Immunomodulatory Therapy (IMT) for Ocular Inflammation
Definition (Immunomodulators and immunosuppressants)
The Merriam-Webster's dictionary defines immunomodulator as 'a chemical agent (as methotrexate or azathioprine) that modifies the immune response or the functioning of the immune system (as by the stimulation of antibody formation or the inhibition of white blood cell activity)'.
On the other hand, immunosuppressant has been defined by the Collins dictionary as 'any drug or substance that suppresses the immune response'. These drugs have been used to prevent rejection of transplants and these are used as chemotherapy for cancers. In ocular inflammation, they are used as steroid-sparing agents to control the inflammation with a target for durable remission and prevention of sight-threatening complications of uveitis. These agents are thought to re-educate the immune system to a level that the recurrent autoimmune inflammation of ocular tissues are prevented.
Side effects of steroid
Though steroids (glucocorticoids) both topical and systemic are very important for acute control of active uveitis, long-term use of steroids can cause various side effects.
Most common adverse effects of systemic steroids are weight gain, fluid retention, stomach upset/acidity, osteoporosis, increased appetite, acne, facial puffiness/moon facies, diabetes mellitus/alteration of glucose tolerance, hypertension, mood changes, and increased susceptibility to infection. Overall side effects of steroids include but may not be limited to:
- General: increased appetite and weight gain,
- Endocrine: development of Cushingoid state, puffy face, weight gain, abnormal fat deposit, worsening of diabetes mellitus/hyperglycemia- need of increasing dose of oral hypoglycemic agents/insulin, menstrual irregularities, facial puffiness/moon facies, suppression of growth in children, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness)
- Metabolic: hyperlipidemia, negative nitrogen balance due to catabolism of proteins
- Fluid and Electrolyte Disturbances: fluid retention, hypertension, hypokalemea/hypokalemic alkalosis, hypernatremia
- Gastrointestinal: peptic ulcer disease with possible perforation and hemorrhage, abdominal distention; hiccups, malaise, nausea, pancreatitis; ulcerative esophagitis, elevated serum liver enzymes (usually reversible upon discontinuation), hepatomegaly, gastro-esophageal reflux disease
- Dermatologic: acne, cutaneous and subcutaneous atrophy, dry scalp, edema, facial erythema, allergic dermatitis, urticaria, hyper or hypopigmentation, impaired wound healing, increased sweating, rash/petechia/ecchymosis, sterile abscess, striae, suppressed reactions to skin tests (eg., Mantoux), thin fragile skin, thinning of scalp hair, increased susceptibility to skin infection
- Musculoskeletal: osteoporosis, avascular necrosis of femoral and humeral heads; vertebral compression fractures, Charcot-like arthropathy, muscle weakness- loss of muscle mass, steroid myopathy; pathologic fracture of long bones; tendon rupture;
- Neurological: emotional instability, euphoria, depression, psychosis, headache; arachnoiditis, convulsions; increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment; insomnia, meningitis, mood swings, personality changes, sensory disturbances, vertigo neuritis, neuropathy, paraparesis/paraplegia, paresthesia,
- Reproductive: loss of libido, gynecomastia in male, alteration in motility and number of spermatozoa
- Cardiovascular: cardiac arrhythmias, bradycardia, cardiac arrest, cardiac enlargement, congestive heart failure, circulatory collapse, myocardial rupture following recent myocardial infarction, pulmonary edema, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, thromboembolism, syncope, tachycardia,
- Allergic Reactions: anaphylaxis, anaphylactoid reaction, angioedema
- Ophthalmic: posterior subcapsular cataracts; glaucoma; increased intraocular pressure; Exophthalmos, central serous retinopathy, pigment epithelial detachment, delayed healing of corneal epithelial defect, in active epithelial viral keratitis, topical steroid may worsen the disease, and may even cause corneal perforation
Indications of IMT
- sight-threatening ocular inflammation
- unacceptable/intolerable side effects due to steroids
- inadequate response to corticosteroids
- long-term dependence on steroid therapy, if more than 5-10mg/day of prednisolone is required to keep the disease in control- steroid-sparing IMT is indicated.
- contraindications of steroid therapy/allergy to steroid
For some specific diseases during the acute episode, though steroids are crucial for immediate control, early initiation of IMT is vital. When the ocular inflammation becomes stable and IMT begins to take effect, the steroid is gradually tapered and IMT is continued long-term in these diseases. These diseases include
- Vogt-Koyanagi-Harada syndrome (VKH)
- Sympathetic Ophthalmia (SO)
- Amantiades-Behçet disease (ABD)
- Ocular cicatricial pemphigoid (OCP)
- Necrotizing scleritis (NS) associated with systemic vasculitis (granulomatosis with polyangiitis, polyarteritis nodosa)
- Serpiginous choroiditis (SC).
Although these entities may respond to steroids alone during acute episode, initial treatment with IMT has been noted to improve long-term prognosis and maintain visual acuity.
