Category IV indications for therapeutic apheresis: ASFA fourth special issue.

Abstract

The American Society for Apheresis (ASFA) Committee on Clinical Applications systematically and critically reviews published information on the use of therapeutic apheresis in clinical practice. On the basis of this review, selected diseases are assigned one of five categories (category I, II, III, IV, and P). The diseases, which were classified as category IV indications, and the rationale for such assignment are reviewed in this article. The diseases assigned to category I, II, III, and newly created category P are discussed in a separate article in this issue.

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Category IV Indications for Therapeutic
Apheresis—ASFA Fourth Special Issue
Beth H. Shaz,1* Michael L. Linenberger,2* Nicholas Bandarenko,3Jeffrey L. Winters,4Haewon C. Kim,5
Marisa B. Marques,6Ravindra Sarode,7Joseph Schwartz,8Robert Weinstein,9Ashka Wirk,10
and Zbigniew M. Szczepiorkowski11{
1Department of Pathology and Laboratory Medicine, Grady Hospital, Emory University, Atlanta, Georgia
2Department of Pathology and Laboratory Medicine, Seattle Cancer Care Alliance, Seattle, Washington
3Department of Pathology and Laboratory Medicine, University of North Carolina Hospitals, Chapel Hill, North Carolina
4Division of Transfusion Medicine, Mayo Clinic, Rochester, Minnesota
5Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
6Division of Transfusion Medicine, University of Alabama, Birmingham, Alabama
7Transfusion Medicine and Coagulation Laboratory, Department of Pathology, University of Texas
Southwestern Medical Center, Dallas, Texas
8Division of Laboratory Medicine, Department of Pathology, Columbia University Medical Center, New York, New York
9University of Massachusetts Medical Center, Worcester, Massachusetts
10Malachite Management, Vancouver, British Columbia, Canada
11Transfusion Medicine Service, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
The American Society for Apheresis (ASFA) Committee on Clinical Applications systematically and critically
reviews published information on the use of therapeutic apheresis in clinical practice. On the basis of this review,
selected diseases are assigned one of five categories (category I, II, III, IV, and P). The diseases, which were classi-
fied as category IV indications, and the rationale for such assignment are reviewed in this article. The diseases
assigned to category I, II, III, and newly created category P are discussed in a separate article in this issue.
Apheresis 22:000–000, 2007
V V
J. Clin.
C2007 Wiley-Liss, Inc.
Key words: apheresis; plasma exchange; immunoadsorption; leukocytapheresis; photopheresis; categories
INTRODUCTION
The American Society for Apheresis (ASFA) Aphere-
sis Applications Committee is charged with a review and
categorization of indications for therapeutic apheresis.
This elaborate process had been undertaken every 7
years resulting in three prior publications in 1986, 1993,
and 2000 of ‘‘The ASFA Special Issues’’ [1–3].
The Fourth ASFA Special Issue is significantly modi-
fied in comparison with the previous editions. A new
concept of a fact sheet has been introduced. The fact
sheet succinctly summarizes the evidence for the use of
therapeutic apheresis. All diseases assigned category I–
III as well as category P (pending) are discussed in a sep-
arate article in this issue [4].
The category IV indication is used for diseases that
therapeutic apheresis has shown no benefit in random-
ized controlled trials or where there is a consistent lack
of efficacy among multiple case series/case reports [1–
3,5]. Therapeutic apheresis should not be used to treat
diseases in category IV except within the context of an
IRB-approved research protocol. Some diseases listed
herein were specified as category IV indications in the
2000 ASFA Clinical Applications guidelines [2]. Others
have been added to provide a more complete list of dis-
eases for which existing data fail to support the use of a
therapeutic apheresis modality. In one case, the use of
plasma exchange for acute humoral (vascular) rejection
of a renal allograft, new data have resulted in a change
from a category IV indication in 2000 to a category III
indication in 2007 [4]. Diseases may have some presen-
tations or apheresis treatment modalities which are cate-
gory IV and others which are category I–III. Those pre-
sentations and apheresis treatment modalities that are
category I–III are discussed in the accompanying article
[4] with only the category IV indications discussed here.
An example of different categories based upon disease
presentation is systemic lupus erythematosus (SLE). The
*These authors contributed equally to this publication.
