Transcript Plasmapheresis: Graves’ Disease

Autoimmunity III
Therapeutics of
Autoimmune Diseases
Autoimmune Therapeutics
• General
– Ag-specific
– Gene therapy
– IVIg
– Plasmapheresis
– BMT
• Specific
– SLE
– RA
– MS
Antigen-specific Therapy
• Induce tolerance
• Determined by
– Form and purity of Ag
– Dose
– Route of administration
– Co-stimulation
• Systemic or mucosal
Ag-induced Tolerance
Gene Therapy/Anti-cytokine
• Local delivery of regulatory proteins by
insertion and expression of foreign DNA
in a host cell
– Viral vectors: replication defective,
infection-competent
• Anti-cytokine
– -TNF Abs, sTNFR, IL-6 Abs,
inhibitors; IL-4, IL-10, IL-13
NFB
Intravenous Immunoglobulin
(IVIg)
• High doses of IgG pooled from healthy
donors
• Mechanism of action:
– Regulatory properties of anti-idiotypic Abs
– Effects on cytokine synthesis, Rs, C’ Rs
– Block FcR on phagocytes, other cells
– Simultaneous ligation of FcR and B cell R
– Acceleration of rate of IgG catabolism
Yu, Z. 1999. NEJM.
Plasmapheresis
• Plasma components can be selectively
removed; remaining components
combined with replacement plasma or inert
substitute and returned to patient
• Without replacement = immunoadsorption
• Density gradients; affinity, hollow fiber, or
filtration membranes; columns
• Without immunosuppressants: Ab rebound
Cearlock, D.M.
2000. MLO.
Plasmapheresis
• Plasma components one normal means for
plasmapheresis is to:
– Remove the plasma
– Replace with fresh frozen plasma
• This method removes Ig but does not
remove immune cells.
• This method does afford the opportunity to
administer B-cell immunosuppression.
Bone Marrow Transplant
• Hematopoietic stem cells (HSCs)
– Transfer and prevent disease
• Intense immunosuppression
(immunoablation) followed by autologous
or allogeneic HSC transplant
– Total body irradiation, immunosuppressants
– T cell and B cell depletion
• Coincidental hematological malignancies
SLE
• Goals: treat active phase w/out causing
long-term damage
– Limiting corticosteroid, immunosuppressive
exposure
– Combinations of drugs
– Treat organ/system manifestations
Summary of both established therapies and novel therapies for SLE
New uses for established
therapies
Novel
agents
Cytokines and
inflammatory mediators
Nonsteroidal
antiinflammatory drugs
Plasmapheresis
LJP 394
Anti-IL10 antibody
Hydroxychloroquine
Intravenous
immunoglobulin
IDEC131
TNF alpha inhibitors
Prednisone
Mycophenolate mofetil
BG9588
BlyS blockers
Cyclophosphamide
Tacrolimus
CTLA4I
g
Anti-C5a antibody
Azathioprine
Methotrexate
Established
pharmacological therapies
Leflunomide
Rituximab
Cyclosporine
Stem cell transplantation
SLE
• Clinical Trials:
– Regulation of CD154 (CD40L)
– SELENA (Safety of Estrogens in SLE
National Assessment) – Phase III
• OCP: Ortho-Novum 777 (oral contraceptive)
• HRT: Premarin and Provera (replacement)
– II: Dehydroepiandrosterone (GL701)
– UV A-1 light therapy
IL1 and TNFα are central
mediators in RA
IL1 TNF
Inflammation
Synovial pannus
formation
Cartiage
breakdown
Bone
resorption
TNF-α central to the
pathogenesis of RA
Goals of Therapy for RA
• Relieve pain and Inflammation
• Prevent joint destruction
• Maintain function
RA
• Non-steroidal anti-inflammatory drugs
(NSAIDs)
• Glucocorticoids
RA
• Non-steroidal anti-inflammatory drugs
(NSAIDs)
– Reduce inflammation, relieve pain
– COX-1 and/or –2
– COX-2: celecoxib (Celebrex), rofecoxib
(Vioxx) may be not now!
