Transcript Immunosuppresion for SLE

Immunosuppressants
Very, very powerful Immunosuppressants available
 Non-Pharmacological:
• Irradiation
• Plasmapheresis  removal of
autoantibodies in diseases like MG
 Pharmacological:
• deplete T cells or B cells completely with anti-CD3
or anti-CD20 antibodies
• chemotherapy
• calcineurin inhibitors, steroids
Problem: Immunosuppression (infections)
Side-Effects of Immunosuppressants
1) General Side Effect: Immunosuppression
• Reactivation of latent viral infections
(e.g. herpes, varicella, CMV, PML)
• Bacterial and fungal infections
• Bone marrow suppression
• Increased risk of cancer
2) Specific Side Effects:
• Nephrotoxicity of the calcineurin inhibitors
• Metabolic changes with steroids
• “cytokine release syndrome” with anti-CD3 Ab
Corticosteroids
 broad anti-inflammatory effects
 High dose pulses of i.v. methylprednisolone (SOLUMERDOL, A-METHAPRED) used to reverse acute
transplant rejection and acute exacerbations of
autoimmune diseases like MS or SLE
 also used to suppress allergic reactions to biologics (e.g.
first-dose cytokine storm in transplantation with
muromonad-CD3 or thymoglobulin)
Invaluable for short-term use!!!
Cytotoxic Agents
Are typically covered in Oncology.
For this lecture it is sufficient you to know that all
cytotoxic drugs that are used for cancer therapy
also hit all fast dividing cells in the body:
• immune system
• gut mucosa
• hair follicles
Cyclophosphamide and methotrexate often
used in RA and MS
Calcineurin Inhibitors:
• Cyclosporine
• Tacrolimus
 Bind to immunophilins (cyclophilin or FK506binding protein [FKBP]) forming a complex that
inhibits calcineurin
 Calcineurin does not dephosphorylate NFAT
 NFAT does not translocate to the nucleus
 Inhibition of T cell proliferation and IL-2
production
Cyclosporine (Cyclosporin A)
 cyclic 11 amino acid polypeptide (very lipophilic,
orally absorbed)
 very effective against T cell dependent responses,
less effective against B cells
Therapeutic uses:
• kidney, liver, heart and other organ transplantation
• severe cases of RA
• severe disabling psoriasis where other therapies have failed
Pharmacokinetics:
• Administered i.v. (SANDIMMUNE Injection) or orally
• oral availability 20-50% [Different formulations like SANDIMMUNE
gelatine capsules and NEORAL microemulsion are NOT bioequivalent;
should not be freely substituted!!!]
• plasma peak between 1.5 to 2 h; t1/2 5-18 hours
• extensively metabolized through CYP3A4; excreted through bile
 Plasma drug levels must be monitored, drug interactions avoided
and doses adjusted for hepatic insufficiency
Drug Interactions with Cyclosporine
 any drug that is metabolized through CYP3A4 affects CsA metabolism
 CYP3A4 blockers (ketoconazole, fluconazole, verapamil, idinavir, grape
fruit juice) increase CsA plasma levels
 CYP3A4 inducers (phenobarbital, phenytoin) reduce CsA plasma levels
Cyclosporine Side Effects
1. Nephrotoxicity: occurs in nearly all patients  cessation
or modification of therapy
2. Hypertension: occurs in ~50% of kidney and 100% of
heart transplant patients
3. Hyperlipidemia
4. Tremor
5. Hirsutism and hypertrichosis
6. Diabetogenic in combination with glucocorticoids
Tacrolimus (FK506)
 macrolide antibiotic produced by Streptomyces tsukunaensis
 available for oral and i.v. administration (PROGRAF)
 t1/2 ~12 hours, PK variable. Metabolized through CYP3A4
(same interactions like CsA)
Therapeutic Uses:
• Similar to CsA but much less commonly used
• “Rescue Therapy” in patients who show rejection
despite therapeutic CsA plasma levels
Side Effects:
• Same as CsA, nephrotoxicity is limiting
Sirolimus (Rapamycin)
RAPAMUNE
 Macrocyclic lactone produced by Streptomyces
hygroscopicus (soil of Easter Islands)
 Originally developed by Wyeth as an antifungal
when it was found to be an immunosuppressant
Mechanism of Action:
• Inhibits T cell activation downstream of the IL2 receptor by binding to
the immunophilin FKBP-12
 sirolismus-FKBP-12 complex inhibits the protein kinase mTOR
(mammalian target of rapamycin), which is a key enzyme in cellcycle progression
 cell cycle arrested in G1-S phase transition
PK:
• oral availability ~15%, plasma peak after 1-2 hours, t1/2 = 62 h,
metabolized by CYP3A4
Sirolimus continued
Therapeutic Uses (introduced in 1999):
• used in combination with calcineurin inhibitors and
glucocorticoids for organ transplantation (Synergy!!)
