Download Therapeutic Stepladder Algorithm In Uveitis

Update on Medical Treatment
in
Non-infectious Uveitis
Alireza Hedayatfar MD
Ocular Inflammation and Uveitis Fellowship
Iran University of Medical Sciences
Noor Eye Hospital
9th Annual Congress of Vitreoretinal Diseases
April 2016, Kermanshah, Iran
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
Systemic NSAIDs
are mainly indicated in cases of
Non-necrotysing Scleritis
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
To treat acute anterior uveitis
always remember:
• Hit it fast! hit it hard!
• Use appropriate steroid
– High corneal penetration
– High potency
Corneal Penetration
For a steroid to
effectively penetrate
Acetate
the cornea, it must be
biphasic
Phosphate
Bethamethasone
phosphate 0.1%
Loteprednole
Etabonate 0.5%
Dexamethasone
phosphate 0.1%
Prednisolone
acetate 1%
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
Periocular Steroid Injections
– Unilateral involvement
– Exacerbation of inflammation in patient already on systemic treatment
– Uveitic macular edema
– Bilateral sight-threatening disease in special cases (e.g. Pregnancy)
– Infective cause (Toxoplasmosis, Herpetic uveitis, ARN)
– Steroid responder
Periocular Steroid Injections
Transseptal Route
Sub-tenon's Injection
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
Systemic Corticosteroids
• Oral therapy used when there is failure to respond to
periocular injections or in bilateral sight-threatening uveitis
• Start with high dose then taper to the minimum required dose
to keep inflammation under control
• Supplementary doses of corticosteroids required during acute
stress e.g. surgery
Intravitreal
implants
Ozurdex®
(dexamethasone)
Type
of
Implants
Duration
of
Action
Disadvantage
Non-ideal release
kinetics
Biodegradable
6 months
Short duration of
action
Iluvien®
(fluocinolone acetonide)
Biodegradable
Retisert®
(fluocinolone acetonide)
Non-biodegradable
I-vation™
(triamcinolone acetonide)
Non-biodegradable
1.5 or 3 years
Same as above
30 months
Require
explantation
2 years
Same as above
Sample
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
Indications for lmmunomodulatory Medications
• Control of inflammation require unacceptably high doses
of steroid for long period of time
• Inadequate control of inflammation with steroids alone
• Unacceptable steroid side effects (especially in children)
Before initiating any immunosuppressant!!!
•
Obtain thorough history
– Co-morbidities
• DM, hypertension, renal or liver dysfunction
– Social history
•
•
plans to start a family, alcohol intake
Discuss with patient
– Reason to use medication(s)
– Informed consent
History
No
Yes
Remarks
Investigation
Peptic ulcer
Hepatitis
WBC
FBC
Hb
TB
Liver disease
Renal failure
Plt
Cr.
RFT
BUN
Pregnant
Plan to conceive
Alb
LFT
SGOT
Alcohol intake
Hepatotoxic drug
N
SGPT
CXR
A
Remarks
‫?‪How adverse effect will be monitored‬‬
‫‪• Start from minimum dosage to maximum allowed dosage‬‬
‫‪• Ask specifically about the expected side effects‬‬
‫‪• Serial follow up laboratory test‬‬
‫تاريخ‬
‫‪Medication‬‬
‫بی اشتهایی و کاهش وزن‬
‫تهوع ‪ /‬استفراغ‬
‫اسهال‬
‫درد معده ‪ /‬سوءهاضمه‬
‫تغییر رنگ (قیری شدن) مدفوع یا وجود خون در مدفوع‬
‫زردی پوست ‪ /‬تغییر رنگ ادرار‬
‫سوزش یا تکررادرار‬
‫خیر‬
‫بله‬
‫خیر‬
‫بله‬
‫خیر‬
‫بله‬
‫خیر‬
‫بله‬
‫خیر‬
‫بله‬
‫خیر‬
‫بله‬
‫خیر‬
‫بله‬
‫‪Dosage‬‬
‫‪FBS‬خیر‬
‫‪ BP‬خیر‬
‫تب‬
‫لرز‬
‫‪Hemoglobin‬‬
‫خیر‬
‫گلو درد‬
‫دیر بند آمدن خونریزی ‪ /‬خون مردگی غیر عادی ‪WBC‬خیر‬
‫‪Lymphocyte‬‬
‫خیر‬
‫زخم ‪ /‬تاول دهان یا زبان‬
‫‪Platelets‬‬
‫خیر‬
‫ضایعات پوستی‬
‫‪Creatinine‬‬
‫خیر‬
‫ریزش موهای سر‬
‫‪BUN‬‬
‫‪SGOT‬‬
‫‪SGPT‬‬
‫‪ALP‬‬
‫بله‬
‫بله‬
‫بله‬
‫بله‬
‫بله‬
‫بله‬
‫بله‬
lmmunomodulatory Treatment
I.