{Correspondence to: Zbigniew M. Szczepiorkowski, MD, PhD, Trans-
fusion Medicine Service, Department of Pathology, Dartmouth-Hitch-
cock Medical Center, One Medical Center Drive, Lebanon, New
Hampshire 03756, USA. E-mail: ziggy@dartmouth.edu
Published online in Wiley InterScience
(www.interscience.wiley.com).
DOI: 10.1002/jca.20131
V V
C2007 Wiley-Liss, Inc.
Journal of Clinical Apheresis 22:000–000 (2007)

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use of therapeutic plasma exchange (TPE) to treat lupus
nephritis is a category IV while the use to other disease
treat manifestations is a category III. An example of dif-
ferent categories for different apheresis treatment modal-
ities in the same disease is idiopathic thrombocytopenic
purpura (ITP). The use of TPE to treat ITP is a category
IV while treatment of this disorder with immunoadsorp-
tion (IA) is a category II. All diseases assigned category
IV are listed in Table I.
Amyloidosis, Systemic
Procedure: Therapeutic plasma exchange.
Rationale for category IV: The most common forms
of acquired systemic amyloidosis involve the deposition
of protein aggregates and amyloid fibrils composed of
immunoglobulin light chain (AL amyloidosis), serum
amyloid A protein (AA amyloidosis), or b2-microglobu-
lin (dialysis-related amyloidosis; DRA). Case reports and
small case series have described the use of specialized
adsorption columns or membrane filters to remove b2-
microglobulin, serum amyloid A, or light chains. Anec-
dotally, TPE has been used in combination with hemo-
dialysis in two patients with AL amyloidosis and renal
failure, one of whom had amyloid arthropathy. However,
no positive data exist, supporting the use of TPE for neu-
ropathy or other complications associated with AL,
DRA, or AA amyloidosis [6–8].
Amyotrophic Lateral Sclerosis
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Multiple small series and a
small controlled trial in the late 1970s and early 1980s
failed to show any benefit for TPE alone or TPE in com-
bination with immunosuppressive therapy for patients
with ALS [9–11].
Cutaneous T-Cell Lymphoma, Nonerythrodermic
Procedure: Extracorporeal photopheresis.
Rationale for category IV: CTCLs, which mostly
consist of mycosis fungoides and Se ´zary syndrome,
comprise of a heterogeneous group of non-Hodgkin’s
lymphomas. A randomized crossover trial comparing
PUVA with ECP for the plaque stage (stage T2) CTCL
showed improvement with PUVA but not with ECP. In
contrast, the literature suggests that ECP may be the
most effective treatment for erythrodermic (stage T4)
mycosis fungoides (see Cutaneous T Cell Lymphoma;
Mycosis Fungoides fact sheet) and should be considered
as first-line therapy for patients at that stage of disease,
therefore it is a category I in this setting [4,12,13].
Dermatomyositis or Polymyositis
Procedure: Therapeutic plasma exchange and leuko-
cytapheresis.
Rationale for category IV: The benefit of TPE was
initially suggested by early anecdotal reports in pediatric
patients and two large retrospective case series that
described improvement following prolonged courses of
TPE in conjunction with oral immunosuppressives. In a
prospective, randomized, sham-controlled trial, 39 corti-
costeroid refractory patients with inflammatory myopa-
thies were assigned to treatment with TPE, leukocyta-
pheresis, or sham apheresis in double-blind fashion. All
patients were maintained on prednisone. Although serum
levels of muscle enzymes decreased significantly with
TPE and lymphocytes decreased with leukocytapheresis,
no significant differences were seen among the three
TABLE I. Category IV Indications for Therapeutic Apheresis
Disease ProcedureASFA 2007 ASFA 2000
Amyloidosis, systemic
Amyotrophic lateral sclerosis
Cutaneous T-cell lymphoma, nonerythrodermica
Dermatomyositis or polymyositis
TPE
TPE
ECP
TPE
LCP
TPE
TPE
TPE
LCP
TPE
TPE
TPE
TPE
ECP
TPE
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
NC
NC
III
IV
NC
NC
III
IV
III
NC
IV
NC
NC
NC
Diarrhea associated pediatric hemolytic uremic syndromea
Idiopathic thrombocytopenic purpura
Inclusion body myositis
POEMS syndrome
Psoriasis
Rheumatoid arthritisa
Schizophrenia
Scleroderma/progressive systemic sclerosisa
Systemic lupus erythematosus, nephritisa
ECP, extracorporeal photopheresis; LCP, leukocytapheresis; NC, not categorized; TPE, therapeutic plasma exchange.
aThese diseases are also discussed in the fact sheet format in the main article of this Special Issue as noted in the text [4].
