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Rituximab therapy and autoimmune disordersProspects for antiB cell therapy.

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ARTHRITIS & RHEUMATISM
Vol. 48, No. 6, June 2003, pp 1484–1492
DOI 10.1002/art.10947
© 2003, American College of Rheumatology
REVIEW
Rituximab Therapy and Autoimmune Disorders
Prospects for Anti–B Cell Therapy
Gregg J. Silverman and Stuart Weisman
tural homologies, CD20 has been postulated to function
as a calcium channel subunit (for review, see ref. 4),
which may explain the finding that ligation of CD20 can
affect B cell activation, differentiation, and cell cycle
progression from the G1 to the S phase (5,6). Important
for its use as a therapeutic target, binding of CD20 does
not modulate its expression or result in substantial
internalization. CD20 is also not shed, and there are no
other known membrane or secreted analogs to interfere
with its use for B cell targeting (7).
In recent reports, the properties of different monoclonal antibodies against human CD20 have been investigated (8). The clinical potential of CD20-targeted therapy
derives, in large part, from the unexpected finding that
treatment with an antibody to CD20 induces the death of B
lymphocytes, even without the need to conjugate the
antibody to a toxin. The best-explored mechanism has been
the properties of rituximab (trade name Rituxan), a chimeric monoclonal antibody specific for human CD20,
comprising the variable regions of a murine anti-human
CD20 B cell hybridoma fused to human IgG- and
␬-constant regions (9) (see Figure 1). Rituximab has a
binding affinity for human CD20 of ⬃8 nM.
The clearance of B cells is, in part, mediated
through induction of complement-mediated activities
and triggering of antibody-dependent cellular cytotoxicity. This latter activity is dependent on interactions with
cellular receptors for the IgG1-constant regions (i.e.,
Fc␥ receptors), especially Fc␥ receptor type IIIa, which
is expressed on a variety of cells including phagocytic
cells (10). Rituximab has also been shown to directly
trigger intracellular pathways for apoptotic B cell death
that involve the activation of phospholipase C␥, interruption of the signal transducer and activator of transcription 3/interleukin-6 pathway, down-regulation of
c-myc, and up-regulation of the proapoptosis molecule
Bax, a member of the Bcl-2 family (11,12). This sequence of molecular events results in the activation of
Introduction
In recent years, advances in our understanding of
the regulation of the immune system have enabled the
identification of cellular and molecular targets that
could potentially affect the pathogenesis of many autoimmune diseases. In particular, the demonstration that
B lymphocytes could play a central role in pathogenesis
suggests that their elimination may be a highly beneficial
therapeutic goal in a variety of diseases. Hybridoma
antibody technology has been applied as a first step
toward developing such specific agents. One of the
initial applications of this technology was the characterization of the surface molecules on lymphocytes, to
enable the discrimination of each type of lymphocyte.
These early studies identified CD20 as a specific marker
for B cells (1). CD20 has been found to be highly
expressed on the surface of pre–B lymphocytes as well as
on both resting and activated mature B lymphocytes,
whereas it is not expressed by hematopoietic stem cells,
pro–B cells, or other normal tissues (Figure 1). However, despite extensive investigation, the role of CD20 in
B cell physiology has remained a mystery; there is no
known natural ligand, and CD20-knockout mice are
without a discernible immunologic phenotype (2).
From the characterization of its encoding gene,
CD20 has been predicted to be a 33–37-kd membraneassociated phosphoprotein, with a structure of 4 transmembrane regions, a 44–amino acid extracellular loop,
and cytoplasmic N- and C-termini (3). Based on strucSupported by grants AI-40305, AR-47360, and AI-46637 from
the NIH, and a grant from the Alliance for Lupus Research.
Gregg J. Silverman, MD, Stuart Weisman, MD: University of
California, San Diego.
Address correspondence and reprint requests to Gregg J.
Silverman, MD, Department of Medicine, University of California San
Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663. E-mail:
gsilverman@ucsd.edu.