Antimetabolites
II.
Inhibitors of intracellular signaling
III.
Alkylating agents
lmmunomodulatory Treatment
I.
Antimetabolites
II.
Inhibitors of intracellular signaling
III.
Alkylating agents
•
It is generally safe, well tolerated, easily administered
•
MTX possesses a variety of anti-inflammatory effects
(humeral > cellular)?
•
Administered PO, IM or SQ, at a weekly dose of 0.2-0.3
mg/kg.
•
Methotrexate is cleared more rapidly from children than
from adults, and thus, doses must be higher on a per-mass
basis in children (10 to 30 mg/m2).
•
MTX should be supplemented by folic acid
Methotraxate
•
Azathioprine is an imidazolyl derivative of 6mercaptopurine (6-MP) which antagonizes
purine metabolism and may inhibit synthesis
of DNA, RNA, and proteins.
• Cellular immunity being suppressed to a
greater degree than are antibody responses.
• Administered at a dose of 2mg/kg/day. Many
clinicians start the drug at 50mg/day for 1
week to see if the patient develops any
gastrointestinal side effect .
Azathioprine
(Immuran, Azaram)
Mycophenolate mofetil
• Mycophenolate mofetil is a reversible
inhibitor of inosine monophosphate
dehydrogenase (IMPDH)
• It blocks de novo biosynthesis of guanosine
nucleotides by inhibition of the enzyme
inosine monophosphate dehydrogenase.
• MPM has good oral bioavailability and is
given at a dose of 1gm twice daily
lmmunomodulatory Treatment
I.
Antimetabolites
II.
Inhibitors of intracellular signaling
III.
Alkylating agents
Cyclosporine
•
As a calcineurin inhibitors, inhibits T-lymphocyte
proliferation by blocking the production and release of
various cytokines, especially interleukin-2.
•
Cyclosporine preferentially inhibits the T1 helper and
cytotoxic subsets, with minimal effects on regulatory
(suppressor) T lymphocytes.
•
Monthly blood pressure, serum creatinine levels, and
complete blood counts are used to monitor patients .
Tacrolimus
•
Tacrolimus is a macrolide antibiotic and calcineurin
inhibitors.
•
Tacrolimus interacts with and inhibits calcineurin thus
inhibiting both T-lymphocyte signal transduction and
IL-2 transcription and therefore, directly interferes with
helper T-lymphocyte proliferation.
•
Its main side effect, nephrotoxicity, is less common than
it is with cyclosporine. Serum creatinine and complete
blood counts are monitored monthly.
Sirolimus
•
A macrolide compound obtained from Streptomyces
hygroscopicus that possesses both antifungal and antineoplastic
properties.
•
Despite its similarities to tacrolimus, its mechanism of action is
different.
•
Sirolimus blunts the responses of both T Lymphocytes and B
lymphocytes to specific lymphokines (Interleukin IL-2, IL-4,
and IL-15) in the G1 phase of the cell cycle rather than
inhibiting their production.
lmmunomodulatory Treatment
I.