2 Shaz et al.
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groups with respect to muscle strength or functional
capacity [14,15].
Diarrhea-Associated Pediatric Hemolytic Uremic
Syndrome
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Hemolytic uremic syn-
drome (HUS) is a thrombotic microangiopathy (TMA)
predominantly affecting the kidneys. HUS is character-
ized by the triad of microangiopathic hemolytic anemia
(MAHA, schistocytes on peripheral blood smear), throm-
bocytopenia, and acute renal failure. Two types of HUS
have been described: diarrhea-associated HUS (dþ
HUS) and nondiarrhea-associated HUS (d? HUS). dþ
HUS is the most common form and occurs about a week
after onset of bloody diarrhea caused by Shiga toxin-pro-
ducingbacteria,predominantly
O157:H7, in about 6% of patients (9–30% of children).
In children with dþ HUS, acute renal failure predomi-
nates but the majority recovers spontaneously with a
mortality rate of 3–5%. In dþ HUS, Shiga toxins may
attach to glomerular capillary endothelial cells and stim-
ulate endothelial cells to release ‘‘unusually large’’ von
Willebrand factor (UL-vWf) multimers from the Wei-
bel–Palade bodies. In addition, Shiga toxin may activate
platelets and promote adhesion and aggregation of plate-
lets onto UL-vWf multimers. In children with dþ HUS,
supportive care is the mainstay of therapy, including
RBC transfusion, dialysis, and renal transplantation if
indicated. Corticosteroids, plasma infusion, or plasma
exchange have no proven role in dþ HUS in children,
and therefore this disorder is a category IV indication for
TPE. By comparison, atypical HUS (including d? HUS),
dþ HUS in adults, and TMA are category III indications
and thrombotic thrombocytopenic purpura (TTP) is a
category I indication for TPE (see Thrombotic Thrombo-
cytopenic Purpura and Hemolytic Uremic Syndrome;
Thrombotic Microangiopathy; and Transplant Associ-
ated Microangiopathy fact sheets) [4,16,17].
Escherichiacoli
Idiopathic Thrombocytopenic Purpura
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Anecdotal case reports and
small case series of patients with chronic idiopathic
thrombocytopenic purpura (ITP) have described a poten-
tial benefit for TPE when combined with other salvage
therapies, such as prednisone, splenectomy, intravenous
immunoglobulin(IVIG),
Responses with combination therapy were often tran-
sient. No improvement was reported among five patients
who underwent TPE for refractory ITP after splenec-
tomy. In one controlled trial, the 6-month response rate
and rate of splenectomy were no different among
12 patients who received TPE plus prednisone compared
andcytotoxicagents.
to seven patients treated with prednisone alone. In con-
trast to the category IV, indication for TPE, chronic, re-
fractory ITP is a category II indication for extracorporeal
IA with protein A (see Idiopathic Thrombocytopenic
Purpura fact sheet) [4,18–20].
Inclusion Body Myositis
Procedure: Therapeutic plasma exchange and leuko-
cytapheresis.
Rationale for category IV: A single case report
described a patient with biopsy confirmed inclusion body
myositis (IBM) who received 22 leukocytapheresis pro-
cedures combined with prednisone and azathioprine. Af-
ter improvement, during the early induction phase with
frequent cytaphereses, the clinical response was subse-
quently lost during a maintenance course with less fre-
quent procedures. One uncontrolled study reported
improved muscle strength in 32 of 35 patients with treat-
ment-resistant idiopathic inflammatory myopathy after
weekly TPE was performed for up to 10 weeks together
with either cyclophosphamide or chlorambucil. How-
ever, the diagnosis of IBM was not specified and the
potential role of TPE in these responses could not be
determined. The lack of benefit for TPE and leukocyta-
pheresis in patients with other inflammatory myopathies
casts further doubt on the utility of these modalities for
IBM [15,21,22].
