The XLH community (there really isn’t an official community for TIO or the other genetic hypophosphatemias that I’m aware of) has done some really great work, like the International XLH Alliance’s annual symposiums of hypophosphatemia, but there are a lot of projects that no one seems to be working on. So, in lieu of resolutions for 2023, I’ve got some pre-resolutions, things we could be doing but aren’t.
What am I talking about? Here are some examples of what I think the community needs, but isn’t committed to doing or doesn’t have the necessary volunteers for:
Clear, consistent, joint messaging on how conflating XLH (and other genetic hypophosphatemias) with rickets is both wrong and harmful to patients. There’s absolutely no reason why clinicians/researchers should still be calling a phosphate-wasting disorder a “form of rickets,” or, even worse, still using the Vitamin D Resistant Rickets terminology, when we’ve known for something like fifty years that it’s the phosphorus, stupid, and it affects more adults than kids (although kids have time-sensitive needs for treatment). It’s lazy and wrong and harmful. Clinicians/researchers should be ashamed of themselves for perpetuating this bad science, and patient advocates should call them out on it at every possible opportunity until it’s no longer easy for them to use the bad terminology. I thought it was getting better, but then there was a spate of journal articles, all using the “rickets” misnomer, including articles specifically about adult patients.
A campaign to bring phosphorus back to the list of standard labs for toddlers. Phosphorus used to be one of the standard orders for pediatricians and was dropped at some point. Bringing it back would increase the odds of catching spontaneous cases of chronic hypophosphatemia earlier, allowing earlier treatment, which is particularly critical now that we have a truly effective treatment. There’s no real down side to this test either; it’s cheap, and when added to an existing blood draw, not particularly invasive. Delays in diagnosis, especially for spontaneous cases, is something else the medical community should be ashamed of — with all the advances we’ve made in medicine in the sixty-plus years since I was diagnosed at three years old, there’s been no change in the typical age of diagnosis for spontaneous XLH, which is still around three years old. Phosphorus tests done in the first six months, even up to a year, are highly unreliable, due to fluctuating phosphorus levels, so it can’t be added to newborn testing, but a test around twelve months of age would immediately highlight the abnormal blood phosphorus levels. Then we could add a patient-driven campaign to help pediatricians recognize the problem. Something like “Phos low? Oh no! Call an endo!” Otherwise, pediatricians might disregard it as a glitch in the testing, rather than an indication of a problem.
Take advantage of the power in numbers. From what I’ve seen, many of the rare bone disorders share a number of lived experiences, regardless of the biochemistry differences. There is a Rare Bone Disease Alliance that produces some good educational programs, but it doesn’t actually do any advocacy or really leverage the power of its member organizations. Among the many useful things it could be doing is a combined registry for all rare bone disorder patients and encouraging research across the bone disorders, not just within a single rare or ultra-rare disorder. While some research, especially the search for a cure, needs to be tied to a specific disorder, other important insights could come from looking at the commonalities of the patient experience. Whenever I attend a rare disorder event where other rare bone disorders are represented, I’m struck by how much we share when it comes to (not) being heard by clinicians, dealing with chronic pain, and coping with career/social/emotional/family challenges. We could learn a lot from each other, but the members of our communities hardly ever interact.
Demand to be heard by Institutional Review Boards. Researchers (and pharma) bemoan the difficulties of recruiting patients for clinical trials, but they should look to themselves for at least part of the patient resistance. Patients (and their advocates) are generally excluded from the development of the protocols, and even from commenting on the protocols before they go into effect, despite having the expertise to make those protocols more patient-friendly. What the researcher may think is an “easy” requirement for participants in the study may in fact be burdensome for those participants, but the researcher will never know that that’s why they can’t recruit enough patients. If we set the process up so that patients feel that their concerns (either directly or through their advocacy group) are being heard by the researcher and accommodations are being made for them, then patients may be more willing to participate. As it stands, the relationship between principal investigator and patient-volunteer is less of a partnership than a situation where a strict parent is demanding that a child follow the house rules or move out. That attitude leads to rebellion, and patients, unlike children, can move out easily by simply not enrolling in a study.
Let the journal editors know when they’re publishing materials that are harmful to patients. Yes, I’m talking about the rickets nomenclature again. But there are other examples, like the article I wrote about last year when a clinician advocated reserving state-of-the-art treatment for only those who have “severe” symptoms (despite the lack of any objective test, and the inability to see into the future to know which patients’ relatively mild visible pediatric symptoms will morph into severely disabling ones in adulthood if not given state-of-the-art treatment early in life). And the growing consensus (that I believe goes against what we patients/parents know about the value of early treatment) that it’s okay to start patients on an old treatment that offers mediocre results, at best, and then transition to the state-of-the-art treatment only if the old treatment fails completely (rather than simply offering less benefit than the better treatment). Why are we sitting back and accepting these bad pronouncements from respected journals? We need to push back, push back again, and then push back some more until we’re truly heard.
