Therapeutic plasma exchange (TPE) has the potential to treat digital ulcers and Raynaud’s symptoms in patients with scleroderma, as recently reported by Scleroderma News. Now, the researcher behind the study — Edward Harris of the Scleroderma Education Project, a research fellow at the Department of Medical Microbiology and Immunology, University of Wisconsin, Madison — shared his thoughts on the research in an exclusive interview.
The study, “Therapeutic Plasma Exchange for the Treatment of Raynaud’s and Digital Ulcers in Systemic Sclerosis: A Systematic Review,” recently presented at the American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) 2016 Annual Meeting, was a review of data published between 1978 and 2016 exploring TPE for scleroderma.
TPE is a procedure in which a patient’s blood plasma is removed and replaced by an albumin solution. Researchers believe that it is possible to remove disease-causing factors present in the blood using the method.
As Raynaud’s phenomenon and digital ulcers are common problems in scleroderma, the review specifically focused on these disease manifestations. Out of 40 articles examining TPE for scleroderma, 13 reported assessments of Raynaud’s phenomenon and digital ulcers.
The review showed that among the 13 selected studies, several reported that a single course of treatment — most often one treatment per week for four weeks — improved Raynaud’s symptoms.
The approach also improved digital ulcers, blood flow, and blood vessel parameters, with symptoms often reported to entirely disappear. The included studies also tended to report that the effect of TPE was durable, with a treatment course being effective for at least six months.
Today, treatments used to relieve Raynaud’s and digital ulcers rely on making blood vessels dilate to improve blood flow. According to Harris, it is a strategy that does not impact the cause of symptoms in the first place.
Harris believes that a possible contributing factor to digital ulcers are the clumping of red blood cells, making the blood abnormally thick, or viscous. The clumps of red blood cells block, and ultimately damage, the microscopic vessels in the hands and feet, causing Raynaud’s symptoms and the development of digital ulcers.
Several of the included studies reported abnormally thick blood before the treatment, and a tendency of red blood cells to aggregate more rapidly than what is normal. These measures were improved after the treatment, they reported, supporting Harris’ theory.
Harris has successfully treated his own scleroderma with TPE for the past two decades.
Scleroderma News spoke with Harris about TPE treatment and its effects on the prevention of digital ulcers in Raynaud’s. The interview is provided below in a Q&A format:
Q: On the work recently presented at the ACR meeting, you reported that a single course of a small number of weekly TPE treatments had significant effects on both Raynaud’s phenomenon and digital ulcer symptoms in patients with systemic sclerosis. What is the burden of these symptoms for scleroderma patients?
Harris: First, it is important to understand that digital ulcers are a progression of Raynaud’s rather than a separate symptom. About 95% of patients diagnosed with scleroderma have or will develop Raynaud’s, and about 50% go on to develop digital ulcers.
Several studies have shown that digital ulcers have a major impact on quality of life in scleroderma patients because they can be extremely painful and may become infected, potentially leading to gangrene and autoamputation.
Certain subgroups of patients are more likely to develop digital ulcers. Research has shown that male gender, the degree of nailfold capillary abnormalities, increased erythrocyte sedimentation rate (ESR), anti-Scl-70 antibodies, and earlier age of onset are all correlated with an increased risk of developing digital ulcers.
Q: Can one say that TPE can reverse these symptoms?
Harris: There is not enough solid research to say this with certainty.
At this point, the data is observational rather than experimental. In the studies that noted that after three-to-four weekly TPE treatments, Raynaud’s symptoms frequently disappeared and digital ulcers started to heal, this was not the primary focus of the research, and long-term follow-up of the status of these two symptoms was generally not reported.
However, in the 1991 study by Jacobs, the focus of the research was on the effect of TPE on Raynaud’s symptoms and red blood cell (RBC) aggregation and blood flow. They did a single round of four weekly TPE treatments, and then followed these patients for three years after the fourth TPE treatment.
The researchers found this single course of TPE treatments lead to complete elimination of Raynaud’s symptoms in all 18 scleroderma patients, as well as healing of digital ulcers. At the three-year follow-up, four patients were still completely free of Raynaud’s and digital ulcer symptoms, but in 14 patients Raynaud’s symptoms reappeared after six to nine months following the last of the four TPE treatments. Notably, there was no recurrence of digital ulcers at three-year follow-up in any of these patients.
To fully understand how effective TPE is as a treatment for Raynaud’s and digital ulcers in scleroderma patients, additional studies need to be done with larger groups of patients. It would also be important to see if outcomes are different for patients diagnosed with limited scleroderma versus faster-progressing diffuse scleroderma.
Q: TPE was also found to improve blood flow and blood rheology, namely the patient’s elevated blood viscosity and abnormal aggregation of red blood cells. The improvements reported in both Raynaud’s and digital ulcer symptoms, and also blood rheology, were surprisingly long lasting, persisting for several months. Interestingly you suggested a new mechanism of action for TPE not based on its potential direct effects on blood vessels. Could you briefly explain what is this potential novel mechanism?
Harris: Current treatments for Raynaud’s and digital ulcers work by increasing blood flow through changes in the reactive properties of blood vessels. Vasodilators such as calcium channel blockers (e.g., nifedipine), PDE5 inhibitors (e.g., sildenafil/Viagra), or prostaglandins (e.g., iloprost) work by relaxing the blood vessels and allowing increased blood flow.
