Last week I attended the 2016 annual meeting of the American Society for Apheresis (ASFA) in Palm Springs, CA and presented a research poster titled “Therapeutic Plasma Exchange for the Treatment of Systemic Scleroderma: A Comprehensive Review and Analysis”. The poster was well received, I was able to meet with vendors and others that are important to my research, and overall it was a very successful and important meeting for me to attend.
I know that many of you are closely following my writings on the potential use of therapeutic plasma exchange (TPE or sometimes called plasmapheresis) as a treatment for systemic scleroderma as well as the rationale for using TPE. Now that the research poster has been officially presented, I am free to post more information about this topic. As a side note, I recently learned that the news service “Scleroderma News” is planning on doing a feature story on this poster in the near future.
So what is this study about and why is it important? The study is a comprehensive review of all of the published research that has been done on using TPE to treat systemic scleroderma (or probable systemic scleroderma in some of the earliest studies). This has never been done before. One major reason for this is that clinicians and even scleroderma researchers have no idea that more than a couple of studies have actually been published about using TPE to treat scleroderma! This is part of an email sent to me in June 2014 statement by the Scleroderma Foundation’s Medical Advisory Board:
“One small open label trial looking at whether plasmapheresis had utility in scleroderma was performed and published in 1991 and showed some improvement in Raynaud’s and digital ulceration with plasmapheresis.”
In contrast to this statement, I reviewed 40 published research papers dating from 1978 to 2015 that included a total of 533 patients. Obviously, there is a huge knowledge gap on the part of many top scleroderma researchers with regard to this topic.
But there is actually a second important aspect of this review paper that may ultimately be more important than the results of trying TPE as a treatment option for systemic scleroderma. As you might expect, pretty much all of the studies showed positive results from trying TPE, whether as a treatment for a crisis situation or a long-term treatment. In reality, very few researchers publish negative results, so that in itself is not surprising.
However, in reviewing all of the literature, it quickly became clear that there is a fundamental problem with some of the research results. Ironically, the problem is that a limited number of TPE treatments appear to work too well and for too long, at least if you accept the stated rationale for trying TPE in the first place! That stated rationale is that the benefits that are seen from TPE treatments occurs because TPE temporarily removes some circulating blood factor that is presumably involved in the development of scleroderma symptoms, for example, autoantibodies. (And in fact, that is definitely the case when TPE is used to treat some other disease, for example, Guillain-Barre syndrome.) Because of this “problem”, a significant portion of the review paper is actually focused on a potential new (actually first proposed in 1993) disease model for systemic scleroderma that may well explain the unexpected longevity of the positive results from TPE treatments in scleroderma patients.
Digression: About Medical Research
Before I talk about the paper and the ASFA conference, let me start by first explaining a bit about how medical research gets published. In recent years, it is very common for researchers to start by presenting a summary of their research in poster format at a medical conference. As an example, last October I presented my own case report at the AABB conference in Los Angeles. It is actually fairly easy to get posters accepted for research conferences. They are not formally peer reviewed and just need to pass the muster of a review committee to make sure that the topic is appropriate and the research that is presented makes sense. What begins this entire process is the submission of a short abstract. The poster is an expanded version of the abstract. In most cases, the abstract is formally published in a special issue of a research journal associated with the conference but the poster itself is usually not made available in print form or formally published online.
The vast majority of posters are never turned into actual research papers. It takes a lot of time and effort to write a formal research paper and even more work to go through the peer review process. It is not uncommon to get rejected by one or two research journals before the manuscript is accepted. Even then, you often have to go through several rounds of revisions before you get final sign off on the paper and it is ready to be added to the queue of papers that have been accepted for publication. This can a long time, sometimes a year or longer from start to finish.
The ASFA Conference
With that background information, let’s return to the ASFA conference and the poster I presented. For those of you curious to see what a typical research poster looks like, here is a link to the actual poster (which was 48” x 96” in size): http://sclerodermainfo.org/pdf/ASFA-Poster.pdf. Don’t bother to try to print it – it won’t be readable in print form, but you might find it useful to read it online as a first step.
