Page 919 - Clinical Immunology_ Principles and Practice ( PDFDrive )

888 PARt SEVEN Organ-Specific Inflammatory Disease

Methotrexate has been used in some uncontrolled studies, been used to inhibit pathogenic IgG autoantibody-induced
but there is no information to indicate that it is more efficacious antigenic modulation. Bortezomib, a proteosome inhibitor
or safer than azathioprine and its onset of action may take as approved for usage in multiple myeloma and mantle cell lym-
long as several months. As is true for corticosteroid therapy, it phoma, has been found to reduce anti-AChR antibody titers,
is the rare patient who enjoys a permanent remission following inhibit damage to the postsynaptic muscle membrane, and lead
institution of immunosuppressive therapy, and those who show to clinical improvement. Moreover, this agent was shown to
some improvement often require treatment indefinitely. suppress anti-AChR antibody production and deplete plasma
Cyclosporine, a potent immunosuppressive agent, has been cells from cultures of cell suspensions obtained from thymus
investigated because it interferes with IL-2–mediated T-cell specimens of patients with MG. 34
proliferation and thus would be expected to interfere with the The induction of antigen-specific immune tolerance, the
generation of T cells that would “help” the anti-AChR antibody therapeutic holy grail in autoimmune diseases, has received
response. A retrospective study suggested that cyclosporine considerable attention in EAMG. Early studies utilized extracel-
provided benefit in patients whose disease was refractory to lular domain sequences that form epitopes for pathological
corticosteroids and azathioprine. Serious renal toxicity and autoantibodies to induce tolerance to AChR. However, this
treatment withdrawal, which plagued earlier studies, were reduced approach risks provoking autoimmunity rather than suppressing
by careful selection of patients. In a 12-month European trial, it. To avoid this risk, one group has recently developed a novel
cyclosporine appeared to be as efficacious as azathioprine in vaccine consisting of bacterially expressed human AChR cyto-
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producing clinical improvement. Tacrolimus has a similar plasmic domains. To date, this group has used this vaccine to
mechanism of action to cyclosporine. When used in low dosage, prevent development of chronic EAMG when administered
it has proved as effective as cyclosporine as a corticosteroid-sparing immediately after the acute phase of EAMG and to rapidly reverse
agent with fewer side effects. Nevertheless, most practitioners established chronic EAMG when started during the chronic phase
reserve these agents for use in patients whose disease is refractory of EAMG. Treatment effects are robust and long-lasting. Although
to the combination of azathioprine and prednisone. the mechanisms of action of this novel approach have yet to be
Mycophenolate mofetil (MMF), another immunosuppressive fully elucidated, they may involve a combination of antibody-
agent that affects both T and B cells, was widely touted following mediated feedback suppression and regulatory T cell–mediated
the completion of early trials as a steroid-sparing agent in patients active suppression.
with MG. That experience suggested that it was effective 70–75% Complement inhibition has shown efficacy in the treatment
of the time, although probably less so in refractory MG. It has of EAMG and represents a target in patients with MG now that
an acceptable safety profile with adverse effects largely related complement inhibitors have demonstrated benefit in the treatment
to gastrointestinal intolerance. Benefit may require many weeks of a number of human disorders. A phase II placebo-controlled
of administration. However, two randomized, placebo-controlled cross-over study with a fully humanized monoclonal anti-C5
trials have challenged the early optimism. In one, the addition antibody was initiated only to be terminated because of inadequate
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of MMF treatment at the initiation of a 36-week schedule of recruitment. Nevertheless, given the importance of the terminal
prednisone tapering was not found to be superior to placebo in complement pathway in the pathogenesis of cases of MG and
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maintaining myasthenia control. In the second, the coadministra- the continued development of a number of complement inhibi-
tion of MMF and prednisone provided no better control of tors, it is likely that this strategy will be revisited.
myasthenic weakness than prednisone alone in the initial A B-cell targeting agent that has gotten much attention in
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management of generalized MG. However, none of the patients patients with MG is rituximab, a mAb specific for CD20, a protein
included in these two studies was known to be steroid resistant. expressed on B lymphocytes. Anecdotal reports and small
Thus whether MMF has long-term benefits with respect to uncontrolled case series using rituximab have shown improvement
myasthenic weakness or steroid-sparing effects in the population of MG. Interestingly, responsive patients do not demonstrate a
of steroid-resistant patients remains an open question. reduction in anti-AChR antibodies, suggesting an effect on
nonantibody functions, such as antigen presentation and pro-
POSSIBLE FUTURE THERAPEUTIC OPTIONS inflammatory cytokine secretion. Although most treated patients
have been anti-AChR antibody positive, benefit has also been
Many possible experimental avenues of investigation that have observed in anti-MuSK-positive/anti-AChR antibody–negative
been opened by studies in EAMG. These are aimed at interrupting patients, in whom longstanding remission has been seen in
the sensitization process of helper CD4 T cells, interrupting their association with reduction of anti-MuSK antibody titers. A
effector function, or interdicting the action of downstream controlled clinical trial of rituximab in anti-AChR–associated
proinflammatory molecules. Studies directed at CD4 T cells MG is currently underway. A number of other mAbs directed
include impeding their activation by inhibitors of the costimula- at CD20, including fully humanized ones, are under study in
tory molecules CD28 and ICOS and the induction of anergy or other autoimmune diseases and will likely attract attention with
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apoptosis of AChR-reactive T cells. In addition, inhibition of regard to MG.
factors that contribute to AChR antibody production, and against
which monoclonal antibodies (mAbs) are now available for CONCLUSIONS
human use, make this approach possible and, in some cases, are
now under clinical trials. This includes agents that abrogate the MG is a prototypic autoimmune disease in which the autoantigen/s
action of IL-6, IL-17, and BAFF. Additional studies directed at are well defined as are the mechanisms that mediate dysfunction
AChR-specific B cells include the use of AChR/Fcγ fusion proteins of the target tissue, skeletal muscle. EAMG, in which many of
to induce apoptosis of AChR-specific B cells by cross-linking the features of MG are faithfully recapitulated, has provided a
their B-cell AChR receptors and inhibitory FcγRIIb receptors. useful vehicle for elucidating the immunoregulatory abnormalities
In addition, non–cross-linking IgG4 anti-AChR antibodies have that underlie the pathogenesis of the human disease, and the