TPE has been tried as a possible treatment for SSc since 1978. While TPE is rarely used as a treatment modality for SSc in the United States, it is more commonly used in Europe and is a mainline, government-approved treatment option in Italy. 5 Medicare and some US healthcare companies cover TPE as an available treatment option for SSc patients who are unresponsive to conventional therapy. 6 The American Society for Apheresis (ASFA) currently classifies TPE for treating SSc treatment as a Category III treatment: “Optimum role of apheresis therapy is not established. Decision making should be individualized.” 7 Our impression is that clinicians and researchers who work with SSc patients are largely unaware that a large volume of research has been published about the use of TPE as a treatment for SSc.

The usual rationale and the primary post hoc explanation for any benefits seen from TPE is that TPE treatments temporarily reduce the levels of circulating factor(s) (e.g. autoantibodies or immune complexes, cytokines, or adhesion molecules) that are presumed to be involved in SSc disease pathogenesis. A single TPE treatment of 1–1.5 blood volumes removes approximately 65% of any potential circulating pathogenic factors. 3 It is important to note that certain plasma components are also present in the extravascular space, so post-TPE plasma concentrations may be different than expected due to tissue–plasma equilibration. 4

Therapeutic plasma exchange (TPE), also called therapeutic apheresis, is a procedure in which a large volume of plasma (typically 1–1.5 blood volumes) is replaced by a substitute fluid (most commonly 4%–5% sterilized albumin) in a continuous flow process. Cellular components (RBC, WBC, and platelets) are separated from the plasma by either centrifugal separation or filtration, combined with the replacement fluid and returned in a process that typically takes 1.5–2 h. In the United States, almost all TPE is done using centrifugal separation. A related procedure—plasmapheresis—removes a smaller amount of plasma (typically less than 15% of blood volume) that is inadequate to cause significant hypovolemia, so no replacement fluid is required. Unfortunately, the terms “therapeutic plasma exchange” and “plasmapheresis” are often used interchangeably in the published literature, creating potential confusion when researching the effects of TPE.

Management of SSc is usually done through a combination of systemic and symptom-specific interventions. Standard systemic treatments focus on immunoregulation (hydroxychloroquine or intravenous immunoglobulin (IVIG)) or immunosuppression (methotrexate, mycophenolate mofetil, cyclophosphamide, and rituximab). Raynaud’s phenomenon (RP) and digital ulcers (DUs) are almost universal in SSc and are treated with a variety of approaches, including vasodilators (calcium channel blockers, phosphodiesterase type 5 (PDE5) inhibitors, and prostaglandins), vasoconstrictor antagonists (endothelin-1 and angiotensin II receptor antagonists), or, in more severe cases, surgical or chemical sympathectomy. GI symptoms, such as gastroesophageal reflux disease (GERD), gastroparesis, malabsorption, and small intestinal bacterial overgrowth (SIBO), are managed through a variety of mostly pharmaceutical treatments although surgical interventions are sometimes employed in severe cases. Scleroderma renal crisis (SRC) is generally treated with ACE inhibitors. To date, no medications have proven to be very effective in treating either pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD), and as a result, lung-related complications from both PAH and pulmonary fibrosis (PF) are the leading causes of SSc-related mortality. 1 According to a recent study, 2 it is not clear that any standard treatment for SSc has led to improved SSc survival rates over the past 40 years, beyond what would be expected by overall improvements in survival rates in the general population during this same time period.

There are two recognized subsets of SSc: diffuse cutaneous systemic sclerosis (dcSSc) and limited cutaneous systemic sclerosis (lcSSc). Patients with dcSSc generally have rapid onset of symptoms and significantly reduced survival, mostly due to lung, heart, and kidney involvement. In contrast, patients with lcSSc typically have a much slower progression rate with near normal lifespans but with increasing disability and disfigurement over time.

