Download Eulji University Hospital

Eulji University
New Therapeutics
in Rheumatoid Arthritis
Seung-cheol Shim M.D., Ph.D.
Division of Rheumatology
Eulji University Hospital
How to take care of these ?
보건의료 환경의 변화
의료소비자의 서비스 질에 대한 기대 증대
•
의료소비자의 의식수준, 생활수준향상
•
건강정보의 대중화로 매스컴, 인터넷을 통해
의료정보 습득용이
건강, 질병에 대한 관심고조
양질의 서비스요구
의료기관에서 환자 건의 사례 및 의료분쟁증가
의료소비자 욕구의 다양화
의료수혜자로써의 의식변화
Treat what?
Rheumatoid arthritis (RA) is
a systemic disorder
characterized predominately
by a chronic
inflammatory polyarthritis,
with frequent progression to joint destruction
and disability.
Eicosonoid pathway
류마티스 질환의 치료제
Pyramid therapy
Radiographic joint damage develops in 75% of
patients within the first 2 years of disease
Dimaryp therapy
Severity (arbitrary units)
류마티스관절염의 진행
0
5
10
15
20
25
RA Duration of Disease (years)
30
Kirwan et al, J rheumatol, 2001
Needs for developing novel therapy
Methotrexate (MTX) remains the first-choice DMARD
for the treatment of moderate to severe RA, and is often
the anchor drug for combination regimens.
Combined use of MTX and a TNF-a inhibitor
is among the most potent of treatment regimens,
Yet clinical trials of early RA show that this
combination produces ACR70 responses of only 35% to
45%
Cell types and cytokines involved in RA pathogenesis
as potential targets for treatment with biologic drugs.
Cytokine targeting
류마티스관절염에서 싸이토카인의 불균형
TNF란?
생물학적제제
•
TNF-α
APC
Inflixmab(Remicade)
Etanercept(Enbrel)
Adalimumab(Humira)
T
B
Apoptotic Pathways within the Cell
Should be balanced
Comparison of ACR20, ACR50, ACR70, and ACR90 responses.
Change in radiographic scores*
Serious infections observed in 0.5% of patients who received
at least 1 dose of study drug*
Pharmaceutical companies are developing other TNF-a inhibitors
pegylated form of an antibody fragment (certolizumab
pegol [CDP-870]) and
human anti–TNF-a monoclonal antibody (CNTO 148).
IL-
Anakinra
Although the results of randomized, placebo-controlled
trials have shown anakinra (recombinant human IL-1
receptor antagonist) to be effective in treating RA,
the reduction in signs and symptoms is modest compared
with TNF-a blockade.
Moreover, IL-1 blockade may not be a useful strategy for
treating patients who fail therapy with a TNF-a
antagonist.
IL-1-TRAP
developed to create a more potent IL-1 blocker.
high-affinity inhibitor of IL-1 consisting of the Fc
portion of human IgG1 and the extracellular
domains of both IL-1 receptor components.
However, the results from a phase 2 trial involving
201 patients who had RA show that
weekly subcutaneous administration of IL-1 TRAP
produces only modest clinical improvements
compared with placebo.
Efficacy of combined biologic agents
Serious adverse events that occurred during the study*
Anakinra in AOSD
Anakinra in adult-onset Still’s
disease who are refractory to
corticosteroids, methotrexate,
and TNF-a blockade
Proposed cytokine cascades
in AOSD.
IL-
Pleiotropic action of IL-6
Role of interleukin-6 (IL-6) in murine models of arthritis*
recombinant,humanized, monoclonal antibody against the IL-6
receptor (MRA, tocilizumab).
Adverse events observed in at least 3% of patients*
Increase level of cholesterol in the patients on tocilizumab
IL-
IL-15
is a proinflammatory cytokine produced in rheumatoid
synovium by macrophages, fibroblasts, and endothelial
cells.
essential for the development of natural killer (NK) cells,
NK T cells, and intraepithelial lymphocytes, and the
proliferation and maintenance of CD8+ memory T cells
Clinical responses to anti–IL-15 antibody in RA patients*
human IgG1 anti–IL-15 monoclonal antibody (HuMax-IL-15, AMG714)
IL-15 binds to the heterotrimeric, high-affinity IL-15
receptor (IL-15R), which consists of the α-subunit (IL15R α ), IL-2/IL-15β-subunit, and common γ -chain
(γc). IL-15 alone binds with high affinity to IL-15R α ;
it shares the common γ c-subunit with IL-2, IL-4, IL-7,
IL-9, and IL-21
IL-
IL-12
A heterodimer consisting of a p40 and p35 subunit,
critically involved in the development of Th1 immune
responses.
RA is often assumed to be a Th1-mediated disease
process.
Signals that Influence Th Cell Differentiation
Currently, a monoclonal antibody to human IL-12 p40
subunit is in early clinical development.
Results are available from a phase 1 study using this
antibody in patients who had psoriasis,
but not yet for studies of RA.
IL-
IL-18
a member of the IL-1 family of cytokines, was initially
discovered based on its interferon-γ–inducing activity, and is
produced by macrophages and dendritic cells.
IL-18 is a Th1 cytokine, and can induce the synthesis of
proinflammatory cytokines and chemokines
Phylogenetic tree of IL-1 family amino acid sequences.
