of the harms that taking corticosterids like prednisone can cause (the best we get is “many unwanted side effects”) — would have put the harms and benefits of the adalimumab treatment into clearer context.
This is perhaps the greatest strength of the release. It not only clearly explains the reasons for the drug trial and the metrics of measurement, but also the activity through which the drug might work.
The report involves a randomized controlled trial, so a strong evidence level is expected, and the release did note the industry sponsorship. It’s well known that studies sponsored by industry report favorable results more frequently, which makes some sense, in that companies wouldn’t test drugs they didn’t have strong preliminary evidence for. But it’s also possible that industry sponsorship can bias the conduct and reporting of such studies to make a positive outcome more likely.
We couldn’t find anything that would scare a reader. In fact, the release perhaps went a little too far to the other end of the spectrum and didn’t mention the word “blindness” once, which is a possible outcome of uveitis if left untreated.
The release dedicates a whole paragraph to summarizing potential conflicts of interest, which is welcome and we hope to see this kind of transparency showing up in more releases in the future. It further directs readers to the published study’s supplementary documents for more extensive disclosure information.
In the PDF of supplementary materials we learned that only two out of the 17 authors had no conflicts of interest to declare.
Although the release mentions the weakness of corticosteroids in uveitis treatment, it doesn’t go far enough in explaining how steroids compare with adalimumab, even though steroids were given to the patients concurrently with adalimumab in “diminishing doses” throughout the trial.
It’s worth noting, especially for comparison with adalimumab, how the long-term use of corticosteroid drugs work against uveitis symptoms by suppressing the body’s entire immune system — and, as a side effect, metabolism — not just one specific target of inflammation. Humira also suppresses the body’s immune system although through a different mechanism.
The level of detail is good here, noting that the FDA recently approved adalimumab for noninfectious uveitis, how it was previously approved for other conditions, and in which types of uveitis it’s generally ok to treat.
The novelty is somewhat nuanced, but explained well enough: Uveitis is a bag full of symptoms, and the damage involved can span across the entire eye. By measuring how it affected the most frequent symptoms, “the study’s results broaden the applicability of treatment for patients” and possibly help lead to longer-term solutions for uveitis.
We didn’t see anything that’s cause for alarm.
Systematic, Criteria-Driven
The tale of two “negative” studies. Or, how spin is applied to make research findings look more impressive. A must read. https://johnmandrola.substack.com/p/the-tale-of-two-negative-studies
The @nytimes chose to interview one of the editors of the @AnnalsofIM (publisher of this paper) who "gushed with extraordinary glee: It’s huge! There are very few things that reduce your mortality by 30%."
Turns out coffee is not one of those few things despite all that glee. https://twitter.com/garyschwitzer/status/1533202075928215558
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