Systemic sclerosis (SSc) is an umbrella term for a family of rare autoimmune diseases with the common factor being abnormal skin fibrosis and thickening in association with Raynaud’s. While the degree of skin fibrosis varies depending on the specific disease variant, all forms of SSc include dysregulation of the immune system and extensive microvascular injury leading to fibrotic damage to internal organ systems, including the lungs, gastrointestinal (GI) system, kidneys, and heart.

Each article was independently graded by authors E.S.H. and M.M. using standard checklists for the appropriate article category, as is shown in Table 1 . Any differences in grading were resolved by discussion. We also reviewed each article to determine whether any observed treatment effects could reasonably be attributed to TPE alone. A number of studies listed additional simultaneous interventions along with TPE, making it impossible to determine whether any observed effects were from TPE, alternative treatments, or synergistic effects from multiple simultaneous treatments.

Initial searching (using the above search phrase) was done using Google Scholar during November and December 2015 in preparation for an abstract that was presented as a poster at the ASFA meeting in May 2016. 8 For all articles that met our inclusion criteria (original research, English abstract), we reviewed all of the references and included any additional articles that had been missed in the original search. An updated search that also included PubMed/MEDLINE, Scopus, and the Cochrane Library was conducted in September and October 2017.

(plasmapheresis OR “plasma exchange” OR apheresis OR “plasma filtration”) AND (“systemic sclerosis” OR SSc OR scleroderma OR Raynaud’s OR PSS OR CREST OR (“mixed connective tissue” AND (disorder OR disease) or MCTD)

TPE was very well tolerated by almost all patients. Adverse events were rare and, in almost all cases, mild, with no reported deaths.

While the effects of even a few TPE treatments often lasted for several months, only continued long-term treatments resulted in stabilization of symptoms or, in one recent CR, sustained remission over a 22-year period.

In almost all studies, the majority of patients receiving TPE showed improvements in both symptoms and laboratory markers, whether in short-term treatment of crisis situations or from long-term administration of regular TPE.

TPE safety and venous access issues are discussed more fully later in this article. Table 7 lists all of the reported TPE-related complications in the reviewed articles.

Of the 46 papers, 11 reviewed for this article described complications directly related to the use of TPE. There were two main types of complications: (1) venous access issues and (2) short-term side effects directly associated with the TPE procedure. There were no reported fatalities associated with TPE, and short-term side effects were generally minor and usually did not prevent TPE from being completed. In one early study, 21 4 patients (out of 40) had allergic reactions. This primarily occurs only when fresh frozen plasma is used instead of sterilized albumin. In a small percentage of the cases, venous access difficulties prevented TPE from being performed using the preferred method of peripheral venous access, leading to cessation of TPE. In other cases, implanted central venous catheters were used for short-term TPE or an arteriovenous fistula was surgically created for long-term TPE.

A 2017 very long-term (22-year) CR 40 documented the effects of regular TPE as the sole systemic intervention in a patient with rapidly progressing anti-centromere-positive lcSSc. TPE was administered in a pulsed protocol (one TPE treatment per week for 4 weeks and 8 weeks with no TPE, and the procedure was repeated). All symptoms (except for very mild residual Raynaud’s), including reduced diffusing capacity for carbon monoxide (DLCO)/valveolar volume (VA), disappeared after 2–3 years. The patient remains in excellent health with continued regular TPE treatments on the original pulsed protocol (approximately 370 to date); however, discontinuing or reducing TPE treatment frequency led to an eventual return of GI symptoms in two attempts.

Hertzman et al. 43 treated a 12-year-old patient diagnosed with mixed connective tissue disease (MCTD) with an initial series of 10 TPE treatments over a 5½ week period, resulting in significant improvement in nodular lesions and complete elimination of hand swelling. TPE was reduced to one TPE every 3 weeks, and the patient remained asymptomatic at 2-year follow-up with no other treatment intervention.

