Use of Staphylococcal Protein
A (SPA) Immunoadsorption in Rheumatoid Arthritis and Immune
E. Kiss, M.D.
Medical Director, Hemapheresis and Blood Services
Food and Drug Administration (FDA) approval of the staphylococcal protein A
column for treatment-resistant moderate to severe rheumatoid arthritis has
prompted increased requests for this therapy by physicians and patients
alike. This edition of the TMU
will address the role of SPA immunoadsorption in the only two approved
indications for it's use: rheumatoid arthritis (RA)
and immune thrombocytopenic purpura (ITP).
column consists of 200 mg. of purified staphylococcal protein A covalently
linked to a silica matrix. SPA
avidly binds IgG, particularly in the form of IgG-containing circulating
immune complexes (CIC). In the "on-line" mode, the column is
connected to the plasma return line of a plasmapheresis
instrument; the plasma is perfused through the column at a rate of
10-20 mls/min. The treated
plasma is then recombined with the cellular components and reinfused.
A variable amount of plasma may be processed, depending upon the clinical
indication. As little as 250 mls processed per treatment has been
reported to be efficacious in the management of refractory ITP, while most
studies reporting the efficacy of Prosorba®treatment
in RA processed approximately 1,250 ml of plasma per apheresis.
basis for the salutary effects of SPA immunoadsorption remains obscure.
Because the column becomes saturated after removal of only ~1 gm of
IgG, its efficacy clearly is not based on quantitative immunoglobulin
depletion. Instead, an
immunomodulatory effect is believed to occur, resulting from alterations in
CIC. Column treatment
appears to reduce the population of small molecular weight CIC. These
CIC may interfere with antigen presentation to T-helper cells, thus blocking
the formation of "protective"
antibodies involved in immune clearance. CIC may also inhibit the formation of
anti-idiotypic antibodies, which down-regulate autoantibody
responses. Alternative hypotheses have also been proposed.
from several clinical trials support the efficacy of SPA column treatment in
patients with refractory rheumatoid arthritis.
In two non-controlled trials, RA patients treated at approximately
weekly intervals had response rates of 54-60%, as assessed by 20% or greater
improvement in signs and symptoms.
of the complexity of the endpoints for assessing clinical status in RA and
the recognized placebo effect of apheresis treatment itself, Felson et.al.,
studied the efficacy of SPA column treatment in comparison to a control
group who received apheresis without column plasma perfusion (i.e., a sham
arm) in a randomized double-blind study1. The treatments
wwere performed weekly in patients with RA who had failed to respond to
treatment with methotrexate or at least two other second-line drugs
(so-called DMARDS, or Disease Modifying Anti-Rheumatic Drugs).
Efficacy was assessed 7-8 weeks after the course of treatment ended.
Improvement was measured according to American College of Rheumatology
response criteria. The trial
was stopped after the completion of 91 randomized patients because the
safety monitoring board determined a significant advantage existed in favor
of SPA. Of 47 patients in the SPA group, 31.9% experienced improvement
in comparison to 11.4% in the control group
(P=0.019). Most of the
responses were seen late in the course of 12 weekly treatments, but lasted a
mean of 37 weeks. SPA therapy
may allow RA patients to be managed with fewer or lower doses of DMARDs.
However, procedural issues (i.e., availability, venous access) as well as
the expense (about $1000 for each column plus apheresis fees) should also be
SPA column was approved by the FDA in 1987 for treatment of ITP patients
with platelet counts less than 100,000/ml.
Snyder et.al., evaluated 72 patients with initial platelet counts
less than 50,000/ml who had failed at least two other therapies2.
They treated patients 2-3 times per week for a total of 6-12
treatments. A response was
reported in 33 (46%); platelet counts rose to over 100,000 in 18 and to
50-100,000/ml in 15 patients, with median time to response of 2 weeks.
Although transient responses of less than one month were seen in 7
(10%), the authors noted the apparent durability of responses in the
remaining patients: the mean duration was 8 months, with some responding
> 26 months.
Institute for Transfusion Medicine recently reviewed it's experience
using SPA in 24 patients with refractory ITP. Disease duration ranged from 9 months to 23 years in 22 patients; 2
had disease less than 8 weeks. All
patients were refractory to at least two forms of therapy. Splenectomy had been performed in 15. A median of 8 procedures were performed over a 2-3 week
period processing 500 mls of plasma. Treatment
responses were defined as both a doubling of the baseline platelet count and
a post-treatment platelet count to > 50,000/ml. The overall response rate was 33%; 7 of the 8 responses
achieved platelet increments > 100,000. The two patients with disease
duration < 8 weeks (i.e., acute ITP) had continuing responses > 18
months follow-up. Of the 6 patients with longer disease duration, 2 relapsed
within 3 months, 2 had continuing responses requiring low-dose
corticosteroids or danazol therapy, and 2 had unmaintained responses which
lasted > 17 months. In our experience, the overall response rate of 33%
is consistent with that previously reported, however, unmaintained
remissions in patients with longstanding ITP appear to be uncommon after
recent consensus guideline published by the American
Society of Hematology listed protein A column as an intermediate
preference treatment option in patients with refractory ITP and platelet
counts less than 10,000/ml3.
Higher preference therapies included intravenous gammaglobulin,
accessory splenectomy (where appropriate), danazol, and azathioprine.
Lower preference alternatives included
Rh immune globulin, ascorbic acid, colchicine, cyclosporine, and interferon.
It should be noted that these recommendations were published in 1996,
when there was less experience using intravenous Rh immune globulin.
effects experienced by patients during SPA column treatment vary somewhat
with the nature of the underlying disease and the medications the patient is
receiving. Most common adverse
events reported in conjunction with treatment of ITP include hypertension,
nausea/emesis, chills and/or fever, rash, arthralgias, diarrhea, and
abdominal pain. Symptoms are
less common if the patient is receiving prednisone. Regardless,
pretreatment with acetaminophen, 650 mg. and diphenhydramine 25-50 mg. is
recommended. The most common side effects reported in conjunction with RA
treatment include joint pain (essentially a "flare") involving the
target joints, fatigue, hypertension, nausea, abdominal pain, flushing, and
headache. The possibility of
severe reactions exists, including anaphylactoid manifestations, vasculitis,
thrombosis, or exacerbation of underlying disease. Most of the serious
reactions were reported in the older literature. However, catheter
complications should also be considered as part of the risk/benefit
assessment of any patient in whom SPA column therapy is considered. In
addition, the column is contraindicated in patients receiving angiotensin-converting
enzyme (ACE) inhibitors because of the risk of profound hypotensive
reactions. These drugs inhibit
the metabolism of bradykinin, which is formed during column perfusion.
column therapy is efficacious in some patients with ITP and RA. Appropriate
patient selection is essential. In
general, such patients should be refractory to standard modes of therapy
(including use of the newer anti-inflammatory medications), and a risk v.
benefit v. cost metric should be carefully considered.
D, Lavalie MP, et al. The Prosorba®
for treatment of refractory rheumatoid arthritis:
a randomized, double-blind, SHAM-controlled trial.
Arthritis Rheum. 1999; 42: 2153-59.
HW, Cochran SK, et al. Experience
with protein A-immunoadsorption in treatment-resistant adult
immunothrombocytopenic purpura. Blood
1992; 79: 2237-45.
JN, Woolf SH, et al. Idiopathic
thrombocytopenic purpura: a practice guideline developed by explicit
methods for the American Society of Hematology.
Blood 1996; 88: 3-40.