• meloxicam, flusolide, nimesulide
RA
• Corticosteroid therapy
– Can be used to bridge gap between initiation of
DMARD therapy and onset of action
– Anti-inflammatory and immunosuppressive effects
– Intra-articluar injections can be used for individual
joint flares
– Does not conclusively affect disease progression
– Tapering and discontinuation of use often
unsuccessful
Newer drugs in the treatment of
RA
• DMARDs
• Etanercept (Enbrel)
• Infliximab (Remicade)
• Leflunomide (Arava)
Etanercept
• Etanercept binds specifically to tumor
necrosis factor (TNF) and blocks its
interaction with cell surface TNF receptors.
• It plays an important role in the inflammatory
processes of rheumatoid arthritis (RA),
juvenile polyarticular rheumatoid arthritis
(JRA), and ankylosing spondylitis and the
resulting joint pathology.
Etanercept
• Two distinct receptors for TNF (TNFRs), a
55 kilodalton protein (p55) and a 75
kilodalton protein (p75), exist naturally as
monomeric molecules on cell surfaces
and in soluble forms.
• Biological activity of TNF is dependent
upon binding to either cell surface TNFR.
Etanercept
• Etanercept is a fusion protein made up of two
recombinant p75 soluble TNF receptors fused
with the Fc portion of human IgG1. The dimeric
structure of etanercept makes it approximately
1000 times as efficient as the monomeric
soluble p75 TNF receptor at neutralizing TNF.
• Etanercept inhibits binding of both TNF and
TNFb (lymphotoxin alpha) to cell surface
TNFRs, rendering TNF biologically inactive.
Etanercept
• Etanercept can also modulate biological
responses that are induced or regulated
by TNF, including expression of adhesion
molecules responsible for leukocyte
migration (i.e., E-selectin and to a lesser
extent ICAM-1], serum levels of cytokines
(e.g., IL-6), and serum levels of MMP-3 or
stromelysin.
Etanercept - STUDY
• A study evaluated 234 patients with active
RA who were = 18 years old, had failed
therapy with at least one but no more than
four disease-modifying antirheumatic
drugs (DMARDs; e.g.,
hydroxychloroquine, oral or injectable
gold, methotrexate [MTX], azathioprine,
D-penicillamine, sulfasalazine), and had =
12 tender joints, = 10 swollen joints, and
either ESR = 28 mm/hr, CRP > 2.0 mg/dL,
or morning stiffness for = 45 minutes.
Etanercept - STUDY
• Doses of 10 mg or
25 mg ENBREL® or
placebo were
administered SC
twice a week for 6
consecutive months.
Etanercept - STUDY
• Among patients receiving ENBREL®, the
clinical responses generally appeared within 1
to 2 weeks after initiation of therapy and nearly
always occurred by 3 months.
• A dose response of 25 mg ENBREL was more
effective than 10 mg.
• ENBREL was significantly better than placebo in
all components of the measures of RA disease
activity, such as morning stiffness and disease
progression.
Heart Failure
• Decreased tissue TNF- levels, it did not
improve cardiac function, and at high doses it
was associated with higher mortality.
• These results in a rodent model confirm the
results of clinical trials with etanercept and
infliximab (ie, that decreasing TNF levels in
plasma or tissues does not improve cardiac
function and may actually increase mortality).
Infliximab: Pharmacology
• A chimeric IgG1 antibody against TNFα, composed of human constant and
murine variable regions
• Binds specifically to human TNF-α
• Binds both to soluble and
transmembrane forms, thus inhibiting
binding of TNFα with its natural
receptors
Leflunomide
• Reduce pain and inflammation
• Retards structural damage erosion and
joint space narrowing
• Inhibit pyrimidine nucleotides formation
• Hepatotoxicity and gastrointestinal
toxicities
MS
MS – RR
• Recombinant IFN-b
– Reduce proliferation of T cells and TNF
production
– Inhibits TH1 cytokines, cellular migration,
Ag presentation, adhesion molecule and
protease expression
– Induces TH2 cytokines
– RR: s.c. or i.m.