Other indications for early initiation of IMT includes
- Birdshot chorioretinopathy (BSCR)
- Uveitis associated with juvenile idiopathic arthritis, ankylosing spondylitis
- Autoimmune retinopathy (nonparaneoplastic)
- Necrotizing scleritis and peripheral ulcerative keratitis associated with
- Rheumatoid arthritis
- Granulomatosis with polyangiitis (formerly known as Wegener's)
- Relapsing polychondritis
Prerequisites before starting IMT
Before starting IMT certain conditions must be fulfilled:
- Active infection including tuberculosis/fungal infection must be ruled out
- There should be no hematological/renal/hepatic contraindication
- The patient must understand the nature of therapy and must be able to come in a regular follow-up every 4-8 weekly depending on the medication used. The follow-up also includes blood work to check for adverse events related to the medicine.
- Informed consent of the patient with an explanation of the side effects of the drug including allergy, increased risk of infection and rarely malignancy; though most of the patients tolerate these drugs well. Compliance with follow-up is important. If they do not tolerate the medication, there is a plenty of options of other IMT drugs.
- The patient should not plan pregnancy/conception during the IMT. However, some drugs have FDA pregnancy category of class B and may be safe. These drugs include infliximab and adalimumab (see below).
- The patient should not receive any live vaccines.
- Maintainance of good hygiene, hand washing is important considering the increased risk of infection when on these medications.
- Meticulous follow-up and regular blood labs to monitor any early side effects. The patient should preferably be co-managed with a physician/managed by ocular immunologist who by the virtue of experience and training is qualified to prescribe and monitor such medications and can manage the toxicities personally
- Objective documentation/evaluation of disease process with time.
- If the patient develops any illness, infection, or fever (>101 Farhenheit), he/she should contact his/her doctor immediately or visit emergency room of a hospital.
- Good hydration, exercise and smoking cessation are good practices during this therapy.
Safety of IMT
Though the drugs used for IMT can potentially cause serious infection, malignancy and death, the dosage at which they are used for uveitis is very well tolerated and may be much less than used for chemotherapy for malignancy. A supporting evidence is that rheumatologists and dermatologists have been using low dose IMT for various indications including rheumatoid arthritis, psoriasis, and others successfully with an excellent safety track record. The dosage of IMT may differ from dosage used for arthritis and may be higher than the rheumatoid arthritis dosage in aggressive sight-threatening ocular inflammation. The national eye institute sponsored Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study showed that 'most commonly used immunosuppressive drugs (azathioprine, methotrexate, mycophenolate mofetil, ciclosporin, systemic corticosteroids, or dapsone) do not seem to increase overall or cancer mortality' The study also noted that cyclophosphamide did not increase overall mortality, but a nonsignificant increase in cancer mortality was noted. However, the study found that TNF inhibitors significantly increased overall and cancer-related mortality.
Types of IMT
|Group||Drug||Mechanism of action||Dose||Maximum dose||Major indications||Side effects||Strategies to prevent side effects||Information|
||7.5 mg to 25mg qWk SQ or PO
SQ is preferred for higher dosage and may prevent
GI side effects.
Splitting the dose in 2 days may also reduce side effects.
|25 mg/week (PO),
50 mg/week (SQ),
|Uveitis associated with arthritis: JIA, AS, RA, psoriatic arthritis, reactive arthritis
||Folic acid 1mg qD reduces mouth sores but can potentially reduce effect.
Use sunscreen with SPF 35 or greater for outdoor.
Diarrhea and ulcerative stomatitis need interruption of therapy, otherwise hemorrhagic enteritis/death from intestinal perforation may occur.
Dry nonproductive cough may require evaluation/cessation of therapy.
Folinic acid/leucovorin treats MTX toxicity.
|Mycophenolate mofetil/CellceptⓇ||Inhibits Inosine-5'-monophosphate dehydrogenase- alters purine metabolisms||1-3g qD PO in empty stomach||3g qD||Scleritis, methotrexate
in adults and children,
adjuvant to cyclosporine
in ABD and BSCR'
|Azathioprine/AzoranⓇ/ImuranⓇ||Purine analogue||1mg/kg/day PO (100-250mg qD)||3mg/kg/day||Scleritis in RP, GPA
iridocyclitis in JIA, reactive arthritis
uveitis in sarcoidosis, SLE
|Inhibitors of T cell signaling||Cyclosporine A||Calcineurin inhibitor||2.5- 5mg/kg/day PO||10mg/kg/day||ABD, BSCR, sarcoidosis,
pars planitis, VKH, MS,
SO, idiopathic posterior
uveitis, PUK and scleritis
with GPA, corneal
||NeoralⓇ soft getalin capsules have higher bioavailability than SandimmuneⓇ. The dose should be reduced by 20% when shifting from Sandimmune to Neoral.|
|Tacrolimus/FK 506||Calcineurin inhibitor||0.05-0.2mg/kg/day PO||0.3mg/kg/day||ABD
Idiopathic posterior uveitis
|Similar to cyclosporine, but
the following are seen less commonly (Hypertension, hirsutism and gum hyperplasia).