Submitted for publication September 16, 2002; accepted in
revised form January 28, 2003.
1484
RITUXIMAB THERAPY AND AUTOIMMUNE DISORDERS
1485
Figure 1. Rituximab (trade name Rituxan) is a chimeric monoclonal antibody specific for human CD20 (9). An IgG
antibody molecule is composed of 2 heavy chains and 2 light chains connected by disulfide bonds. The variable regions
determine the antigen binding specificity, while the constant regions are highly conserved between different antibodies
and determine antibody effector functions within the body. Because the treatment of patients with mouse antibodies can
result in severe allergic responses, the mouse antibodies are often engineered so that the murine portions are replaced
by human protein sequences that do not adversely affect antibody functional capacities. One approach is to generate a
chimeric antibody in which the variable-region domains from a mouse antibody are grafted by protein engineering
techniques to human constant-region domains. To generate rituximab, the variable regions of a murine anti-human
CD20 B cell hybridoma were fused to the human IgG- and ␬-constant regions.
the mitogen-activated protein kinase family members
p44 and p42, and induction of activator protein 1 (13),
ending in the activation of caspases, a special set of
cysteine proteases that degrade cellular proteins. These
final stages of the process are associated with nuclear
condensation, DNA degradation, and cytoplasmic membrane changes that enable the efficient clearance of
these dying cells by adjacent cells, including phagocytes,
without the induction of inflammation or damage to
neighboring cells or tissues. The importance of each of
these mechanisms for in vivo B cell deletion is uncertain.
Rituximab for B cell lymphoma
In late 1997, rituximab became the first therapeutic monoclonal antibody approved by the Food and Drug
Administration for the treatment of cancer (14), and
since its introduction, there have been more than
300,000 treatments with this agent administered to patients with relapsed, low-grade, follicular non-Hodgkin’s
B cell lymphoma (NHL) (for review, see refs. 15 and 16).
Rituximab is administered as an intravenous infusion
with a recommended dosage of 375 mg/m2 given once
weekly for 4 weeks. Shortly after treatment, in more than
70% of these patients, the mature and malignant B cells
become greatly diminished in the blood and bone marrow and generally remain greatly depressed for a median
of 9–12 months. Similarly, in patients with relapsed
NHL, responses to this single-agent therapy are usually
of limited duration, lasting a median of 1 year. However,
treatment does not affect stem cells or plasma cells,
1486
SILVERMAN AND WEISMAN
Figure 2. A simplified view of the surface phenotype of B lymphocytes undergoing differentiation, from pro–B cells to
plasma cells. Differentiation to the transitional B cell stage is associated with emigration from the bone marrow into the
periphery, where a small proportion of recently emergent lymphocytes enter the recirculating pool of mature B cells.
Following antigen (Ag) encounter and clonal selection in peripheral germinal centers (GC), certain progeny
differentiate into antibody (Ab)–secreting cells and plasma cells that may return to the bone marrow or are selected into
the long-lived memory B cell pool. During differentiation, the surface phenotype of these cells changes, and CD20 is
expressed only at intermediate stages and not on plasma cells. The level of expression of CD20 on memory B cells has
not yet been determined.
which are the terminally differentiated B cell lineage
cells that are the major source of antibodies in the body
(Figure 2) and which have down-regulated or absent
CD20 (9). The limited capacity to affect plasma cells
may explain why there is little or no effect on the levels
of Ig in these patients, and perhaps may explain why
treatment is associated with a low incidence of opportunistic infections. Infections with common bacterial
pathogens are also not significantly increased.
Rituximab is generally well tolerated in lymphoma patients, and serious adverse effects are uncommon (for review, see ref. 17). However, during the first
infusion, many patients will experience limited, infusionrelated effects such as hypotension, fever, and rigors, but
these symptoms generally subside with temporary cessation of the infusion and subsequent use of a slower
infusion rate. These reactions tend not to recur after
subsequent infusions. Of note, in patients with lymphoma who have undergone treatment with rituximab,
the occurrence of antichimeric antibodies is low (18).
