Page 930 - Clinical Immunology_ Principles and Practice ( PDFDrive )

898 Part Seven Organ-Specific Inflammatory Disease

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of disease-modifying therapies has represented a major advance compared with placebo. In an independent phase III rater-
in the treatment of individuals with RRMS and has had a blinded comparator trial, teriflunomide was found to have a
profound impact by mitigating morbidity and enhancing quality similar efficacy to IFN-β-1a in reducing the proportion of
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of life. participants with at least one relapse over 1 year. Teriflunomide
is teratogenic in rats and rabbits and is therefore contraindicated
Recombinant IFN-β in pregnant women and women of childbearing potential not
IFN-β is a type I IFN with potent antiviral properties. It has using reliable contraception.
pleiotropic effects on the innate immune system. Recombinant
IFN-β was first tested in MS on the basis of the contemporaneous Dimethyl Fumarate
theory that the disease was caused by an active viral infection Dimethyl fumarate (DMF) is the methyl ester of fumaric acid.
of the CNS. Although MS is now believed to be an autoimmune Prior to being tested as a DMA in MS, DMF was used as a biocide
disease, recombinant IFN-β therapy was serendipitously found in furniture and shoes to prevent the growth of molds during
to significantly reduce annualized MS relapse rates. It is manu- storage or transport. A combination of DMF and three other
factured as four different commercial products, all of which are fumaric acid esters was marketed in Germany as a treatment for
self-administered via either subcutaneous or intramuscular psoriasis. In two phase III trials conducted in 2012, oral DMF
injection. There are two distinct structural forms. IFN-β-1a is was demonstrated to decrease the annualized relapse rate of
produced in mammalian cells and has the same sequence as the adults with RRMS by approximately 34–50% compared with
naturally occurring compound, while IFN-β-1b is produced in placebo. 52,53 An additional cohort of subjects treated with GA
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modified Escherichia coli and has a Met-1 deletion and a Cys-17 was included as a reference comparator in one of the trials.
to Ser mutation. IFN-β-1a is glycosylated, and IFN-β-1b is There was no significant difference in the effect of twice-daily
nonglycosylated. Studies of the efficacy of IFN-β in RRMS have oral DMF versus daily subcutaneous GA on relapse rate, but
yielded remarkably consistent results across different formulations significantly fewer new or enlarging hyperintense lesions were
of the drug. In multiple randomized, double-blinded placebo- noted on T2-weighted MRI images in participants treated with
controlled trials, IFN-β therapy reduced annual relapse rates by DMF. These results led to FDA approval in 2013. DMF therapy
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20–35%. However, approximately 30% of patients with MS do is often associated with lymphopenia. Therapeutic efficacy does
not respond to the drug. The mechanism of action of IFN-β in not appear to be inversely related to lymphocyte counts. As with
MS has not been definitively elucidated. Proposed mechanisms IFN-β and GA, the mechanism by which DMF suppresses MS
include induction of the immunosuppressive cytokine IL-10, disease activity remains unclear. The most common side effects
inhibition of pathogenic Th17 cells, and stabilization of the BBB of DMF are flushing and gastrointestinal upset. In the postmarket-
via direct effects on the cerebrovascular endothelium. ing setting, several cases of progressive multifocal leukoencepha-
lopathy (PML), a rare viral infection of the brain, were reported
Glatiramer Acetate in patients who were taking DMF and had persistent lymphopenia.
GA comprises a mixture of polypeptides of different lengths PML has also been reported as a complication of other DMAs,
and sequences, synthesized by the randomized polymerization including fingolimod and, most notably, natalizumab.
of four amino acids, namely, glutamic acid, lysine, alanine, and
tyrosine. These are the most prevalent amino acids in MBP, a Fingolimod
candidate autoantigen in MS. It was originally thought that GA During homeostasis, sphingosine 1 phosphate receptor 1 (S1P1)
would act as a competitive antagonist of MBP peptides for binding signaling into lymphocytes drives their egress from lymph nodes
to MHC class II molecules on APCs. Subsequent mechanistic into the bloodstream. Fingolimod is an orally administered
studies did not support that theory. The mechanism of action S1P1 receptor modulator that effectively traps myelin-specific
of GA in MS is currently unknown, but alternative hypotheses T cells in lymph nodes so that they cannot reenter the circula-
that have been proposed include immune deviation of myelin- tion and gain access to the CNS. In a 24-month randomized,
reactive T cells from a destructive Th1 to an innocuous Th2 double-blinded, placebo-controlled trial, fingolimod was shown
+
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phenotype, increase in frequency and function of FoxP3 regula- to reduce annualized relapse rates by 50%. Furthermore, the
tory CD4 T cells or regulatory CD8 T cells, and induction of probability of disease progression at the 24-month follow-up
antiinflammatory type II monocytes. A pivotal trial of GA versus was lower in the fingolimod-treated subjects. In an independent
placebo in 1995 demonstrated a mean reduction in the relapse 12-month, double-blind, double-dummy phase III comparator
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rate of approximately 30%. In contrast, a multinational, study, fingolimod reduced the annualized relapse rate to a range
multicenter, double-blind, placebo-controlled phase III trial of of 0.16–0.20, as compared with 0.33 for IFN-β-1a, corresponding
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GA in PPMS was stopped after an interim analysis by an inde- to a relative reduction of 38–52%. In 2010, fingolimod became
pendent data safety monitoring board indicated no discernible the first oral DMA approved by the FDA to reduce relapses and
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treatment effect on the primary outcome measure. GA, admin- delay disability progression in patients with relapsing forms of
istered by subcutaneous injection, was approved by the FDA in MS. However, in a phase III randomized, double-blind, placebo-
1996 for reducing the frequency of relapses, but not for reducing controlled trial, fingolimod did not slow disease progression
the progression of disability. in patients with PPMS. 11,12 Fingolimod does not distinguish
between pathogenic and protective lymphocytes, and a number
Teriflunomide of opportunistic infections have emerged as complications of
Teriflunomide, an oral pyrimidine synthesis inhibitor, was the treatment. Patients taking fingolimod are susceptible herpes
approved by the FDA in 2012 for relapsing forms of MS. It has virus infections, particularly shingles. In the phase III comparator
broad immunosuppressive effects, including a cytostatic effect study with IFN-β-1a, two fatal infections occurred among the
on proliferating T and B lymphocytes. In a pivotal phase III fingolimod-treated subjects: disseminated primary varicella zoster
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trial, teriflunomide reduced annualized relapse rate by 31% and herpes simplex encephalitis. Consequently, patients are