The Scleroderma Education Project is Expanding Our Mission

Our Mission: Education

Since 1995 my focus has been on providing comprehensive, up-to-date, research-based information on systemic scleroderma diagnosis and treatment written in a language that patients can readily understand.  It is my strong belief that patients who are thoroughly educated about their disease can work more effectively with their team of physicians to make the best possible individual care decisions.

While new information is constantly being added to the Scleroderma Education Project website (SclerodermaInfo.org), we believe that we have achieved many of our education goals.  Our website is now an important resource for patients and others who want to understand more about this complex disease.  On a typical day, more than 500 new people around the world access our website and in the past six months we have had visitors from 164 different countries.

The Current State of Scleroderma Research

Over the past few years, I have become increasingly concerned about the lack of progress in systemic scleroderma (SSc) treatment research.  It is easy to get lulled into thinking that a “cure” is just around the corner, especially if you follow websites such as “Scleroderma News” that monitor research journals and medical conferences that are focused on scleroderma research.  Unfortunately, there are no current treatments that fundamentally alter the course of the disease.  In fact, recent research has showed that relative mortality rates have not improved in the past 40 years! [1].  Yes, patients diagnosed with SSc live significantly longer than they did 40 years ago, but so does everybody else, and that is what appears to account for almost all of the improved survival rates for SSc patients.

While the SSc disease process is not completely understood, most researchers feel that antibodies are involved in disease pathogenesis, either directly or indirectly.  As a result, a lot of current scleroderma research is focused on early stages of the disease process – regulating or suppressing the immune system.  Treatments such as plaquenil and IVIG are designed to “regulate” the immune system, while drugs such as methotrexate, mycophenolate mofetil (Cellcept), cyclophosphamide (Cytoxan), or rituximab (Rituxan) are general or selective immunosuppressants.  Autologous stem cell transplants (HSCT) are also part of this treatment approach.  HSCT works by attempting to “reboot” the immune system in the hope that your immune system will work better the second time around.  It is also possible that after HSCT, you might not be re-exposed to whatever triggered your autoimmune response initially, e.g., a construction worker who might have been exposed to silica dust (a known trigger for systemic scleroderma) in the past but is no longer working in this type of environment.

There is also new research focused on a much later stage of the disease process – fibrosis.  Early stage testing is currently underway for several drugs that are designed to reduce or stop the fibrotic processes that directly lead to systemic organ damage.

From my perspective, immunosuppressant treatments will never be an effective way of treating SSc.  Any time you suppress the immune system, even if there are modest short-term benefits, you are inviting problems that can be quite severe, including increased risk of infections and cancer.  And while the new treatments that are being tested attempt to interfere with late-stage fibrotic processes and may have the potential of reducing or delaying organ damage, it is too early to know if these drugs will be effective or safe for long-term use.  Also, a fundamental issue with this treatment approach is that it is late in the disease process.

Our New Mission: Research

We think there may be a better way to develop treatments for SSc beyond what is currently being researched.  As early as 1979 [2], researchers noted that all symptoms that eventually develop in SSc start with repeated trauma to the endothelial layer that lines the microvascular system.  This eventually triggers the complex fibrotic processes that lead to system wide organ damage.

There are a number of research papers [e.g., 3,4,5,6,7,8] that document that blood in patients with SSc has abnormal physical characteristics (rheology).  There are several different aspects of this abnormal rheology including overall increased blood viscosity (hyperviscosity) and abnormal clumping of red blood cells (RBC).  Consistent with this research, many patients in patient support forums that I am active in have reported that when they first started developing SSc symptoms, lab technicians commented that their blood was too thick and that blood draws were taking much longer than usual.

It is worth noting at this point that other autoimmune diseases such as rheumatoid arthritis (RA) also show increased blood viscosity and RBC aggregation [9].  However, there appears to be something fundamentally different in SSc blood rheology as compared to RA blood rheology.  One of the best indications of this stems from several studies that have demonstrated that therapeutic plasma exchange (therapeutic apheresis, TPE, plasmapheresis), significantly reduces symptoms in patients with systemic scleroderma but has no effect on patients with RA [5,7,10,11].  TPE is a procedure that mechanically separates blood into plasma, red cells, white cells, and platelets using a centrifugal separation process.  The plasma component is replaced, typically with sterilized albumin that contains no antibodies or other potentially harmful circulating blood components, and the albumin plus separated blood cells are then returned to the patient in a process that typically takes about 90 minutes.

How TPE works in various diseases is not completely understood.  What is known is that in patients with SSc, the effects of a few TPE treatments are often dramatic (Raynaud’s symptoms are eliminated and digital ulcers begin to heal) and these effects are very long lasting, typically six months or longer [5,7,12,13].  What is also known is that a few TPE treatments also normalize blood rheology in patients with SSc, eliminating RBC clumping and overall increased blood viscosity.  This effect is also surprisingly long lasting, around nine months in one study [7].

It is our working hypothesis that what is leading to the repeated trauma to the endothelial layer of the microvascular system is the abnormal blood rheology itself.  We do not understand the mechanisms of this damage, but if our hypothesis is correct, then any treatment that eliminates the abnormal blood rheology and is able to maintain normal blood rheology over time will prevent SSc symptoms from ever developing in the first place if started early enough.   If treatments that maintain normal blood rheology are started later, they should stop additional symptom progression and in some cases the body may be able to self-repair if organ systems are not too badly damaged.