With any antibody-based therapy, the potential for the
induction of human antichimeric antibodies (HACA) is
a topic of great concern, because sensitization may lead
to more serious allergic adverse events, and upon retreatment, the effectiveness of the agent may become
greatly diminished.
For the treatment of more advanced lymphoma,
investigators have also begun to evaluate the use of
RITUXIMAB THERAPY AND AUTOIMMUNE DISORDERS
rituximab in combination with chemotherapeutic agents.
In a recent study, a French cooperative group reported
the outcome of a clinical trial involving elderly patients
with diffuse large B cell lymphoma who received a
standard combination regimen (i.e., cyclophosphamide,
doxorubicin, vincristine, and prednisone [CHOP]) with
or without rituximab. At a median followup of 2 years,
event-free and overall survival were significantly higher
in the CHOP-rituximab group (P ⬍ 0.001 and P ⫽ 0.007,
respectively) without a clinically significant increase in
toxicity. Moreover, although tumor expression of bcl-2,
an antiapoptotic protein, is generally associated with a
worse prognosis, the addition of rituximab was also
shown to prevent treatment failure in bcl-2–positive
patients (19).
Rituximab for autoimmune thrombocytopenia
Based on the success of rituximab for the treatment of lymphoma, it was inevitable that it would soon
be used to treat patients with a broader range of diseases
involving B cells (for review, see refs. 20 and 21).
Autoimmune thrombocytopenia (also known as idiopathic thrombocytopenic purpura [ITP]), the most common hematologic autoimmune disease, has been useful
for the development of innovative clinical trials, in part
because of its perceived simple pathogenetic process;
high titers of autoantibodies directed against platelet
glycoproteins lead to depressed platelet counts and a
bleeding diathesis. Moreover, it has been reported that
up to 16% of patients presenting with autoimmune
thrombocytopenia will later develop systemic lupus erythematosus (SLE) (22), suggesting that a subset of
patients with these autoimmune conditions share the
common features of genetic predisposition and pathogenesis.
In a prospective, dose-escalation, phase I/II trial
of chronic ITP, adult patients with or without a history
of splenectomy who, despite corticosteroid therapy, still
had platelet counts of ⬍75,000/mm3 were studied (23).
The first group received 50 mg/m2 for the first infusion,
followed by 150 mg/m2 on each of 3 subsequent weeks.
However, although no significant toxicity was observed,
none of these 3 patients had a clinical response. The
second group received an initial dose at 150 mg/m2,
followed by a weekly infusion of 375 mg/m2 for 3 weeks.
A third group received 375 mg/m2 at each of the 4
weekly treatments. Of the 10 patients in these latter
groups, 2 had partial responses lasting at least 3 months,
as demonstrated by a platelet count of ⬎100,000/mm3
without additional therapy, while 1 patient had a com-
1487
plete response that was characterized by normalization
of the platelet count to ⬎150,000/mm3 without additional therapy, lasting for more than 6 months. Notably,
although pretreatment levels of platelet-associated IgG
antibodies were significantly increased in 6 of these
patients, only 1 of the responders displayed a posttreatment decline in these autoantibody levels (23).
In another study, 25 adult patients with chronic
ITP who had demonstrated resistance to conventional
treatment regimens received the full 4-week regimen of
rituximab at 375 mg/m2 (24). Of these 25 patients, 5 had
increases in their platelet counts to ⬎100,000/mm3, and
5 had increases in their platelet counts to the range of
50,000–100,000/mm3. An additional 3 patients displayed
minor responses, with stabilization of their platelet
counts at ⬍50,000/mm3, without the need for continued
treatment. Several patients had reductions to subnormal
levels in their serum IgG, IgM, or both. In general, the
infusions were well tolerated in these studies of ITP
patients, since no major toxic effects and only minor
infusion-related fevers and chills were reported (23,24).