Vasoconstrictor antagonists, such as bosentan, work by reducing the tendency of blood vessels to constrict upon exposure to cold. The other current approach is sympathectomy, where either surgery or chemical injections of Botox are used to cut or block the nerves that are involved in the constriction of blood vessels.
There is no known direct effect of TPE on blood vessels, so an alternate hypothesis is needed to explain the elimination or reduction of Raynaud’s and healing of digital ulcers seen following a small number of TPE treatments.
While we do not know the exact mechanism of action, one potential candidate stems from the fact that several studies have documented abnormal blood rheology (physical characteristics of blood) including aggregation (clumping) of red blood cells in patients with scleroderma.
Studies that have looked at the effects of TPE on blood rheology have shown that a few TPE treatments normalizes blood rheology and this effect persists for a significant period of time, about nine months in the Jacobs study.
We do not know if this abnormal clumping of red blood cells is, in fact, the cause of the Raynaud’s phenomenon that is almost universal in scleroderma, but one working hypothesis is that the continuous presence of clumped red blood cells might directly or indirectly lead to the endothelial damage that is the hallmark of early scleroderma and is thought by many researchers to be the key early aspect of scleroderma pathogenesis [disease mechanisms] that eventually leads to all symptoms, including internal organ damage and skin fibrosis.
It is important to note that there are different ways that red blood cells clump together. One way is through “Rouleaux formation,” where red blood cells stack together usually from increased presence of serum proteins such as fibrinogens. Another type of red blood cell clumping, normally referred to as agglutination, occurs when antibodies or complement directly binds red blood cells together. This is known to occur in cold agglutinin diseases, for example, where (typically) large IgM antibodies directly bind to antigens on the surface of red blood cells, leading to clumping that can directly impair blood circulation and can lead to Raynaud’s symptoms.
Unfortunately, none of the papers that have documented the abnormal clumping of red blood cells in scleroderma have described the exact nature of the observed red blood cell aggregation.
Q: How could these findings impact the lives of scleroderma patients?
Harris: In May 2016, I presented a research poster at the American Society for Apheresis annual meeting titled “Therapeutic Plasma Exchange for the Treatment of Systemic Scleroderma: A Comprehensive Review and Analysis.” That review paper concluded that, “In contrast to current treatment modalities such as immunosuppression that carry significant risk and show limited efficacy, the results shown in the clinical studies reviewed for this article suggest that long-term TPE may offer a low-risk way to control and in some cases reverse scleroderma symptoms.”
While additional, well-designed research is needed to validate the potentially efficacy of TPE as a treatment for scleroderma, it is more important to understand exactly why the effects of a few TPE treatments appear to last for many months, which is much longer than would be expected if the beneficial effects of TPE stem solely from a temporary reduction of circulating pathogenic factors, such as autoantibodies.
For example, if it turns out that clumped red blood cells are involved in scleroderma pathogenesis, then it may be possible to develop alternative treatment approaches for scleroderma, including pharmaceutical interventions, that directly target this aspect of the scleroderma disease process. Interventions at this early stage of the scleroderma disease process might prevent scleroderma from ever progressing to later stages, such as internal organ damage and classic skin changes that result from tissue fibrosis.
Q: What do you believe should be the next step on this line of research?
Harris: There are two separate types of research that are needed to examine the issues raised by the body of research on the effects of TPE on patients with scleroderma:
1. While there have been more than 40 published papers on the results of trying TPE to treat patients with scleroderma, ranging from case reports to full clinical trials, no large-scale well-designed randomized control trial has been done on TPE that has looked at long-term results of regular TPE treatments, especially on issues such as whether TPE is equally effective on patients with different scleroderma diagnostic and antibody profiles.
It is inherently not possible to do a full double-blinded study with an intervention like TPE, but some preliminary data suggests that a modified version of TPE, where the patient’s plasma is not replaced by albumin but is instead recirculated back to the patient, may have significant clinical benefit and this could potentially be a control group for this type of research.
Notably, if clinical benefit is seen from this modified procedure, it suggests that the benefits of TPE may not entirely be from the reduction of potential circulating pathogenic factors, but may at least in part stem from the mechanical separation of blood components including disaggregation of clumped red blood cells.
2. Over the past 41 years, many published studies have consistently documented that blood rheology is abnormal in patients with scleroderma. Individual studies have focused on differing aspects of this abnormal rheology, including elevated whole blood viscosity, plasma viscosity, and abnormal red blood cell aggregation.
We need to do additional research in order to understand the nature of this abnormal blood rheology and its potential role in scleroderma pathogenesis.
As part of this goal, our research group recently submitted a proposal to NIH for a pilot study focused on examining blood rheology in a large group of scleroderma patients. The proposed study will compare blood rheology in patients with limited scleroderma versus diffuse scleroderma against age and gender matched control patients with rheumatoid arthritis (RA), as well as against age and gender matched healthy controls.
Interestingly, patients with RA also have elevated whole blood viscosity but do not benefit from TPE treatments, suggesting that these two autoimmune diseases may have very different mechanisms of disease pathogenesis.
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