Szekanecz et al. 49 followed a male patient with dcSSc for 11 years. The patient received a combination of regular TPE treatments combined with IVIG during the first year and was maintained on a reduced frequency of TPE/IVIG during the 10-year follow-up period. Unfortunately, because of the simultaneous use of TPE and IVIG, it is impossible to determine whether the observed improvements were from TPE, IVIG, or a synergistic combination of both.

A second Italian study 20 summarized the results of long-term treatment of 97 SSc patients using TPE as an adjunct treatment in addition to D-penicillamine or an immunosuppressant. While the authors rated TPE efficacy as either “excellent” or “good” in 52.4% of the patients, the simultaneous use of adjunct treatments make it impossible to determine to what extent these positive effects are attributable to TPE.

Only a small number of studies have examined the efficacy of long-term TPE on patients with SSc. The 2001 Cozzi study 16 compared pre- and post-TPE laboratory markers reflecting disease activity in a group of 28 Italian patients who received regular TPE combined with D-penicillamine over a 6-year period (mean 33 months) against a control group of 25 SSc patients who received D-penicillamine alone. Significant improvements in clinical scores and laboratory markers only occurred in the TPE treatment group even though at pre-treatment the TPE group had worse laboratory measures and clinical scores than the control group.

Of the reviewed studies, 16 discussed improvements in RP and DUs following TPE treatments; 4 studies were confounded by simultaneous use of drug therapies and were excluded from further analysis. A commonly reported finding was that a single course of a small number of weekly TPE had major impact on both RP and DU as well as blood flow and microvascular patency. These findings are discussed later in this article.

Mixed connective tissue disease (MCTD) is a complex connective tissue disorder defined by coexisting and overlapping clinical features of SLE, SSc, and dermatomyositis/polymyositis. 59 It is considered to be a distinct disease by most authors. 60 Of the 19 CRs, 6 CRs 41 , 43 , 47 , 52 , 54 , 56 were about patients diagnosed with MCTD. In all 6 cases, TPE was initiated because of an acute or crisis situation rather than as a general treatment. Improvements were reported in all of these cases, although multiple simultaneous interventions in 3 of these cases make it difficult to determine the role of TPE in observed improvements.

In 12 of the 19 CRs included in this study, 41 , 42 , 44 , 46 , 48 , 50 , 52 – 57 TPE was used to treat an acute or, in some cases, critical medical situation such as SRC. Typically, these studies look at the effects of TPE over a short period of time (a few weeks or months); TPE was discontinued once the acute situation resolved or improved. Three of the CRs are notable in that they reported on the results of long-term, regular TPE as a systemic treatment approach. 40 , 43 , 49 Eight of the CRs used TPE as the sole treatment intervention. Of the CRs, 12 received a Grade I rating; however, only 4 of these used TPE as the sole treatment intervention.

Of the studies, 18 are best categorized as single-group pretest–posttest studies with no control group. In this type of study, a number of laboratory markers and clinical symptoms are assessed before treatment; patients then receive TPE (and sometimes other) treatments for a period of time, and the laboratory markers and clinical symptoms are re-assessed immediately following cessation of TPE and at follow-up intervals that can be anywhere from a few days or weeks to several years. Of these studies, 12 used TPE as the sole treatment intervention. Seven studies were rated Grade I, although two of these studies combined TPE with another treatment intervention. Potential issues with interpretation of pre-post studies are discussed later in this article.

Only three long-term OS on the use of TPE have been published. 19 – 21 Unfortunately, in all of these studies, TPE was used in conjunction with other treatments including immunosuppressants and ACE inhibitors, making it impossible to determine to what (if any) degree TPE contributed to any observed improvements in laboratory markers and clinical symptoms. None of these papers were rated Grade I because of these issues.

Even though a large 2001 study 16 was not a RCT, it actually provides strong data suggesting positive effects from TPE. Patients admitted into the TPE treatment group had more severe and/or rapidly progressing disease and at baseline were significantly worse (p < 0.05) than patients in the control group. However, improvements in laboratory markers and clinical scores were only seen in the (worse) TPE treatment group.