Rituximab for SLE
At the 2001 and 2002 annual meetings of the
American College of Rheumatology (ACR), interim
results were reported on a therapeutic trial of SLE
patients with clinically active disease but without severe
organ-threatening disease activity (i.e., SLE Disease
Activity Measure score of ⬍6) (25,26). In this singledose escalation study, infusions of either 100 or 375
mg/m2 of rituximab often resulted in significant depletions in the levels of peripheral B cells, which correlated
with improvements in disease manifestations such as
rash, arthritis, and fatigue. However, during the 6
months of followup, the levels of autoantibodies to
native DNA and complement were not affected. Although these treatments were well tolerated, inductions
of antichimeric antibodies were noted in 3 of the 12
patients studied.
In another recently reported open study, 6 female
patients with SLE who were resistant to standard immunosuppressive therapy received 2 infusions of 500 mg of
rituximab in combination with 2 infusions of 750 mg of
cyclophosphamide and oral prednisolone (27). These
patients had active disease manifestations, including
renal disease in 3 patients and central nervous system
disease in 1 patient, in addition to Raynaud’s phenomenon, arthritis, lymphopenia, anemia, and cutaneous
vasculitis. All of these patients had elevated levels of
anti–native DNA antibodies and depressed levels of
1488
complement. After treatment, the levels of B lymphocytes were depleted in the peripheral blood for at least
3–16 months. During followup periods of 6–18 months,
most patients demonstrated significant improvement,
with mean British Isles Lupus Assessment Group global
scores of 15.3 at the start to a mean of 8.3 at 6 months.
In general, fatigue, arthralgia/arthritis, serositis, and skin
vasculitis exhibited good responses, while there was
improvement of renal involvement in 2 of 3 patients. C3
levels normalized, at least transiently, in most patients.
Although modest decreases in the levels of serum Ig
were common (IgA decreased a mean of 0.2 gm/liter,
range 0–0.6; IgG decreased a mean of 3.9 gm/liter, range
0–6.3; IgM decreased a mean of 0.5 gm/liter, range
0–1.6), these levels remained within the normal range,
and no consistent trends in anti–native DNA antibody
levels were demonstrated. For some patients, treatment
appeared to provide benefits that extended beyond the
period of B lymphocyte depletion, enabling decreases in
the maintenance doses of corticosteroids, although disease activity subsequently flared in most patients. In
general, treatment was safe and well tolerated, with only
minor infections reported.
Rituximab for rheumatoid arthritis (RA)
In 2001, Edwards and Cambridge reported their
initial experience in an open study of 5 patients with
classic erosive RA that was refractory to at least 5
disease-modifying agents (i.e., disease-modifying antirheumatic drugs) (28). These patients received the standard dosing regimen of rituximab in conjunction with 2
intravenous doses of 750 mg of cyclophosphamide and
oral prednisolone at 60 mg per day for 11–22 days,
followed by tapering of each dosage. All patients exhibited significant reductions in synovitis, and at 6 months,
3 patients displayed an ACR 70% improvement
(ACR70) response (29), while the other 2 achieved an
ACR50 response, and clinical benefits persisted for at
least 1 year in most patients. In all patients, blood B cells
were undetectable shortly after the infusions and remained depressed for at least 6 months. Even though
total Ig levels displayed only modest declines (IgA
decreased a mean of 0.7 gm/liter, range 0–3; IgG decreased a mean of 3.1 gm/liter, range 0–8.2; IgM decreased a mean of 0.5 gm/liter, range 0–1.5) (30),
primarily in the first 10 weeks, the levels of rheumatoid
factor remained depressed for at least 3–6 months in all
patients (28). These regimens were well tolerated and
lacked major infusion-related events, since there were
only 2 episodes of limited respiratory infections and a
SILVERMAN AND WEISMAN
case of minor thrombocytopenia that resolved without
complication (28).
