Page 932 - Clinical Immunology_ Principles and Practice ( PDFDrive )

900 Part Seven Organ-Specific Inflammatory Disease

depletion of circulating B cells that lasts approximately 6–9 well as pathogenic immune responses may be undermined,
months. In a phase II clinical trial of rituximab in RRMS, subjects increasing the risk of infection. Furthermore, DMAs are generally
in the active treatment arm experienced a significant reduction ineffective in progressive forms of disease. Critical goals of the
in clinical relapses and in the formation of new or enhancing MS research community at present are to better define the cellular
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MRI lesions compared with subjects in the placebo arm. and molecular mechanisms that link neuroinflammation to
Ocrelizumab is a next-generation fully human recombinant end-organ injury (namely, demyelination and axonopathy) and
anti-CD20 mAb that binds to a different epitope from rituximab to elucidate the pathogenic pathways that underlie clinical
and with higher affinity. In two large phase III studies, ocrelizumab progression. It is also imperative to develop a deeper understand-
reduced the annualized relapse rate in subjects with RRMS by ing of obstacles to endogenous repair pathways in the CNS. This
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nearly 50% compared with IFN-β-1a over a 2-year period. knowledge could ultimately lead to the discovery of laboratory-
Additionally, ocrelizumab delayed confirmed disability progression based surrogate biomarkers of both acute and chronic disease
by approximately 40% and the total number of gadolinium- activity, as well as drugs that block, or even slow, disability
enhancing lesions by >90% compared with IFNβ-1a. accumulation in progressive MS and promote remyelination and
Interestingly, some patients with progressive MS might also axonal regeneration across clinical subtypes.
+
benefit from the depletion of CD20 cells, particularly if there
is evidence of ongoing activity at the time of treatment initiation.
Hawker et al. found that rituximab significantly delayed the time On tHe HOrIZOn
to confirmed disease progression in a subset of patients with • The introduction of disease-modifying therapies has represented a
primary progressive MS who had gadolinium enhancing lesions major advance in the treatment of individuals with relapsing–remitting
9
on baseline MRI scans of the brain. The benefit was most multiple sclerosis (RRMS). However, these drugs have global effects
dramatic in subjects aged <51 years. In a recently completed on lymphocytes, thereby increasing the risk of infection. A future goal
trial of ocrelizumab in PPMS, the risk of progression of clinical will be to develop drugs that specifically target pathogenic leukocytes
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disability was reportedly reduced by 24%. As a result, in early and/or autoreactive lymphocytes.
2016, the FDA granted ocrelizumab “breakthrough therapy • Disease-modifying therapy is currently focused on the modulation of
lymphocytes. Drugs that target innate immune cells may enhance
designation” for PPMS. MS therapy in the future.
The mechanism by which B cell–depleting therapy alleviates • Recent studies suggest that B cell–depleting therapy may be beneficial
MS does not appear to be reduction in antibody titers. Rituximab for some patients with primary progressive MS (PPMS). There is a
depletes B cells from the CSF of patients with RRMS with little dire need for drugs that slow, or even halt, disability accumulation in
64
effect on CSF IgG levels. B cells are professional APCs, and progressive forms of MS and that are effective in older patients without
evidence of recent neuroinflammatory activity.
there is some evidence that they are important for sustaining • An increased understanding of the mechanisms by which inflammatory
myelin-specific Th17 responses in MS. The frequency of GM-CSF– cells cause central nervous system (CNS) damage and of the obstacles
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producing B cells was found to be elevated in RRMS. Hence, to endogenous repair pathways in MS may inform the development
ocrelizumab and rituximab may eliminate an important cellular of neuroprotective and neuroregenerative agents.
source of GM-CSF, a monocyte/macrophage–mobilizing cytokine
that has been implicated in the pathogenesis of autoimmune
demyelinating disease. Disruption of meningeal follicle–like Please check your eBook at https://expertconsult.inkling.com/
structures is yet another putative mechanism of action that might for self-assessment questions. See inside cover for registration
be particularly relevant to progressive forms of MS. details.

tHeraPeUtIC PrInCIPLeS REFERENCES
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