Two studies done in 1985 17 , 18 reported hemorheological characteristics of patients with primary versus secondary Raynaud’s and the effects of four weekly TPE treatments on hemorheology and symptoms. Both studies demonstrated that blood rheology is essentially normal in patients with primary Raynaud’s but highly abnormal (increased whole-blood viscosity (WBV) and RBC aggregation) in patients with secondary Raynaud’s. TPE led to long-lasting improvements in hemorheology and symptoms, including reduced Raynaud’s attacks and healing of DUs, only in the secondary Raynaud’s group.

A 1986 study, 14 only available as a short abstract, compared TPE with a related procedure—lymphoplasmapheresis—as well as a non-treatment control group on a very small group of patients. A study done in 1988 15 compared the effects of TPE plus immunosuppressants against immunosuppressants alone. Unfortunately, this study suffered from numerous design issues, including using different types of plasma exchange (PE) equipment and frequent alterations of the protocols on an individual basis. A third study, 13 while well designed, was performed in China using procedures and equipment than are different from those used in other studies done in Europe or the United States.

Only three RCTs have ever been published where TPE was evaluated against a randomly assigned control group. While RCTs are normally considered the “gold standard” for clinical treatment research, all three of these studies provided limited information that can guide a modern clinician. Only two of these studies used TPE as the sole treatment intervention, and none of these studies were rated Grade I on our rating scale.

Detailed summaries of randomized clinical trials, clinical trials (quasi-experimental studies), OS, single-group pre-post studies, and CRs are shown in Tables 2 – 6 and are discussed in the following. Tables are sorted by (1) TPE Only (yes/no), (2) Grade (I, II, and III), and (3) reverse chronological order (most recent first). In 25 out of the 46 studies, TPE was the only treatment intervention.

We identified 46 articles that met our search criteria, involving a total of 572 patients. Of the articles, 19 were CRs, involving a total of 26 patients. The remaining 27 articles (546 patients) ranged from letters to the editor describing a small group of patients treated with TPE to a large-scale review of 102 patients treated over a 15-year period at a single clinic in Italy. Out of the 572 patients, 455 received TPE. The rest were in control groups.

Discussion

While TPE was introduced in the 1950s, it was not until 1976, when the Haemonetics Model 30 Apheresis system became commercially available, that clinicians began to try TPE as a potential treatment for more than 100 diseases.3,61 Early successes of TPE, such as the unprecedented reversal of clinical symptoms in patients with Waldenstrom macroglobulinemia and as a mainline treatment for Goodpasture syndrome and myasthenia gravis, have stood the test of time and clinical research. In contrast, using TPE as a treatment for diseases such as rheumatoid arthritis (RA) and SLE nephritis has been shown to be ineffective in clinical trials despite early reports of successes with individual patients. Currently, TPE for treating SSc is classified as a Category III treatment by the ASFA.7 Category III treatments are defined as “optimum role of apheresis therapy is not established; decision-making should be individualized.”

While there have been (at least) 46 published studies on the use of TPE as a treatment for SSc, none of the published studies reviewed for this article meet the rigor of a well-designed, RCT. Of the studies, 21 used more than one simultaneous treatment intervention, making it impossible to isolate out the effects of TPE versus other co-treatments. Out of the 25 studies that used only TPE as a systemic treatment intervention, only 10 of these studies received our highest rating on our level of evidence grading scale. (Notably, 10 other studies where TPE was used in conjunction with at least one other simultaneous treatment intervention demonstrated clear treatment benefit and received a Grade I rating.) It is clear that additional, well-designed studies are needed to evaluate fully the efficacy of TPE treatments in different SSc patient populations. However, the consistency of the findings showing significant clinical benefit from TPE treatments with very low risk suggests that TPE may be an appropriate treatment option to consider even as these additional studies are being done.