In a followup report, interim results were reported on a total of 22 patients who received different
regimens that included lower and higher doses of rituximab (30,31). However, among these patients, clinical
responses correlated with the use of higher doses of
rituximab in conjunction with cyclophosphamide and
oral corticosteroids, and several patients required retreatment. At the 2002 ACR annual meeting, the first
results were presented from a randomized, double-blind,
placebo-controlled trial involving patients with seropositive RA. According to these interim results, 4 groups of
30–31 patients in each treatment arm received either
methotrexate alone, methotrexate plus rituximab, rituximab alone, or rituximab plus cyclophosphamide. After
24 weeks of followup, each regimen was well tolerated,
although responses with rituximab alone surpassed those
with the current clinical standard, methotrexate. However, rituximab in combination with methotrexate or
cyclophosphamide produced the highest ACR20 (32),
ACR50, and ACR70 responses. Specifically, only 10% of
the patients receiving methotrexate alone (⬎10 mg/
week) achieved an ACR50 response, whereas this level
of response was noted in 32% of patients receiving
rituximab alone, with comparable responses seen in 45%
of patients receiving rituximab and cyclophosphamide
(at the above-described doses), and in 50% of those
receiving rituximab and methotrexate (33).
In another recent study, 5 female patients with
RA that was refractory to remittive agents received the
standard 4-week rituximab regimen (i.e., 375 mg/m2),
and only low-dose oral prednisone, nonsteroidal antiinflammatory drugs, and antimalarial agents were allowed
(34). At followup, improvements were confirmed by
radiographic and ultrasonographic imaging studies, and
1 patient had an ACR70 response, while a second
patient had an ACR50 response, each of which lasted at
least 10 months. Two additional patients had ACR20
responses that were more limited in duration. The fifth
patient displayed no benefit. All responders demonstrated a significant reduction or normalization of the
levels of C-reactive protein and serum rheumatoid factor. All patients had significant depletion of peripheral B
cells, and 4 of 5 patients demonstrated 30–50% drops in
their serum IgM levels, but these remained in the
normal range. These patients also tolerated the treatment regimen, since no major adverse effects were
noted, and 2 patients experienced uncomplicated lower
urinary tract infections.
RITUXIMAB THERAPY AND AUTOIMMUNE DISORDERS
Table 1. Rituximab treatment of autoimmune diseases
Table 3.
Refs.
Autoimmune thrombocytopenia
Systemic lupus erythematosus
Rheumatoid arthritis
Autoimmune hemolytic anemia
Cold agglutinin disease
Mixed cryoglobulinemia
Neuropathies associated with autoantibodies
Myasthenia gravis
Wegener’s granulomatosis
Dermatomyositis
23,24,50
25–27
28,31,33,34
51–54
55–58
59,60
61
62
63
64
Mechanisms of autoimmunity and rituximab
Following the dramatic successes with the treatment of lymphoma, rituximab has become an appealing
candidate for the treatment of nonmalignant diseases
involving B cells (Table 1). For these disorders, the
effective targeting of B cells may also affect pathogenesis
by removing the many functional contributions of B
lymphocytes to the cell-to-cell interactions that drive the
disease process (35) (Tables 2 and 3).
The clinical responsiveness of these disorders to
rituximab treatment will also reflect the inherent differences between the B cells involved in neoplasias and
those involved in autoimmune diseases. Specifically, the
pathogenesis of B cell lymphoma is largely a reflection of
the accumulation of neoplastic clonal sets of B cells,
which are directly susceptible to anti-CD20–mediated
induction of cell death. In contrast, the B cells in
different autoimmune diseases can play several different
roles that support the underlying pathologic process
(Table 3). For example, B cells can act as highly efficient
antigen-presenting cells (APCs), supporting the activation and autoreactivity of T cells involved in the process.
In fact, by virtue of the high affinity of a specific
membrane-associated Ig for an antigen, an antigenspecific B cell can take up, process, and present peptides
from nominal antigen with ⱖ1,000-fold more efficiency
than a “professional” APC.