Antimetabolites
II.
Inhibitors of intracellular signaling
III.
Alkylating agents
Cyclophosphamide
• Cytotoxic to resting and actively dividing lymphocytes.
• Administered orally (2mg/kg/day) or monthly intravenous pulses
• Cyclophosphamide has been shown to be effective in treating
necrotizing scleritis associated with systemic vasculitides such as
Wegener granulomatosis or relapsing polychondritis and severe
retinal vasculitis including Behcet disease.
Therapeutic Stepladder Algorithm In Uveitis
Systemic
NSAIDs
Topical
Cs
Periocular
Cs
Systemic
Cs
IMT
Biologic
agents
Biologic response modifiers
Target pro-inflammatory cytokines or their receptors
monoclonal antibodies
Biologic response modifiers
fusion proteins
When to Use Biologics in Uveitis?
• Biologics are useful when
– Standard immunosuppression has failed to control inflammation
– Standard immunosuppression has poorly been tolerated
– Patients with concomitant ocular and systemic inflammation that
might benefit from these medications e.g.. JIA
Generic names
Trade names Specific target
Route
Dosage
Potential side effects
TNF inhibitors
Infliximab
Remicade
TNF-α
IV
3–5 mg/kg loading at weeks 0, 2, and
6, then maintenance 3–10 mg/kg
every 4–8 weeks; maximal dose 20
mg/kg in children
40 mg every 1–2 weeks (if
bodyweight <30 kg; 20 mg every 2
weeks); loading doses of 80–160 mg
are recommended for CD and PsO
Adalimumab
Humira
TNF-α
SQ
Etanercept
Enbrel
TNF-α,-β
SQ
Golimumab
Simponi
TNF-α
SQ
Certolizumab
Cimzia
TNF-α
SQ
Susceptibility to
infections, including:
reactivation of
tuberculosis,
histoplasmosis, hepatitis
B, and fungal infection;
Adults 50 mg weekly (may be given
hypersensitivity
50 mg twice weekly for first 3
reactions; demyelinating
months for PsO); children 0.8
disease; lupus-like
mg/kg/week (max 50 mg/week)
syndrome; malignancy;
thromboembolic events;
congestive heart failure
50 mg SQ monthly; except for UC
200 mg at week 0, 100 mg at week 2,
then 100 mg every 4 weeks
400 mg SQ at weeks 0, 2, and 4, then
200 mg every 2 weeks or 400 mg
every 4 weeks
•
Infliximab (Remicade) is a chimeric anti-TNF-α
•
Concomitant administration of infliximab with methotrexate
(5-7.5 mg/week) has been associated with a decrease in the
formation of human anti-chimeric antibodies
•
Administered in the form of IV on day 0, at 2 weeks ,at 6
weeks and then every 6-8 weeks
•
May cause reactivation of TB to disseminated form so use
in patients with positive PPD test is contraindicated
•
Besides BD and JIA, infliximab may also be effective to treat
– Recalcitrant uveitic CME
– HLA-B27-related anterior uveitis
– Pars planitis
Infliximab (Remicade)
Adalimumab (Humira)
•
Adalimumab (Humira) is a fully human
monoclonal antibody against TNF-á.
•
Due to its promising results and subcutaneous
route of administration, experience in both
rheumatologic and ocular indications is
growing.
•
Several clinical studies have shown its potential
efficacy for the treatment of juvenile uveitis
(mainly JIA) and BD uveitis .