While we believe that a well-designed clinical trial of therapeutic plasma exchange is justified based on previous research [14], this type of research requires significant funding and is beyond the scope of the basic research that we are trying to support.  Here instead are two initial, relatively inexpensive research projects we believe are critical in understanding the role (if any) that abnormal blood rheology plays in SSc pathogenesis:

  • Examining blood rheology in two groups of SSc patients: 1) limited SSc (anticentromere antibody positive), versus 2) diffuse SSc (Scl-70 antibody positive); comparing these two groups against age and sex matched normal controls and age and sex matched rheumatoid arthritis patients. If our disease hypothesis is correct, patients with these two variants of SSc should exhibit significantly different blood rheology profiles and these should be different from RA patients and normal controls.  We have submitted a proposal to NIH to obtain funding for this key study.
  • Understanding the biomechanics of the observed red blood cell clumping, well documented in SSc patients. There are two known ways that RBC clump together: aggregation and agglutination.  At this point we don’t know if the observed RBC clumping results from one of these processes or if something else completely different may be going on.  Determining the exact nature of the RBC clumping may help us to figure out if this aspect of abnormal blood rheology in SSc patients may be directly or indirectly leading to the endothelial damage, and if so, may give us specific targets for new therapeutic interventions.

Note: these proposed research studies will be done in partnership with the University of Wisconsin in Madison.

Coming Soon: A Completely Redesigned Website!

Over the next several months, we will be completely redesigning the Scleroderma Education Project website to better support our new focus on targeted scleroderma research in addition to our educational focus.  The educational portion of the website will be redesigned to make it even easier to navigate.  We will also be adding a completely new research section to the website. This new section will greatly expand upon the ideas that are presented briefly in this paper.  Once the new website is complete, we will begin fundraising in support of our new research focus.  If you have experience in fundraising and/or would like to help, please contact Susan Kwolkoski, Director of Communications, at susan@sclerodermainfo.org.

For additional information about the Scleroderma Education Project and our educational and research goals, contact:

Ed Harris
CEO
Scleroderma Education Project Ltd
eharris@sclerodermainfo.org

Research Fellow
Dept. of Medical Microbiology and Immunology
University of Wisconsin, Madison, USA
eharris5@wisc.edu

References

  1. Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012;51(6):1017-1026. doi:10.1093/rheumatology/ker269.
  2. Kahaleh MB, Sherer GK, LeRoy EC. Endothelial injury in scleroderma. J Exp Med. 1979;149(6):1326-1335.
  3. McGrath MA, Peek R, Penny R. Blood hyperviscosity with reduced skin blood flow in scleroderma. Ann Rheum Dis. 1977;36(6):569-574.
  4. Dodds AJ, O’Reilly MJ, Yates CJ, Cotton LT, Flute PT, Dormandy JA. Haemorrheological response to plasma exchange in Raynaud’s syndrome. Br Med J. 1979;2(6199):1186-1187.
  5. Weber H, H S-S, J LHA. Plasmapheresis as a Treatment of Raynaud’s Attacks: Microrheological Differential Diagnosis and Evaluation of Efficacy. Clin Hemorheol Microcirc. 1985;5:85-97.
  6. Jacobs MJ, Breslau PJ, Slaaf DW, Reneman RS, Lemmens JA. Nomenclature of Raynaud’s phenomenon: a capillary microscopic and hemorheologic study. Surgery. 1987;101(2):136-145.
  7. Jacobs MJ, Jörning PJ, Van Rhede van der Kloot EJ, et al. Plasmapheresis in Raynaud’s phenomenon in systemic sclerosis: a microcirculatory study. Int J Microcirc Clin Exp. 1991;10(1):1-11.
  8. Volkov S, Utset TO, Schmitz A, Ellman M, Cao D SN. Whole Blood Viscosity (WBV) and Digital Ulcers in Scleroderma Patients. In: ACR/AHRP Annual Scientific Meeting. ; 2006:F56.
  9. Gudmundsson M, Bjelle A. Viscosity of plasma and blood in rheumatoid arthritis. Br J Rheumatol. 1993;32(9):774-779.
  10. Dwosh IL, Giles AR, Ford PM, Pater JL, Anastassiades TP, Group and the QUPS. Plasmapheresis Therapy in Rheumatoid Arthritis. N Engl J Med. 1983;308(19):1124-1129. doi:10.1056/NEJM198305123081903.
  11. Shaz BH, Linenberger ML, Bandarenko N, et al. Category IV indications for therapeutic apheresis—ASFA fourth special issue. J Clin Apher. 2007;22(3):176-180. doi:10.1002/jca.20131.
  12. O’Reilly MJ, Talpos G, Roberts VC, White JM, Cotton LT. Controlled trial of plasma exchange in treatment of Raynaud’s syndrome. Br Med J. 1979;1(6171):1113-1115.
  13. Ferri C, Bernini L, Gremignai G, et al. Plasma exchange in the treatment of progressive systemic sclerosis. Plasma Ther Transfus Technol. 1987;8(2):169-176. doi:10.1016/S0278-6222(87)80026-8.
  14. Harris E, Moriarty P, Meiselman H. Therapeutic plasma exchange for the treatment of systemic scleroderma: a comprehensive review and analysis. J Clin Apher. 2016;31(2):122.
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