In addition, activated B cells can also be the
Table 2. Immunobiologic functions of B lymphocytes in health*
1. Provide cognate help for T cells
2. Produce cytokines (i.e., IL-4 and IL-10) that support other mononuclear cells
3. Antigen uptake via surface Ig for processing and presentation
4. Antigen-induced production of Ig/antibodies
5. Constitutive production of Ig/antibodies by plasma cells
6. Memory cell (semidormant) awaiting antigen re-exposure
* IL-4 ⫽ interleukin-4.
1489
Immunobiologic functions of B lymphocytes in disease*
1. Provide cognate help for autoreactive T cells
2. Produce cytokines (i.e., IL-4 and IL-10) that support other mononuclear cells
3. Autoantigen uptake via surface Ig for processing and
presentation
4. Autoantigen-induced production of autoantibodies that are
directly or indirectly (e.g., immune complex formation)
destructive
5. Constitutive production of autoantibodies by plasma cells
6. Autoreactive memory cell awaiting (sequestered) autoantigen reexposure
7. Disease-associated uncontrolled clonal proliferation (or
prolonged lifespan)
8. Direct infiltration of end organs (e.g., the kidneys in SLE, the
joints in RA, the liver in mixed cryoglobulinemia)
* IL-4 ⫽ interleukin-4; SLE ⫽ systemic lupus erythematosus; RA ⫽
rheumatoid arthritis.
source of cytokines and membrane-associated molecules
that provide cognate help and enlist and support the
activities of autoreactive T cells. For instance, studies of
human synovium–SCID mouse chimeras have confirmed that in RA, the T cell activation is dependent on
B cells, and APCs other than B cells can not substitute
for the maintenance of T cell activation (36). Moreover,
the B cells involved in an autoimmune disease may also
be less accessible to the effects of rituximab. In fact, data
from nonhuman primates with cross-reactive CD20 indicate that treatment with certain anti-CD20 antibodies
may be much less effective at depleting B cells in lymph
nodes (37), but published data on this topic are currently
limited. Presumably, these findings are also relevant to
the effects at sites of tissue infiltration (e.g., joints),
where disease-associated lymphocytes may, in fact, preferentially localize in different disorders (9).
Available clinical experience also suggests that
rituximab as a single agent may not be adequate for the
treatment of diseases resulting from the production of
pathogenic autoantibodies, since it is likely that the
dominant cellular source of disease-associated autoantibodies, especially IgG antibodies, are plasma cells that
do not bear CD20 (Figure 2). Moreover, at least a
fraction of plasma cells are reported to turn over and be
replenished from precursor B cells only very slowly
(38,39). Thus, even after a course of rituximab has
depleted susceptible mature B cells, plasma cells may
still continue to produce disease-causing autoantibodies
for months or even years (39). For this reason, the
optimal treatment of diseases that have autoantibodymediated pathology may require a regimen that also
affects plasma cells. In addition, evolving therapeutic
regimens should also take into consideration the elusive
1490
lymphoid cells that are committed to retaining the
immunologic memory of the autoantigen (i.e., autoreactive memory B cells). These cells may remain relatively
dormant for prolonged periods of time, only to be
reactivated months, or even decades, later to be engaged
in (auto)antigen-specific responses. Therefore, to induce
a durable remission and reestablish immunologic selftolerance in these patients, the long-term goal of therapy
should be to eliminate all components of the diseaseassociated autoimmune process, including the offending
autoreactive B cells, plasma cells, and memory cells.
The efficacy of rituximab as a single agent may
also be diminished when the pathogenesis of the condition provides B cells with additional stimulatory and
prosurvival signals. It has been speculated that lessons
from the “two signal” model of lymphocyte activation
may be applicable to understanding the potentials and
limitations of rituximab therapy. Although the functional role of CD20 in B cells remains controversial, in
vitro treatment of human B cell lines with rituximab has
been reported to induce death signaling pathways that
have many similarities with those for B cell receptor
(BCR)–mediated induction of apoptotic death, but this
has been a controversial topic (13). Therefore, the in
vivo susceptibility to rituximab of B cells in autoimmune
diseases such as SLE and RA may be affected by the
activities and influences of mononuclear cells, including
local activated T cells, since cytokine and cognate “second signals” will potentially oppose the proapoptotic
effects of rituximab. Although, in theory, as long as a B
cell expresses CD20, it should be affected by
complement-dependent and antibody-dependent cytotoxicity mechanisms, interim results from the controlled
RA study indicate that clinical response was improved
by combination regimens with either methotrexate or
cyclophosphamide (33), presumably due to enhanced
deletion of B cells.
