Personalized Healthcare in Autoimmune Diseases - Genomic Biomarkers for Pharmaceutical Development - page 61

might be less effective in those SLE patients who experience an increase in their type I IFN
response activity levels during rituximab treatment.
3.5 A TYPE I INTERFERON SIGNATURE AS A PREDICTIVE MARKER
OF RESPONSE TO INTERFERON- β THERAPY IN PATIENTS
WITH MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous
system (CNS), and is characterized by progressive neurological dysfunction due to demyelina-
tion of the nerves [56] . Destruction of the myelin sheet disrupts the nerve action potential, lead-
ing to muscle weakness, blurred vision and motor symptoms. Clinical experience has revealed
that MS is a heterogeneous disease that is difficult to treat. The heterogeneous nature within
the different forms of MS is reflected by the clinical presentation, which ranges from mild to
severe demyelinating disease. The existence of heterogeneity in the brain of MS patients is pro-
posed to represent different pathogenic processes underlying MS, ranging from an inflamma-
tion-mediated to an immune-independent demyelinating form of brain tissue destruction. The
heterogeneity is also reflected by the considerable variation in responsiveness to treatment and
most likely has its origin in the multifactorial nature of the disease, whereby specific combina-
tions of genetic risk factors together with an appropriate environmental trigger influence not
only susceptibility but also the severity, pathogenesis and outcome of the disease.
No curative therapy is currently available, and the majority of affected individuals are
ultimately disabled. Therapies are mainly directed to protect CNS cells, modulate T cells and
induce remyelination. IFN-β was the first agent to show clinical efficacy in the most common
form of MS, i.e., relapsing remitting (RR) MS. According to results from clinical trials, IFN-β
treatment reduces relapse rates by about 30%, decreases the formation of inflammatory lesions
in the CNS, extends remission periods and possibly slows down progression of disability
[57] . Currently, a prolonged course of IFN-β treatment is still the best available therapy for
RRMS. There are several IFN-β preparations available for therapy (i.e., recombinant IFN-β1b
produced in Escherichia coli (Betaseron® / Betaferon® by Bayer and Extavia® by Novartis), and
recombinant IFN-β1a derived from Chinese hamster ovary (CHO) cells (Avonex® by Biogen
Inc., Rebif® by Merck Serono S.A., and Pfizer and Cinnovex® by Cinnagen).
Unfortunately, clinical experience indicates that there are IFN 'responders' as well as
'non-responders'. A high proportion of about 40% of the patients do not or only poorly
respond to IFN-β treatment [58] . Moreover, IFN-β therapy is associated with adverse reac-
tions such as flu-like symptoms and transient laboratory abnormalities. Given the destruc-
tive nature of RRMS, the risk of adverse effects, and considerable costs for therapy, there is a
strong need to make predictions of success before the start of therapy.
Mechanistically, there are two phases to explain the failure to respond to therapy with a
biological agent. The first phase of unresponsiveness is the consequence of a direct failure
of the agent to suppress the disease, whereas the second phase may follow a period of good
response. The first phase implies that baseline characteristics and / or pharmacodynamic
responses may differ between patients, leading to interindividual differences in clinical effi-
cacy, which relate the heterogeneous nature of RRMS. The second phase can be explained
by immunogenicity, i.e., the development of neutralizing antibody (NAb) directed against