POEMS Syndrome
Procedure: Therapeutic plasma exchange.
Rationale for category IV: POEMS (Polyneuropathy,
Organomegaly, Endocrinopathy, M protein, and Skin
changes) is a rare multisystem paraneoplastic syndrome
usually associated with an underlying plasma cell prolif-
erative disorder. Patients with POEMS have undergone
TPE because they were initially thought to have chronic
inflammatory demyelinating polyneuropathy (CIDP). A
few reported cases have described benefit for double fil-
tration plasmapheresis and IA. Among 30 patients with
POEMS treated with TPE, no responses were seen
among the 16 who received TPE alone. The response
rate was 20% among 14 patients who received TPE with
concurrent corticosteroids, but this rate was similar to the
response rate with steroid therapy alone. Thus, TPE is
likely to be ineffective for this disorder [23,24].
Psoriasis
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Psoriasis is a chronic skin
disorder with a high genetic predisposition. The plaques
and papules are a result of hyperproliferation and abnor-
mal differentiation of the epidermis. One small con-
trolled trial and one small series showed that TPE pro-
vides no benefit in the treatment of psoriasis [25,26].
Therapeutic Apheresis—Category IV Indications3
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Rheumatoid Arthritis
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Rheumatoid arthritis
(RA) is a chronic multisystem autoimmune disease of
unknown etiology with a high genetic predisposition.
The most characteristic feature is an inflammatory syn-
ovitis (relapsing or persistent), usually involving pe-
ripheral joints in a symmetric distribution. Two small
controlled trials did not show benefit with TPE in
patients with refractory RA, and therefore this disorder
is a category IV indication for TPE. By comparison,
benefit has been shown with extracorporeal IA with
protein A in patients with RA refractory to other thera-
pies; thus, refractory RA is a category II indication for
this apheresis modality (see Rheumatoid Arthritis fact
sheet) [4,27,28].
Schizophrenia
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Schizophrenia is a chronic
psychiatric disorder with psychosis and deterioration in
function. A double-blind, randomized trial of TPE versus
sham-pheresis demonstrated no benefit [29].
Scleroderma/Progressive Systemic Sclerosis
Procedure: Extracorporeal photopheresis.
Rationale for category IV: Systemic sclerosis, or
scleroderma, is characterized by the accumulation of
connective tissue in skin and viscera. Three randomized
trials have been performed using ECP on patients with
scleroderma. An early multicenter study of 79 patients
with recent onset and progressive scleroderma showed
improvement in skin and joint parameters at 6 months
among those receiving ECP compared to a lack of
improvement among those treated with D-penicill-
amine. A more recent crossover trial of 19 patients
with progressive systemic sclerosis of less than 5 years’
duration revealed no benefit of ECP with regard to skin
score or quality of life after 1 year of treatment. The
latest multicenter trial randomized 64 patients with a
diagnosis of scleroderma of less than 2 years’ duration
to either active or sham photopheresis on two consecutive
days every month without concomitant treatments. At the
end of 12 months, improvements were observed in the
skin scores and mean joint involvement in both groups.
Although the improvements in the cohort receiving
ECP were greater than those among sham-treated patients,
the difference did not reach statistical significance.
Confirmatory evidence for a benefit of ECP in a random-
ized clinical trial setting is therefore still lacking. By
comparison, scleroderma is a category III indication for
TPE (see Scleroderma/Progressive Systemic Sclerosis fact
sheet) [4,12,30–32].
Systemic Lupus Erythematosus, Nephritis
Procedure: Therapeutic plasma exchange.
Rationale for category IV: Lupus nephritis is a com-
mon complication of systemic lupus erythematosus
(SLE). SLE is a chronic autoimmune disorder caused by
autoantibodies leading to complement-mediated tissue
injury. A controlled trial of TPE plus prednisone and cy-
clophosphamide versus prednisone and cyclophospha-
mide in patients with severe lupus nephritis showed no
benefit of TPE. Smaller later trials have supported these
data. By comparison, some other presentations of SLE
are a category III indication for TPE (see Systemic Lupus
Erythematosus fact sheet) [4,33–35].
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Therapeutic Apheresis—Category IV Indications5
Journal of Clinical Apheresis DOI 10.1002/jca