Generic names
Trade names
Specific target
Route
Dosage
Potential side effects
Lymphocyte inhibitors
Daclizumab
Rituximab
Abatacept
Basiliximab
Zenapax
Rituxan
Orencia
Simulect
T-cells (IL-2Rα)
B-cells (CD20)
T-cells (CTLA-4)
T-cells (IL-2Rα;
CD25)
IV, SQ
Hypersensitivity reactions,
1–2 mg/kg every 2 or 4
headache, and
weeks
gastrointestinal
disturbance
IV
Susceptibility to
500 or 1,000 mg at week
infections, infusion
0 and 2; may repeat at 6–
reactions, gastrointestinal
12 months thereafter
disturbance,
(different regimen for
cardiovascular events,
hematologic
muscle spasm, and
malignancies)
headache
IV, SQ
Adult RA 500–1,000 mg
IV loading, then 125 mg
Susceptibility to
SQ weekly; JIA 10
infections, allergic
mg/kg, max 1,000 mg IV
reactions, headache,
at weeks 0, 2, and 4, then nausea, and malignancy
every 4 weeks
IV
Gastrointestinal
disturbance, headache,
40 mg IV at weeks 0, 2,
susceptibility to infections,
4, 8, and 12
and hypersensitivity
reactions
•
It functions as an IL-2 receptor antagonist
•
It is indicated for the prophylaxis of acute organ rejection
Daclizumab: Anti IL-2
in patients receiving renal transplants
•
Daclizumab has been demonstrated effective for refractory
birdshot retinochoroidopathy and some non-infectious
uveitis
•
However, daclizumab failed to demonstrate effectiveness
in BD-associated uveitis in a randomized trial
Rituximab: Anti CD-20
Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal
antibody
•
Acts by causing B cell apoptosis used in B cell
lymphomas
•
It has shown promising results in the treatment of:
– Orbital inflammation from Graves disease
– Refractory scleritis
– JIA associated uveitis
Generic names
Trade names
Specific target
Route
Dosage
Potential side effects
Specific receptor antagonists
Anakinra
Canakinumab
Tocilizumab
Alemtuzumab
Efalizumab
Kineret
Ilaris
Actemra
Campath
Raptiva
IL-1 receptor
IL-1β
IL-6 receptor
CD52
CD11a
SQ
100 mg SQ daily; children,
Injection-site reaction,
starting 1–2 mg/kg to max 8
infections, headache,
mg/kg daily (dose adjustment gastrointestinal disturbance,
for renal insufficiency)
and fever
IV, SQ
Systemic JIA: 4 mg/kg (max
Susceptibility to infections,
300 mg) SQ every 4 weeks;
headache, nausea, and
CAPS, 2–3 mg/kg SQ every 8
abdominal pain
weeks
Serious infections,
hypersensitivity reactions,
and gastrointestinal
perforation
IV
Initial 4 mg/kg IV every 4
weeks, then increase to 8–12
mg/kg every 2–4 weeks
IV
Cytopenias, infusion
30 mg IV, 3 days per week for
reactions, infections,
12 weeks
gastrointestinal disturbance,
and insomnia
SQ
0.7 mg/kg first dose, then 1
mg/kg weekly (max 200
mg/dose)
Infections, progressive
multifocal
leukoencephalopathy,
malignancy, arthritis, and
thrombocytopenia
Generic names
Trade names
Specific target
Route
Dosage
Potential side effects
Interferons
Interferon α-2a
Roferon-A
Nonspecific
SQ
Injection-site
3–6 million units SQ
reactions, flu-like
daily, tapering over 6
symptoms, and bone
months
marrow suppression
Interferon
•
INFs have antiviral, immunomodulatory, and
antiangiogenic effects
•
Different interferons are used for different conditions.
– INF alphas are used for treating cancers and viral
infections
– INF betas are used for treating multiple sclerosis
– INF gamma is used for treating chronic granulomatous
disease.
•
Main indications in uveitis is for treatment of BD and
MS associated uveitis.
•
Chronic intraocular inflammation is associated with
increased production of inflammatory mediators, including
VEGF, which are hypothesized to disrupt the blood-retinal
barrier on the endothelium of retinal vessels, resulting in
subsequent macular edema.
•
Bevacizumab and ranibizumab have been used to treat and
stabilize secondary complications of uveitis, which include
– Uveitic macular edema,
– CNV related to inflammatory diseases
•
Their use for primary suppression of inflammation has not
been established
Anti VEGF