• in patients experiencing or at high risk for calcineurin-inhibitor
associated nephrotoxicity used with glucocorticoids and
mycophenolate mofetil to avoid permanent renal damage
• also coated onto stents to prevent restenosis following
angioplasty
Side Effects:
• increase in cholesterol and triglycerides
• delayed wound healing ( often started delayed after surgery)
• much less nephrotoxic than calcineurin inhibitors but carries
warning about associated nephrotoxicity since Oct. 2008
Cyclosporine and Sirolismus (rapamycin) are synergistic
 Often combined to reduce CsA toxicity
O2N
N
S
N
Azathioprine (IMURAN)
N
N
Mechanism of Action (Antimetabolite):
Cleaved by nucleophiles like glutathione to 6-mercaptopurine
 Inhibits purine synthesis and thus cell proliferation
N
CH3
N
H
Therapeutic Uses:
• in combination for organ transplantation
• severe RA
Side Effects:
• bone marrow suppression (leukopenia, sometimes thrombocytopenia)
• hepatotoxicity
• increased risk of infections and cancer
OH
O
HO
Mycophenolate Mofetil
(CELLCEPT)
O
O
MeO
Mycophenolic acid (MPA)
 Prodrug (2-morpholinoethyl ester) that is rapidly hydrolyzed to mycophenolic
acid (MPA), which is a reversible inhibitor of ionosine monophosphate
dehydrogenase (IMPDH), an enzyme involved in guanine nucleotide synthesis
 T and B cells highly dependent on guanine nucleotide synthesis ( other
cells can use other pathways)  MPA inhibits T cell and B cell proliferation as
well as antibody production
Therapeutic Uses:
• Prevention of transplant rejection (typically in combination with
glucocorticoids and calcineurin inhibitors)
• approved for renal transplant in 1995, other transplants later; indications
might widen in the future
Side Effects:
• Leukopenia
• Increased incidence of infections (in June 2006 Roche and FDA issued
warning about PML; 17 cases, 7 fatal)
Progressive Multifocal Leukoencephalopathy (PML)
 PML is a rare demyelinating disease of the CNS that usually is fatal
or leads to severe disability. PML is caused by reactivation of the JC
virus, a polyomavirus that resides latently in 70-90% of adults
worldwide.
 PML presents with ataxia, hemiparesis, confusion, apathy, cognitive
deficiencies and radiographic evidence of white matter disease.
 PML should be considered in any transplant or autoimmune disease
patient who is on immunosuppression and who presents with
neurological symptoms.
 Other than reducing the dose of immunosuppressant there are no
interventions that can stop or treat PML.
[see also Natalizumab for MS treatment]
HO
FTY720
NH2
HO
 Fingolimod (FTY720) is sphingosine-1-phosphate receptor 1 agonist
that prevents egress of lymphocytes from lymph nodes
 was not superior to calcineurin inhibitors in Phase-3 clinical trial for
kidney transplantation as a monotherapy
 Very encouraging effects in Phase-2 clinical trial for MS (relapse rate
reduced by 80%); various other trials going on
FTY720 sequesters T cells in
lymph nodes and prevents
them from recirculating
Will probably become a new
drug for combination therapy
Antithymocyte Globin (THYMOGLUBIN)
 Purified gamma globulin fraction from the serum of rabbits immunized with
human thymocytes
 contains cytotoxic Abs that bind to CD2, CD3, CD4, CD8, CD11a, CD18,
CD25, CD45 and MHC class I and II (and probably a lot more!!)