Issues with interpretation of study results Single-group pre-post studies with no control group While the “gold standard” for clinical treatment research is RCTs, studies such as pre-post studies can be very valuable and, if done correctly, can strongly suggest a causal relationship between a treatment and any changes in symptoms,62 especially for SSc treatment studies. Unlike diseases such as multiple sclerosis or lupus, SSc is a disease which is steadily progressive and does not go into remission without an intervention. Because of this, any objective changes in laboratory markers or symptoms following the introduction of TPE are likely to be a result of the intervention as long as there are no confounding co-treatments. Skin scores as outcome measures The Modified Rodnan skin score (MRSS) is a commonly used objective measure of skin thickness that is frequently used as one of the primary outcome measures in clinical trials of SSc treatments. About two-thirds of dcSSc patients show significant spontaneous reduction in skin thickness starting a year or two after initial diagnosis for reasons that are not fully understood. It is important to note, however, that there are no corresponding spontaneous improvements in internal disease markers.63 This means that if a study includes early-stage dcSSc patients, improvements in MRSSs following TPE (or any other intervention) cannot necessarily be attributed to the treatment(s) used in the study.

When does TPE fail to work in patients with SSc? Guillevin et al.39 tried TPE treatments in seven patients with severe diffuse SSc after failure of other treatments. Disease duration at time of initial TPE averaged 8 years. In three patients, TPE treatments had to be stopped because of venous access problems. In the remaining four patients, only one showed benefit: improvement of articular and cutaneous symptoms. This suggests that TPE may not be effective in late stages of dcSSc. Capodicasa et al.46 tried TPE in two patients in SRC. While brief improvement was seen in one patient, the authors concluded that TPE would need to be started earlier to be potentially effective. In contrast to all other reports reviewed in this article, this study used membrane TPE instead of centrifugal TPE. Also, ACE inhibitors are now employed as the treatment of choice for treating SRC. Kfoury et al.50 tried intensive TPE on an 85-year-old patient admitted because of SRC with the rare complication of thrombotic thrombocytopenic purpura. Intense TPE starting with 1 week of daily TPE treatments increasing to twice a day for an additional week had no effect, and the patient died shortly after cessation of TPE and all medications secondary to pulmonary and cardiac conditions related to SRC. While TPE was not effective in all patients in studies with overall positive outcomes, few data were presented about patients who failed to respond to TPE treatments. Nevertheless, most authors clearly felt that TPE would be most effective if started early in the disease process.

TPE and mixed connective tissue disease No clinical trial or other large-scale study of TPE as a potential treatment for MCTD has been done to date. While most of the six MCTD CRs reviewed for this article were focused on the use of short-term TPE to deal with an acute issue, such as renal failure or central retinal vein occlusion, one paper43 followed a 12-year-old MCTD patient who went into remission after 5½ weeks of TPE (10 treatments in total) and remained in remission with regular maintenance TPE at the 2-year follow-up. While MCTD has overlapping symptoms of SLE, it is interesting to note that TPE was not effective in patients with SLE in a short-term RCT.64

TPE and RP/DUs Treatment of RP and DU in SSc is challenging and, in some cases, inadequate to prevent progression to gangrene and eventual digit amputation. One of the more surprising findings in 12 of the papers reviewed here17,22,24–28,30,31,33,44,47 was the fact that three or four TPE weekly treatments often led to complete cessation of Raynaud’s attacks and healing of even long-standing DU. These effects were long-lasting, with RP not returning for 6 months or longer, and in one study,22 patients had no return of DU during at 3-year follow up. Standard treatments for RP and DU in SSc are focused on improving distal blood flow by either increasing vascular dilation or reducing vasoconstriction or vasospasm. Since TPE treatments are not known to directly increase vasodilation or reduce vasoconstriction or vasospastic activity, these results raise the possibility that an entirely different mechanism of action may be involved in the observed improvements in RP and DU healing following TPE.