Prosurvival effects may also be associated with
the dysregulated overproduction of stimulatory factors,
such as interferon-␣ (40), which is currently believed to
contribute to the accelerated B cell differentiation into
plasma cells seen in pediatric lupus patients (41). Similarly, tumor necrosis factor ␣ and stem cell–derived
growth factor 1 may play somewhat similar roles in
supporting the erosive synovitis of RA (42,43).
Although, in the limited studies that have been
reported to date, rituximab has been generally well
tolerated, it remains a concern that patients with autoimmune diseases may be especially predisposed to untoward effects associated with rituximab infusions. For
example, based on their apparent predisposition to drug
SILVERMAN AND WEISMAN
allergies and greater incidence of HACA after infusions,
lupus patients may benefit from the inclusion of premedication with agents such as an antihistamine (e.g.,
benadryl) and acetaminophen, also commonly used before transfusions, and cotreatment with corticosteroids,
to decrease the induction of infusion reactions and
raised HACA titers. Moreover, with regard to patients
receiving immunosuppressive therapy, those who have
recently received rituximab would not be expected to
respond to prophylactic vaccinations. Although the tendency to develop serious or opportunistic infections has
not been observed in such patients, they should still be
managed with a heightened vigilance for signs and
symptoms of infection.
The recent reports of combination regimen trials
in SLE and RA suggest that the efficacy of rituximab
treatments for patients with autoimmune diseases may
be improved by the addition of second agents, such as
conventional chemotherapeutic drugs. Alternatively, it is
likely that future studies will also evaluate cotreatments
with specific biologic agents to interfere with T cell
helper signals, such as blocking antibodies to CD40–
CD40 ligand (44,45) or the use of CTLA4-Ig (46). As an
alternative approach, it may be desirable to utilize
agents that block the recently discovered BLyS/BAFF/
zTNF4 system (for review, see ref. 47), to interfere with
these potent survival signals directed toward membraneassociated receptors on peripheral B cells. It is also likely
that the apoptotic threshold of B cells may be selectively
lowered by cotreatment with an agent such as staphylococcal protein A (SpA) (48,49), which forms proapoptotic BCR complexes on targeted B cells, and which
likely represents the mechanism of action of SpApheresis therapy.
In conclusion, we believe that before rituximab
will come into routine usage by rheumatologists, the
therapeutic regimens will likely need to be tailored to
the inherent differences in the pathogenesis of autoimmune diseases. In particular, it is now generally
accepted that the varied functional capabilities of B cells
involved in autoimmune diseases are intimately intertwined with those of other immunocytes and inflammatory cells that are recruited into the pathologic responses. Thus, the intercellular codependence of these
disease-associated B cells will require the use of B
cell–deleting therapies in combination with other types
of approaches which directly or indirectly interfere with
the supportive signals provided by other cells of the
immune system. With the development of such validated
regimens, B cell–ablative approaches will likely come
into much wider use. Practitioners may get one step
RITUXIMAB THERAPY AND AUTOIMMUNE DISORDERS
closer to using therapeutics that erase from immunologic memory the autoreactive B cells (and perhaps also
pathogenic T cells) that contribute to these selfperpetuating, self-consuming diseases, thus returning
the immune system to an earlier state in which immunologic tolerance has been restored.
ACKNOWLEDGMENTS
We acknowledge the advice provided by Dr. Nathan
Zvaifler during the preparation of this review.
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