 Abs deplete circulating lymphocytes by direct cytotoxicity (complement and
cell mediated) and block cell surface receptors
Therapeutic Uses:
• Approved for acute renal transplant rejection
• Often used immediately after kidney transplant if graft function is
delayed to avoid early use of nephrotoxic calcineurin inhibitors
Toxicity:
• Polyclonal rabbit Ab  xenogenic protein elicits acute allergic
reactions (fever, chill, hypotension)  premedication with
glucocorticoids, acetaminophen and antihistamines
• Anti-ATG Abs develop but do not limit repeated use
Anti-CD3 Monoclonal Antibodies
 Antibodies directed against the e chain of the T cells receptor CD3
 treatment induces rapid internalization of the TCR and is followed
by depletion and extravasation of T cells from the blood and
lymphoid organs (redistribution to the lungs)
 Muromonab-CD3 (OKT3) original mouse IgG2a introduced in 1986
 Fully humanized Ab: hOKTg1; less cytokine release
Therapeutic Uses:
• Mouse Ab still used to reverse glucocorticoid resistant rejection episodes
(repeated use results in neutralizing Abs)
• Humanized Ab for treatment and prevention of acute rejection
• Phase-2/3 clinical trials for prevention of T1DM
Side Effects:
• “cytokine release syndrome” typically 30 min after infusion (TNFa, IL2, IL6,
INFg from activated T cells and macrophages)  high fever, chills, tremor
(worst on first dose)
• Glucocorticoid administration on first dose is now standard
Rituximab (RITUXAN)
 monoclonal anti-CD20 Ab approved in 1997 for the treatment of Bcell non-Hodgkin lymphomas
 binds to CD20 on the surface of B cells and seems to induce
apoptosis of CD20+ cells and/or induce complement and cell mediated
cytotoxicity (ADCC), drastically reduces number of circulating B cells
Therapeutic Uses:
• Leukemia, lymphoma [see Hem/Onc]
• In combination with methotrexate for severe RA
• Clinical trials ongoing for various autoimmune diseases including
idiopathic autoimmune hemolytic anemia, MS, T1DM, Sjogren's
syndrome, SLE
Side Effects:
• Infusion reactions similar to anti-CD3 Abs
• Immunosupppression [carries Box Warning about PML]
Anti-CD25 (Anti-IL-2 Receptor)
 Daclizumab (ZENAPAX): humanized chimeric monoclonal Ab
 Basiliximab (SIMULET): murine-human chimeric monoclonal Ab
 both Abs seem to inhibit activated T cells without significant depletion
Therapeutic Uses:
• Prophylaxis of acute transplant rejection (pre-operatively and
afterwards in biweekly intervals)
• Combination for maintenance therapy with other immunosuppressants (azathioprine, glucocorticoids, cyclosporine)
Side Effects:
• no cytokine release syndrome
• anaphylaxis can occur
Abatacept (ORENCIA)
 fusion
protein
composed
of
human
immunoglobulin fused to the extra-cellular domain
of CTLA-4
 Costimulation of CD28 through B7-1/2
(CD80/CD86) is necessary for full activation of
naïve T cells; Engagement of the related receptor
CTLA-4 inhibits/reduces T cell activation
 Abatacept prevents co-stimulation and can
potentially induce tolerance
Abatacept continued
Therapeutic Uses:
• Currently approved for RA patients who have failed
methotrexate and anti-TNF reagents
• Currently in clinical trials for T1DM prevention, colitis,
psoriasis and transplant rejection
Side Effects:
• usual risk of increased infections and malignancies
• should not be used in combination with TNFantagonist (no additional benefit and greatly increased
risk of infections)
Anti-TNF Reagents
 Infliximab (REMICADE): chimeric anti-TNF-a monoclonal Ab containing
