One of the big challenges for rare-disorder patients is that even after we finally get an effective treatment, we still have an uphill battle to convince clinicians (and insurers) to prescribe it. Approval by the FDA (or the EMA in Europe) confirms that it’s basically safe and effective when used for the relatively short period of the clinical trials, but it can’t necessarily predict what will happen if it’s used for an entire lifetime, which is why sometimes approved drugs end up being withdrawn.
Clinicians are aware of the limits of short-term data, and tend to be extremely resistant to switching to a new treatment that might have unforeseen risks, especially if there is a (supposedly) effective treatment already on the market, and the condition isn’t imminently fatal. As a result, journal articles about burosumab almost always have a caveat along the lines of “but we don’t know if there could be adverse effects from long-term use.” As a lawyer, I understand the need to include that caveat, but as a patient, I’m frustrated by how it gives clinicians an excuse not to prescribe the new treatment until they’re absolutely, positively certain there is no long-term risk, even when the patient knows the risk but believes the risks of non-treatment (or poor treatment) are worse than the risks of the new treatment.
The problem, of course, is that patients with a progressive disorder that causes irreversible symptoms (i.e., enthesopathy) can’t wait the ten or twenty years to start treatment once it’s proven beyond all doubt to be safe and effective in the long term. Especially when there’s no real reason to think there could be long-term risks. As far as I know, no one has proposed any reason why an antibody that basically reverts our defective phosphate metabolism to a normal metabolism would cause any damage. It’s a theoretical risk, not a logically anticipated one.
A real expert in XLH fully understands the risks/benefits, but many, possibly even most patients have a treating clinician with very limited experience with the rare disorder. Inexperienced (with XLH) clinicians may not have seen just how bad the irreversible symptoms can become without treatment (or with marginally effective treatment). These treating clinicians don’t have the necessary experience to be able to confidently discuss the risks and benefits with us and help us make an informed decision on the risk/benefit ratio. These clinicians may have treated a handful of patients — probably all from one or two families — but not enough to have a true impression of the wide range of patient experiences and needs.
These technically qualified but less-experienced clinicians need real guidance on the risks/benefits now, and generally can’t find it in standard medical journal articles, which are all about data and the logical conclusions from that data. But what do you do when there just isn’t any data and can’t be any data, because not enough time has passed?
Historically, journals and their readers have turned to “case reports” when very little is known about a condition or treatment. Case reports are intended to share information about unusual conditions, so, for instance, when the pandemic began, it was useful to publish case reports in order to share experiences with this newly identified coronavirus, when no one was an expert, and everyone was just trying to gather as much information as possible to see what worked (and didn’t) for others in the same boat. But once a disorder, even a rare one, is reasonably well-studied, like XLH is, it seems odd to publish case reports, when the authors are basically just regurgitating what they’ve learned after seeing exactly one (or some similar small number) patient with the disorder. It feels like inadmissible hearsay to my legally trained brain. I want to hear directly from the experts, not from someone who happened to apply the expert advice to one patient.
So, if we can’t have a data-driven article until more time passes, and a case report doesn’t offer much value on the topic, where else can clinicians and patients turn to for information about the likely long-term effect of a new treatment? Frontiers in Endocrinology has offered a “perspective” article, entitled “Anticipated effects of burosumab treatment on long-term clinical sequelae in XLH: expert perspectives.” I encourage you to download it here and share it with your clinician if they’re not already a top expert.
The article is pretty much the exact opposite of a case study. Instead of non-expert authors summarizing their experience with a single patient’s iteration of a rare disorder, the authors are a group of top experts from around the world (U.S., U.K., Germany, France, Canada, Chile) essentially sharing their conclusions from their each having treated dozens if not hundreds of XLHers. The article basically lays out these experts’ views of the risk-benefit analysis for long-term burosumab treatment, based on what is currently known, plus what they’ve observed about the progression of the disorder, both before and after this new treatment.
I’m not sure what the scientific community’s reaction is to perspective articles, since the default position is “I won’t believe anything without close to twenty years of data to support it.” But perhaps the sheer number and qualifications of the authors will make at least a tiny little crack in the resistance, which patients can then wedge further open by advocating for themselves and making it clear that they believe (assuming they do) that the benefits are worth taking the risks of pursuing burosumab treatment now, rather than waiting while their symptoms worsen, until all doubts are resolved.
I strongly encourage you to read the article, even though the conclusions won’t be a surprise to anyone in the XLH community. They’re not even particularly controversial conclusions, and are still wrapped in some caution. From the abstract:
Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia [normal phosphorus blood levels] may optimize patient outcomes, although future real-world investigation is required to support this hypothesis.
It’s not as strong a recommendation for routine burosumab treatment as I’d like and as I expect will happen in the future, after all the data is in, but it’s still a significant endorsement of early and ongoing treatment of adults to prevent or at least slow the progression of symptoms. The authors’ expertise ought to carry some weight where hard data is lacking, so I’m really pleased to see these expert conclusions in print, not just shared behind closed doors with those who are fortunate enough to be able to talk to these experts in person. Now it’s up to patients to make sure that the less-experienced clinicians who may be unduly nervous about a new treatment are aware of this article.
I do worry about the discoverability of this article, since it wasn’t listed at PubMed the last I checked, perhaps because it’s labelled a “perspective.” (I hope I’m just being paranoid, and it’s a routine administrative delay, but for now, I’m concerned about discoverability.) Clinicians who don’t subscribe to and pore over every article in Frontiers in Endocrinology won’t find the article by doing a routine search, and those are exactly the clinicians who need to read it.
Remember the marketing line from The X Files? (No, not Twitter, the tv show.) “The truth is out there.” The thing is, it doesn’t matter if the truth is out there, if no one knows about it. The truth about XLH and burosumab treatment is out there, but now it’s up to patients to make sure clinicians know this truth! That’s why I encourage you to download this article, link to it in your social media for those patients who haven’t seen it yet, and share it with any health care providers you think might benefit from it.
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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