– Side effects: flu-like symptoms, headache,
anemia, injection site reactions
IFN-b
• IFN-b1b (Betaseron)
– Missing carbohydrate side chain, cys17ser
• IFN-b1a (Avonex)
– Prevents brain atrophy
– Delay in time to physical disability
• ~30% reduction in number of exacerbations
• ~$10,000/year
MS – RR
• Glatiramer acetate (Copaxone)
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Acetate salt of mixture of synthetic peptides
Copolymer 1
L-ala, L-glu, L-lys, L-tyr
Daily s.c. – injection site reactions
Mimics MBP
33% reduction in relapse rate
 # of relapses and # and volume of T2
Higher proportion free of relapse, fewer with
worsening EDSS
– Possible benefit over IFN-b over time
MS – Other
• RR
– Relapses: Glucocorticoids
– Symptom specific therapy
• Chronic-Progressive
– IFN-b1a, -b1b, cyclophosphamide,
mitoxantrone, plasma exchange
Mitoxantrone
• Cell-cycle non-specific anthracycline
chemotherapeutic that intercalates with
DMA leading to breaks in DNA.
• Inhibits both DNA and RNA synthesis
• Reacts with P450 reductase causing
formation of free radicals and cell
destruction.
MS – Clincal trials
• I, II, III: ginkobiloba, -lipoic acid/
essential fatty acids, vit E/selenium
• II: Zenepax (-IL-2 R a subunit)
• III: IVIg
• I: M-T412 (-CD4 mAb chimera)
• II: CGP77116 (myelin-like protein)
• II: Yoga
Surprise Rx
• 3-Hydroxy-3-methhylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors, the socalled statins, atorvastatin, cerivastatin,
fluvastatin, pravastatin, lovastatin and
simvastatin, can induce relatively large
reductions in plasma cholesterol levels and
are established drugs for the treatment of
hypercholesterolemia.
Surprise Rx
• It has been demonstrated that statins
decrease the secretion of the proinflammatory cytokines IL-6 and IL-8 but not
tumor necrosis factor- (TNF-), from
activated macrophages, inhibit chemokines
release such as MCP-1 and IP-10 by
endothelial cells (ECs), inhibit adhesion
molecules expression such as CD11 on
monocytes or ICAM-1 on ECs.
Surprise Rx
• Experiments demonstrated that statins inhibit
•
MMPs activity and secretion, such MMP-1,
MMP-3 and MMP-9, by human and rabbit
macrophages in vitro as well as in vivo.
Furthermore, statins have effects on the
coagulation process.
Surprise Rx
• Recently, it has been demonstrated that
•
statins act as direct inhibitors of induction of
MHC-II expression by IFN-g and thus as
repressors of MHC-II-mediated T cell
activation [Nat Med 2000;6:1399; Swiss Med
Wkly 2001;131:41].
This effect of statins is due to inhibition of the
inducible promoter IV of the transactivator
class II transactivator (CIITA). The CIITA is a
master regulator of MHC class II expression.
statins
Functional inhibition
of MHC class II antigens
by statins on
T lymphocytes activation.
[3H]-thymidine
incorporation (a),
and IL-2 release (b)
measured in allogenic
T lymphocytes exposed
to human ECs pre-treated
for 48 h with
IFN- (500 U/ml) alone (1),
or IFN- (500 U/ml) with
atorvastatin (10 M) (2).
Surprise Rx
Numerous other practical clinical applications for
using statins as immunomodulators, particularly in
diseases where aberrant expression of MHC class
II molecules are implicated.
This ranges from autoimmune diseases such as:
type I diabetes, multiple sclerosis and rheumatoid
arthritis to psoriasis and chronic inflammatory
diseases like atherosclerosis.
The high degree of patient tolerance of statins makes
them potentially a welcome addition to the limited
current arsenal of immunosuppressive agents.