a human constant and a murine variable region; binds with high affinity to
TNF-a and prevents it from binding to its receptor
 Etanercept (ENBREL): Fusion protein of Fc portion of human IgG1 and
ligand binding portion of TNF-a receptor
 Adalimimab (HUMIRA): fully humanized recombinant monoclonal antiTNF-a antibody for i.v. use
Therapeutic Uses:
 Infliximab and Adalimimab: approved for psoriasis, Crohn's
disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid
arthritis, sarcoidosis and ulcerative colitis
 Etanercept (various formulations including autoinjector pen):
approved for RA; $4.3 billion sales in 2006!! (7th top selling drug)
Side Effects:
• Increase incidence of lymphomas and infections [Black box warning]
• Rare cases of demylelination (contra-indicated in MS)
Other Biologics
[Recently introduced or in Development]
 Efalizumab (RAPTIVA): targets LFA-1 and blocks T cell
adhesion and activation
 Anakinra (KINERET): IL-1 receptor antagonist approved
for RA
 Alefacept (AMEVIVE): Fusion protein that targets CD2,
approved for moderate to severe psoriasis
Campath-1H (ALEMTUZUMAB): humanized anti-CD52
Ab  depletes T cells, B cells, macrophages and NK cells;
approved for renal transplantation
 Anti-IL-12/IL23 antibody: clinical trials for MS and RA
There will be many more new immunosuppressants in
future as we understand the immune system better.
Therapy of Organ Transplantation
 For solid organs like heart and kidney it is rarely possible to
achieve perfect HLA matching because of limited supply of
organs (exception: live kidney donation from identical twin)
 Strong immunosuppression necessary
 At most transplant centers intensive biologic induction therapy followed
by maintenance therapy
Induction Therapy (delays use of nephrotoxic agents):
• Anti-CD3 Abs ( anti-CD25)
• Antithymocyte globin
• plasmapheresis if high titers of anti-HLA antibodies
Maintenance Therapy (typically triple therapy at low doses for synergy):
• calcineurin inhibitor + glucocorticoid + mycophenolate mofetil
• sirolimus + glucocorticoid + mycophenolate mofetil
• calcineurin inhibitor + sirolimus + third agent
Therapy of Organ Transplantation
Therapy of Established or Acute Rejection:
• High dose methylprednisolone
• Anti-CD3 Abs ( anti-CD25)
• Antithymocyte globin
Calcineurin Inhibitors and kidney transplants:
• Ultrasound guided biopsy best way to differentiate nephrotoxicity (too much CsA) from rejection (too little CsA)
Future??
Currently a lot of research going on into the
possibility of achieving tolerance with sirolimus
(spares Tregs in contrast to CsA) and/or abatacept
Therapy of Autoimmune Diseases
 Typically “milder” immunosuppression used than for
prevention of transplant rejection
 Choice of therapy should be guided by:
1. Knowledge
about
autoimmune disease
specific
pathology
of
2. Careful weighing of benefits of therapy versus side
effects since treatment is typically for the rest of
the patient’s life
Example of a “bad” strategy:
In the late 1980s and early 1990s cyclosporine was used to prevent T1DM
during the “honeymoon” period  very effective at preventing T1DM but
abandoned because of nephrotoxicity
Example: Rheumatoid Arthritis
American College of Rheumatology recommends that
treatment should be chosen based on:
 how long a patient has had rheumatoid arthritis
 the severity of rheumatoid arthritis symptoms
 potential for side effects
 tuberculosis screening (required before starting
biologic DMARDs)
 cost of treatment (real issue with biologics!!)