What I did for this conference was to prepare a much more detailed handout that was made available to interested attendees. This is not typically done but I had important reasons for doing so, which I will explain below. I actually ran out of copies of the extended handout fairly quickly (I brought 25 copies of the handout), which was a good sign that people were interested in the topic. Here is a link to download this detailed handout version of the poster: http://sclerodermainfo.org/pdf/ASFA-Handout.pdf. Even though this handout is intended for an audience of medical professionals, I wrote it in a way that should be understandable by anyone here.
Next Steps for the Research Paper
The next step for this poster and handout is to turn it into a formal research paper and submit it for publication. There is a huge difference in how posters are viewed in the research world and how peer-reviewed research is viewed. Because of the potential importance of this paper, our plan is to submit it to a suitable rheumatology journal rather than a journal focused on therapeutic plasma exchange like the Journal of Clinical Apheresis, where the abstract is published. Normally the way this is done is to pick an initial journal (you can only submit a paper to one journal at a time), focus the research paper for the target audience, format it to their unique requirements, and then submit it for review, hoping that it will make it through the initial screening process where the senior editors figure out if it is even appropriate for that journal. Even getting rejected at this initial stage can take a few weeks.
In order to shorten the review cycle, I decided to try a different approach. I identified seven potential rheumatology journals that are highly regarded and appear to be a good fit for this review article. I then managed to track down the email address of the senior editor of each of these journals (which can be challenging to do in itself) and sent them an email along with the extended version of the handout. I asked them to take a quick look at the handout and let me know if it would be a good fit for their research journal, as I didn’t want to waste their time or my time. I did this a few days ago and I have already had responses from five of these journals, three of which are very interested in receiving the paper for review. The other two indicated the paper would not be a good fit. While this is only the first step, this is a very good sign that there is definite interest in this topic and that there is a reasonably good chance that it will be published at some point in the future.
About TPE and Diffuse Systemic Scleroderma
If you read the review paper and look at the discussion of a proposed clinical trial to determine the efficacy of TPE for treating scleroderma and also to determine if the underlying we disease model hypothesis is correct, you will notice that the initial clinical trial will be restricted to patients who have a diagnosis of limited systemic scleroderma and are positive for anticentromere antibodies. The reason for this is explained in the article. Because of this proposed restriction in the initial clinical trial design, I was asked a couple of times at the ASFA conference whether or not TPE would be helpful in patients with diffuse systemic scleroderma.
In reality, the majority of the research on using TPE to treat scleroderma has actually been done with diffuse scleroderma patients and usually showed positive results unless it was very late in the disease process. However, in most cases, patients were also on immunosuppressants and TPE treatments were considered as an add-on treatment, complicating the interpretation of whether or not the benefits were directly from the TPE or some possible interaction between TPE and the immunosuppressants. In Europe, unlike the US, TPE treatment is actually used fairly frequently to treat scleroderma patients. For example, a clinical/research group in Italy has treated more than 200 patients using TPE with good results and almost all of these patients had diffuse scleroderma. However, almost all of these patients were also on immunosuppressants. The clinical improvement in these patients was seen after an initial round of fairly frequent TPE and then the patients have been maintained by one treatment every two to three weeks, depending on the patient.
Because of this, the question of how effective TPE treatments alone would be with patients with diffuse scleroderma is currently unknown. However, there is no reason why TPE can’t be used with immunosuppressants, as is being routinely done in Italy. If TPE is added to a treatment regimen that is based on immunosuppressants and the patient’s symptoms improve, it may be from the TPE or it could be an interaction between the two treatments. The only way to tell for sure would be to stop the immunosuppressants to see if the improvements were maintained.
The bottom line is this: there is one case report that documents that TPE alone was a very effective long-term (22 year) treatment for a patient with limited scleroderma (Weiss et al. 2015). This lends support to the possibility that TPE treatments alone may be effective in other patients with anticentromere positive limited scleroderma.
In contrast, long-term TPE alone has not been tried with any patient with diffuse scleroderma, so it is currently impossible to know if TPE alone would be equally effective in this patient population. The research certainly suggests that TPE is likely to be helpful as an adjunct treatment for patients with diffuse scleroderma, but anything beyond would be pure speculation until additional research is done.
If you have any questions or comments, please post them here so others can benefit from any additional discussion of this new research paper.