Demand a presence on peer review panels. Patients have some power here that we’re not using. There’s a lot of research happening on XLH and ENPP1 and FGF23 these days. And journal editors are receptive to articles on those topics, but they don’t have reviewers who are capable of doing the peer review thoroughly (and they depend on those reviewers to know more about the details than the editors know, which isn’t always true, especially when it comes to the patient experience). I recently read a published article that was littered with errors (like the assertion that male XLHers are more severely affected than female XLHers, for which there is zero evidence, just old theories that have not been tested with a comprehensive natural history study). And yet this article, full of scientific errors that are easily spotted even by non-scientists, was published. Part of the problem for rare disorders like XLH that are best known as pediatric disorders is that there aren’t many experts on the adult manifestation of the disorder. So what happens is that the author, who specializes in pediatric cases, gets something wrong due to inexperience with adult patients, and then the reviewing panel, which is also exclusively composed of pediatric experts because there are so few adult experts, can’t see the error, because they don’t treat adults. Having a knowledgeable patient on the review panel, someone who is familiar with both the pediatric and adult manifestations, could point out those blind spots.
Prepare for gene therapy. No one (except me) is talking about gene therapy in the chronic hypophosphatemia community. It’s the future of treatment for genetic hypophosphatemias, and the whole field is complicated, both scientifically and possibly ethically in some situations (like recruitment for clinical trials), which is why we need to be educated about it. There is ongoing research into gene therapy that essentially trains the body to produce a burosumab-like antibody, so at least in theory, a child could be treated once, and be all set for life instead of requiring monthly injections. Which would be great! But what if, along the way, before that option becomes available, other researchers finally figure out what it is that triggers the overproduction of FGF23 in the bones, so there’s a way to stop the excess before it even happens? And what if there’s a gene therapy that will shut down that trigger? Wouldn’t that be preferable? Keep in mind that the two gene therapies would likely be incompatible — once a patient has basically had a lifetime of FGF23 antibody built into their bodies, they can’t then undergo treatment to stop the overproduction of FGF23 in the bones, because then we’d end up with low FGF23 (the normal amount of FGF23 allowed by the bones would then be reduced by the antibody at the kidneys), which could result in too much phosphorus going into the blood. So, do we go for the incomplete treatment that will likely be available sooner, or do we hold out for a more complete treatment that may take decades to be available? Gene therapy holds great promise, but it raises all sorts of complicated issues for patients, as well as clinicians/researchers, which is why we need to be learning about it now.
How are we supporting access to state of the art treatment? The XLH Alliance members are working hard behind the scenes to encourage their regulating agencies (the ones that decide whether to pay for treatment, rather than whether it’s safe and effective) to approve payment for burosumab for both kids and adults, but the patient advocates are facing a lot of headwinds. Some of the resistance to providing access, I believe, goes back to the persistent belief that XLH is just a pediatric bone disorder, and if a patient’s bones are straight by the time their growth plates close, then they’ll go on to have perfectly normal health, other than being short, for the rest of their lives, no further intervention needed. There’s plenty of evidence that that’s not true, and I think the deciders at the agencies know, logically, that it can’t be true, but they’re so used to thinking of XLH as a pediatric bone disorder that they can’t quite believe that the adult symptoms are as severe and widespread as we say they are. We need to do more to advocate for state-of-the-art treatment for all patients, not just the lucky few who, in the US, have good insurance (in the U.S.), or have convinced their government (in social medicine countries) to provide treatment for patients of all ages, not just to kids.
Miscellaneous. And then there are projects like producing guidance documents for disability claims to help the reviewers understand how chronic hypophosphatemia affects patients’ ability to work or do other daily activities. Or creating a comprehensive natural history study that includes all of the chronic hypophosphatemias. Or establishing centers of excellence. Or establishing a standard of care that has patient input. Or sponsoring continuing medical education. Or encouraging more endocrinologists with adults-only practices to take on adult hypophosphatemia patients.
Of course, to do these projects requires money and volunteers. I don’t generally believe in “build it and they will come.” It’s a terrible model for capitalist ventures, but I do think it works in the nonprofit setting. The process for patient-advocacy groups is to choose a project, establish an action plan and budget, and then if it gets support (through grants and individual donors), you know it’s something worth pursuing. Once you have a project worth pursuing, plus the money to do it, and an action plan, you know what volunteers you need and can advertise for them.
But it all comes down to choosing a project and committing to it. What project(s) do you think our communities need to do first? Did I miss an important project that would improve your (or your children’s) life, but that no one’s working on?
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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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