 patient preference regarding treatment options
DMARD = disease modifying anti-rheumatic drugs (as opposed to NSADs like
aspirin that purely treat the symptoms)
The 2008 ACR Recommendations
Arthritis Treatments:
for
Rheumatoid
 Initiating treatment with methotrexate or leflunomide for most RA patients
 Methotrexate plus Plaquenil (hydroxychloroquine) for RA patients with moderate
to high disease activity
 Treatment with TNF-a antagonist (etanercept, infliximab, adalimumab) plus
methotrexate for patients with early rheumatoid arthritis (symptoms for less than 3
months) and high disease activity
 For RA with moderate to long disease duration, TNF-a antagonists for those
who failed to get a satisfactory response from methotrexate therapy
 Abatacept and rituximab should be reserved for patients with at least moderate
disease activity and inadequate treatment response to other agents
 Treatment with methotrexate or the biologics should not be resumed or started
during an active bacterial or viral infection
 Severe flair-ups: CsA or methylprednisolone
Example: Multiple Sclerosis
• Chronic,
immune-mediated demyelinating disease of
the CNS that is characterized by inflammation, gliosis
and axonal damage
• Most
common neurological disease in young adults
(age of onset 15-50 years); affects 400 000 people in the
US and about 2.5 million worldwide
MS is a T cell mediated disease
 myelin-antigen specific T cells with a Th1 profile can be
isolated both from the blood and the CSF of MS patients
 Although myelin-antigen specific T cells are also present
in the blood of healthy controls and occur with the same
frequency, their activation state in MS patients is different.
Myelin-reactive MS patients T cells secrete larger amounts
of IL-2, IFN-g and TNF-a than T cells from controls, and are
predominantly of a Th1/Th0 memory phenotype
CD3
Extravasating T cells in a
postmortem brain section
from a MS patient
CD4
FDA APPROVED TREATMENT
OPTIONS FOR MS
Immunomodulatory drugs:
• IFN-b
• Copaxone (Glatiramer acetate)
• Natalizumab
Immunosuppressive drugs:
• Acute severe attack: methylprednisolone
• Cyclophosphamide and mitoxantrone for secondary
progressive and primary progressive MS
[Diagnosis and symptoms of MS will be covered in Neurology]
Interferon-b
 naturally occurring cytokine with still unknown
mechanism of action:
- suppresses T cell proliferation
- reduces T cell migration into the CNS
- changes cytokine profile from Th1 to Th2 (?)
 like most proteins interferons are potentially
immunogenic
(especially
when
produced
recombinantly  altered glycosylation) and
neutralizing Abs appear in many patients  still hotly
debated whether these antibodies reduce efficacy of
INF-b
Glatiramer Acetate (Copaxone)
 random polymer of glutamic acid, lysine, alanine
and tyrosine (which compose MBP) with unclear
mechanism:
1) induction of tolerance to MBP (?)
2) induces a population of GA-reactive Th2-type
“regulatory” T cells that secrete Th2 cytokines
in the brain and create an “anti-inflammatory
milieu” either spontaneously or after crossstimulation with myelin antigens (?)
 long-term treatment also seems to induce serum
Abs
% Reduction in relapse rates
Phase III Trials: Reduction in Annual
Relapse Rate
35
30
32%
P=0.002*
25
31%
32%
29%
29%
P=0.0004
P=0.007
P<0.0001
Betaseron
875-1000 mcg
Copaxone
140 mg
Rebif
66 mcg
P<0.0001
20
15
18%
P=0.04
10
5
0
Avonex
30 mcg
INF-b
Rebif
132 mcg
INF-b
*For patients who had been in the study for 2 years.
Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655;
IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al.
Neurology. 1995;45:1268; PRISMS Study Group. Lancet. 1998;352:1498;
Natalizumab (Tysabri)
Anti-VLA-4 Monoclonal Antibody




66% reduction in relapses
92% reduction in active MRI lesions
Monthly IV administration
2/1200 patients treated developed PML and died
 Tysabri removed from the market in early 2005
March
2006:
an
FDA advisory
committee
recommended that it should return to the market
(massive pressure from MS patients and NMSS)
Symptom Management of MS
 Primary
 Caused by actual demyelination within the CNS
 Fatigue, tremor, incontinence, spasticity, depression
 antidepressants, anti-spastics
 Secondary
 Caused by failure to manage the primary
 Contractures, decubiti, fractures, muscle atrophy
 physiotherapy
 Tertiary
 Psychological, social, marital, vocational, personal
 antidepressants, Viagra, Life-style changes