Page 1245 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 89 Biological Modifiers of Inflammatory Diseases 1207

expressed on the surface of pre-B through activated mature B disease of the CNS. Cases of PML have been reported among
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cells. Rituximab induces lysis of CD20 B cells by several mecha- patients with hematological malignancies, SLE, and RA who
nisms, including complement activation, ADCC, and induction were treated with rituximab, but PML usually occurs in the
of apoptosis. Induction regimens using four weekly doses or context of other therapies impacting lymphocyte survival and
two larger doses administered 2 weeks apart appear to be equally proliferation. 94
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effective at effecting the depletion of circulating CD20 B cells,
which can last up to ≥9 months after a single course of therapy. Ofatumumab
Treatment with rituximab has been shown to cause significant Ofatumumab is a fully human mAb that binds to an epitope
transient decreases in inflammatory CD4 T cells that express encompassing both small and large loops of the extracellular
IL-17; the extent to which this is caused by an indirect consequence domain of the CD20 cell surface antigen on B lymphocytes. The
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of CD20 B-cell depletion or depletion of identified subsets of binding epitope of ofatumumab is distinct from that of rituximab,
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CD4 CD20 T cells is uncertain. 81,82 residing more proximal to the cell membrane. In comparative
Approved for use in patients with RA failing to respond to studies with rituximab using chronic lymphocytic leukemia (CLL)
initial disease-modifying antirheumatic drug (DMARD) therapy, cells, ofatumumab elicits similar ADCC but elicits greater
rituximab has been shown to improve the signs and symptoms complement-dependent cytotoxicity (CDC) because of the greater
of disease, functional status, and quality of life and to slow proximity of the binding site to the cell membrane and/or binding
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radiographic progression of disease in patients with RA. Greater affinity to CD20 epitopes. 95
clinical responses are observed among patients with RA who are
seropositive for rheumatoid factor (RF) and/or anticitrullinated Obinutuzumab
peptide (CCP) autoantibody compared with patients seronegative Obinutuzumab (GA101) is a recombinant, humanized, and
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for RF or CCP. The optimal treatment schedule for use of glycoengineered type II CD20 mAb of the IgG1 isotype that
rituximab in RA remains to be determined, but retreatment is targets the extracellular loop of the CD20 transmembrane
generally recommended no sooner than 6 months following expressed on the surface of pre-B and mature B lymphocytes.
initial treatment for patients in whom the disease flares up in Relative to rituximab and ofatumumab, glycoengineering of the
association with recovery of B-cell counts and for those who Fc portion of obinutuzumab results in a higher affinity for FcγRIII
had initially responded to rituximab therapy. receptors on immune effector cells, such as NK cells and phago-
Rituximab has also been used with considerable success and cytic cells. In vitro studies with B-cell lymphoma–derived cell
is approved for use in the management of ANCA-associated and lines show that compared with rituximab and ofatumumab,
other vasculitis syndromes. Rituximab plus glucocorticoid therapy obinutuzumab mediates greater induction of direct cell death
was shown to be as effective as cyclophosphamide in the treatment and effector cell–mediated ADCC and cellular phagocytosis.
of patients with granulomatosis with polyangiitis (GPA) or However, compared with rituximab and ofatumumab, CDC is
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microscopic polyangiitis (MPA). In a subgroup of patients with significantly reduced with obinutuzumab. 96
relapsing ANCA vasculitis, rituximab was, in fact, superior to
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cyclophosphamide in inducing disease remissions. In patients Alemtuzumab
with cryoglobulin syndromes occurring in the context of either Alemtuzumab is an mAb with specificity for CD52, an antigen
HCV infection or lymphoma, use of rituximab has been shown present on the surface of B and T lymphocytes as well as the
to decrease cryoglobulin and constituent Ig titers and hasten majority of monocytes, macrophages, NK cells, and a subpopula-
resolution of cryoglobulin manifestations, including skin ulcers, tion of neutrophils. Approved for use in the treatment of B-cell
glomerulonephritis, peripheral neuropathy, arthritis, and/or CLL and relapsing-remitting MS, alemtuzumab has also been
hyperviscosity complications. 86 used with success for the treatment of T-cell prolymphocytic
Although not yet formally approved, rituximab has been used leukemia, prevention and treatment of acute GvHD, and preven-
with reported success in the management of other autoantibody- tion of allograft rejection. Alemtuzumab has been used off-label
mediated disorders, including SLE, primary Sjögren syndrome, with reported success in the treatment of patients with severe
inflammatory myopathy, chronic inflammatory demyelinating SLE and Behçet disease refractory to other treatments. 97,98 Despite
polyneuropathy (CIDP), MS, and pemphigus. 87-92 the depletion of T lymphocyte, B lymphocyte, NK cell, and
Despite the potential for immunodeficiency-related to monocyte populations following treatment, reported rates of
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depletion of CD20 B cells, only minimal increases in serious serious infections following treatment with alemtuzumab are
or opportunistic infections have been reported in patients with not significantly increased compared with other immunosup-
RA or ANCA vasculitis treated with repeated cycles of rituximab. pressive regimens employed to manage the disorders for which
Mild decreases in the overall levels of serum Igs may be observed it is used. However, there is a significant occurrence of secondary
during treatment, but Ig levels are rarely depleted, likely due autoimmunity following use of alemtuzumab, most often manifest
to the preservation of more mature B cells and plasma cells as autoimmune thyroid disease and immune thrombocytopenia.
that have lost surface expression of CD20. However, if used The observed autoimmune complications may be caused by
concomitantly with other immunosuppressive agents impacting homeostatic proliferation of self-reactive memory T cells in the
lymphocyte proliferation, significant hypogammaglobulinemia absence of an effective T regulatory response during immune
may ensue over time as a result of the inability to replenish the reconstitution. 99
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plasma cell compartment. Use of rituximab carries a safety
warning related to an observed increased risk of viral infections, Brentuximab Vedotin
including CMV, herpes simplex virus (HSV), varicella-zoster Brentuximab vedotin (BTX-v) is an mAb with specificity for
virus (VZV), HBC, and JC virus. Reactivation of JC virus, CD30 that is covalently linked to the antitubulin agent mono-
latent in more than 80% of the general population, can occur methyl auristatin E. Expressed on subpopulations of T lympho-
in immunosuppressed patients to cause PML, a fatal demyelinating cytes, some populations of B cells, and most notably Hodgkin