IL-1β–converting enzyme (ICE)
release of IL-18 is processed by the IL-1 β –
converting enzyme (ICE) (caspase-1),
then the production of IL-18 and IL-1 may be
simultaneously downregulated by an ICE inhibitor.
oral ICE development program was terminated
because animal toxicology studies found significant
drug-related liver abnormalities.
Inhibition of leukocyte migration
Chemokine family classification.
Adhesion molecule
natalizumab, a monoclonal antibody to the a4 integrin subunit
In multiple sclerosis, one who had Crohn’s disease
No RA clinical data
Cell targeting
approves rituximab for moderate to severe RA
T cell targeting
Anti-CD4, anti-CD5, and anti-CD52 antibodies have failed to
produce significant clinical benefits in RA,
indicating that merely killing T cells is not the answer for
treating this disease.
Too easy……
Woooooooops!!!
Inhibitory T-cell cytokine
IL-10 afforded little or no clinical efficacy
T-cell costimulatory blockade
T 임파구의 활성화 물질
Abatacept
is a fusion protein consisting of cytotoxic Tlymphocyte–associated antigen 4 (CTLA4) covalently
linked to the Fc region of a human IgG1.
Efficacy of Abatacept
AEs and discontinuations at 1 year in the intent-to-treat population*
B-cell targeting
The B cell, the other major arm of the adaptive
immune response, has emerged as a therapeutic
target
Because of
success of rituximab therapy for RA
Rituximab, a chimeric anti-CD20 monoclonal antibody
1.was approved in 1997
2.for use in relapsed or refractory, low-grade or
follicular, CD20+ B-cell non-Hodgkin’s lymphoma.
3.CD20 is expressed on the cell surface of B cells from
the pre–B-cell stage through the mature stage, but is
absent on stem cells and plasma cells.
4.eliminates B cells by a mechanism of antibodydependent cellular cytotoxicity, leading to transient
depletion of CD20+ B cells.
Median Levels of Peripheral CD19+ B Cells and Median
Changes in Levels of Total Rheumatoid Factor during the
24-Week Study Period.
Summary of adverse events
Osteoclast inhibitors
zoledronic acid
The most potent form of the aminobisphosphonates,
protects against bone erosion,
although these studies also suggest that the
aminobisphosphonates may increase the systemic
inflammatory response in animal study.
small, randomized, placebo-controlled study, two
infusions of zoledronic acid
administered 12 weeks apart did not seem to
exacerbate the signs and symptoms of RA,
while decreasing the mean change in the
progression of bone erosions and bone edema over
26 weeks, as measured by MRI
Larger trials are required
Receptor activator of nuclear factor-κB ligand inhibitors
A schematic representation of osteoclast differentiation
receptor activator of nuclear factor-kB/receptor activator
of nuclear factorkB ligand (RANK/RANKL)
a critical mediator of osteoclast differentiation and bone
resorption.
RANKL-positive cells line the synovium of patients who
have RA. Studies have shown that TNF-a enhances
RANKL-induced osteoclast activity in the rheumatoid
synovium.
Soluble RANKL levels are elevated in patients who have RA,
and decrease following anti–TNF-a treatment.
Researchers hypothesize that inhibition of RANKL
protects against structural bone damage in RA.
Preliminary studies have found that a fully human
anti-RANKL monoclonal antibody (AMG162) inhibits
bone loss in postmenopausal women who have
osteoporosis;
it has not yet been tested in RA.
Small molecules
p38 mitogen-activated protein kinase inhibitors
The p38 mitogen-activated protein kinase (MAPK) signaling
cascade in T cells.
p38 mitogen-activated protein kinase (MAP)
Since the identification of the p38 as a key signal-transducing
molecule in the expression of the TNF more than 10 years ago
huge efforts have been made to develop inhibitors of p38 with
the intent to modulate unwanted TNF activity
VX-702 (Vertex Pharmaceuticals),
an oral p38 MAP kinase
The effectiveness and safety of, is currently being
explored in a large phase 2 trial involving patients who
have RA.
Phase 2 trials in RA using BIRB 796, another inhibitor
of p38 MAP kinase, have also begun.
An earlier phase 1 trial showed that BIRB 796 was well
tolerated by patients who had this disease.
SCIOS 469 is another p38 MAP kinase inhibitor under
development.
Three-hydroxy-3-methylglutaryl-CoA reductase inhibitors
The cholesterol synthesis pathway and protein prenylation
Simvastatin, a HMGCoA reductase inhibitor
reduce anti-CD3/anti-CD28–stimulated T-cell
proliferation and interferon-gamma release from
mononuclear cells in synovial fluid and peripheral blood
randomized, double-blind, placebo-controlled trial of
atorvastatin in RA
However, the clinical benefits of atorvastatin are modest
compared with those of MTX, most other traditional DMARDs,
and the TNF-a antagonists.
Summary
With potent induction regimens, drug-free holidays may be
a realistic goal to mitigate the potential risks associated with
the long-term use of immunosuppressive drugs.
In the BEST study, a randomized trial comparing four
different treatment strategies in early RA, 56% of 120
patients who started treatment with infliximab, 3 mg/kg, in
combination with MTX were able to maintain a low disease
activity score even after stopping infliximab.
These encouraging results will provide impetus for further
studies of drug withdrawal in the context of induction
therapy for early RA.
류마티스관절염은 단일 질환인가?
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