New Guidelines Aim to Advance Plasma Exchange as Scleroderma Therapy

The Scleroderma Education Project recently released guidelines for patients and doctors wishing to know more about therapeutic plasma exchange (TPE) as a treatment option for limited scleroderma. The guidelines are designed to facilitate data collection to support the launch of a randomized clinical trial, and follow the same setup as a recently published case report describing the successful 22-year repeat treatment of a patient with limited scleroderma.

By following the guidelines, a physician who decides to use TPE with a scleroderma patient will allow researchers to pool and analyze data from that individual trial. This way, scientists can determine if a randomized clinical trial should be performed.

TPE is a procedure where the blood is taken out of the body, followed by a separation of all the blood cells and proteins from the liquid phase of the blood, called plasma. The plasma is discarded and replaced by a plasma substitute. The main purpose of the technique is to remove potentially harmful circulating factors, such as antibodies, from the plasma.

Doctors applying the guidelines in using the approach are urged to follow a protocol where treatments are given in a pulsed manner — one TPE treatment per week for four weeks, followed by eight weeks of rest. This is to be repeated for a total of 16 TPE treatments over a period of 48 weeks.

Before starting the TPE treatment, physicians are also advised to test which autoantibodies a patient has, and perform lung function tests. Lab test of both blood and urine should also be performed, and doctors are urged to give the Scleroderma Health Assessment Questionnaire to patients. Physicians should then repeat the tests at the start and end of each four-week treatment period.

Patients wishing to test the treatment should stay on their medication while attempting TPE, ideally keeping the same dose, or lowering it during the treatment period. If a patient responds well to the treatment during the first trial year and decides to continue the treatment, it might be worth considering tapering other drugs.

TPE’s safety is good, with most side effects being mild and limited to the hours following treatment. Low blood pressure and fatigue are the most common. A large study of 4,857 TPE treatments concluded that side effects appeared in 4.75% of cases, and a vast majority were mild. Five cases of allergic reactions were reported in the study, but were linked to the use of fresh-frozen plasma, rather than the plasma substitute recommended by the Scleroderma Education Project.

Not all patients are suitable to undergo TPE treatment. Patients who have a blood infection, circulation problems, low calcium levels, or have had an allergic reaction to plasma earlier are advised not to attempt TPE treatment. Also, the guidelines recommend that patients who are allergic to heparin should not use heparin as an anticoagulant during TPE treatment.

Patients who have significant kidney disease should also not attempt the treatment, since it has not been found effective in such patients and other, more severe side effects are possible because of the lower kidney function.

Any patients considering trying TPE should be fully aware that the treatment is currently considered an experimental procedure for treating scleroderma; they should carefully review and discuss the potential risks involved in the treatment with their physicians before attempting such therapy.

If the treatment is found to be of benefit during the 48-week period, and the patient decides to continue with the treatment, he or she needs to be aware that regular treatments are needed to sustain the effects. This can be a costly undertaking, and many health insurers might not cover the treatment. Medicare guidelines for using TPE, however, indicate that the treatment is an approved procedure for: “Treatment of life-threatening scleroderma and polymyositis when the patient is unresponsive to conventional therapy.” Insurance companies following Medicare guidelines for non-standard treatment might agree to cover the cost.

The idea behind TPE, which has been used for various autoimmune conditions, is that the plasma contains autoantibodies and other harmful factors driving disease. By replacing the plasma, the factors are removed, and disease progression is slowed or stopped. In scleroderma patients, researchers have noted that the treatment also reduces the increased viscosity, or thickness, of the blood.

In fact, the observation that the treatment reduces blood viscosity by preventing red blood cells from sticking to each other led the authors of the recent case report to launch a new theory about scleroderma. The hypothesis states that it is the clumps of red blood cells that damage the smallest blood vessels, producing scleroderma’s symptoms.

The proposed clinical trial, now in an early planning stage, will include only patients with limited scleroderma who test positive for anticentromere antibodies, and who do not have any major internal organ involvement.

This limitation is set to give the trial a greater chance of success at detecting differences between treated and placebo groups. Some reports have indicated that plasma exchange might not be as effective in diffuse scleroderma as in the limited type of disease. In case an initial clinical trial offers good results for limited scleroderma, a trial to explore the treatment in patients with diffuse disease can be considered.

In July, Scleroderma News interviewed Edward Harris, founder of the Scleroderma Education Project and himself the patient in the published long-term case report. “We are working with several patients who are actively considering trying therapeutic plasma exchange with the support of their physicians,” said Harris in the interview. “Upon request, we have prepared a document that suggests standardized guidelines for an initial one-year trial of therapeutic plasma exchange. The purpose of these guidelines is to foster the use of a standardized protocol for administering therapeutic plasma exchange along with suggested testing before, during, and after the therapeutic plasma exchange trial. If physicians follow these guidelines, this will greatly facilitate data gathering and analysis that will help shape a proposed full clinical trial of therapeutic plasma exchange.”

“In June of this year, the American Society for Apheresis published the latest edition of its research-based guidelines for the use of TPE for treating many different diseases. Systemic scleroderma is currently classified as a Category III disease, indicating that the current published research on the effectiveness of TPE is unclear and that physicians need to make an individual determination as to whether they feel that TPE may be a suitable treatment option for a particular patient. While a recent review (Harris et al. 2016) of the published research on the use of TPE for treating systemic scleroderma suggests that TPE may be beneficial for at least some scleroderma patients, a carefully done clinical trial is needed to fully evaluate the efficacy of TPE for treating patients with systemic scleroderma,” Harris said recently to Scleroderma News.

“Any physician who reviews the published research on the use of TPE for treating systemic scleroderma will quickly learn that TPE has been used in many different ways in different studies, sometimes as the sole systemic treatment and in other cases as an adjunct to conventional treatment with immunosuppressant drugs. This new guidelines document suggests a research-based protocol for physicians to consider if they decide to try TPE with one or more of their systemic scleroderma patients, as well as several standardized objective measures that will both allow the physicians to gauge how well the TPE treatments are working and also to allow researchers to learn from these individual trials of TPE,” Harris added. “Full clinical trials are always needed to determine if a treatment approach is effective and without side effects that may limit its use. However, if individual trials of a treatment such as TPE are done in a consistent manner, we can obtain important preliminary information that may help to shape future clinical trials as well as provide important information to other physicians who may also choose to try TPE before a full clinical trial is completed and the results published — a process that can take several years.”

The TPE Guidelines document is available by contacting Ed Harris at [email protected], or by going to the Scleroderma Education Project website.