The following side effects are seen more commonly with tacrolimus: diabetes, diarrhea,
neurotoxicity, and alopecia.
|Absorption is not dependent on bile.|
|Voclosporine||Calcineurin inhibitor||0.4mg/kg/day in divided dose PO||Noninfectious sight threatening uveitisEvaluated in LUMINATE trial||Similar to cyclosporine.|
|Sirolimus (Rapamycin)||mTOR inhibitor||Loading dose 6 mg/day, followed by
Maintenance 2 mg/day, PO
|6mg/day ||Recalcitrant non-infectious uveitis
[the intravitreal form is evaluated in SAVE and SAKURA study]
|Alkylating agent||Cyclophosphamide/CytoxanⓇ||Causes DNA cross linking||1 mg/kg/day PO or
1 g/m2 (BSA) infusions
q1-2 weeks (IV pulse)
|3mg/kg/day PO||Necrotizing scleritis/PUK in GPA, RP, PAN, RA
Bilateral Mooren ulcer
||Drink plenty of water.
Cryopreservation of sperm/eggs before using.
Filgrastim may be used for severe leucopenia.
|Aim- TLC 3500-4000/ul, ANC >1500/ul, platelet >75000/ul.|
|Chlorambucil/LeukeranⓇ||Causes DNA cross linking||2-12 mg/day PO||SC
Uveitis in JIA
||Prophylactic treatment of pneumocystis pneumonia to be started.|
|Biologic response modifiers/biologicals|
|TNF α inhibitor||Infliximab/RemicadeⓇ||Inhibits TNF-alpha by binding
Chimeric IgG1k anti-TNFa
monoclonal antibody with a
human constant and mouse
|5-20 mg/kg/day (IV infusion)
Loading dose 0,
2, 4 weeks, then q4Wk for
6 months after
has been achieved.
off with 3 infusions
at 6, 8, 10, 12 week
interval each, before
|20 mg/kg/IV infusion||Refractory ABD,
uveitis and scleritis
secondary to JIA, AS,
conventional immunomodulator therapy-resistant uveitis
||Stop in serious infection or sepsis.
Quantiferon TB Gold (interferon gamma release assay) before starting. Rule out active tuberculosis/infection before initiating treatment.
|Adalimumab/HumiraⓇ||fully human anti-TNF-alpha monoclonal antibody||40mg SQ q2wk||40mg SQ qwk||Ocular inflammation in RA, JIA,
AS, psoriatic arthritis
and plaque psoriasis,
BSCR, VKH, orbital
||Stop in serious infection or sepsis.|
|400mg/wk IV||1000mg/wk IV||To reduce anterior uveitis (AU) flares in subjects with active axial Spondyloarthritis (axSpA) in trial||
||Stop in serious infection or sepsis.
Not indicated in children
|Golimumab/SimponiⓇ||Fully human anti-TNF-alpha monoclonal antibody||50mg SQ q4wk||JIA associated uveitis
idiopathic retinal vasculitis
||Stop in serious infection or sepsis.|
[chimeric anti-CD20 monoclonal antibody with mouse variable and human constant regions]
|'Rheumatoid arthritis' protocol:
'two-1000 mg IV infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.'
|'Foster protocol', 375 mg/m2 IV qWk for 8 consecutive weeks, and then, q4Wk for 4 consecutive months; then reassessment for tapering or continuing monthly infusion||Scleritis- RA, GPA
orbital inflammatory syndrome
|IL 1 receptor antagonist||Anakinra/KinretⓇ||Humanized anti
|100mg/day SQ||CINCA associated panuveitis (anterior uveitis, disc edema, vitritis)
||Use with TNF blocking agents is not recommended- higher rate of infection when used in combination.|
|IL 2 receptor antagonist||Daclizumab/ZinbrytaⓇ||Humanized IgG1
|150mg q4Wk SQ
1 mg/kg q2Wk for 5 doses IV (renal transplant dosage)
and bilirubin levels before initiation
Stop in severe liver injury/ severe immune mediated disorder/severe infection.
|Consider discontinuation if severe depression and/or suicidal ideation occur|
|IL 6 receptor antagonist||Tocilizumab /ActemraⓇ||Recombinant humanized
IgG1k anti IL-6 receptor
|4 mg/kg q4wk followed by an increase to 8 mg/kg q4wk based on clinical response.
|8 mg/kg q4wk||
||Do not start if ANC below 2000 per mm3
, platelet count below 100,000 per mm3 , or who have ALT or AST above 1.5 times the upper limit of normal
|Antibiotic||Dapsone||Stabilizes lysosomal membrane- anti-inflammatory effect
Inhibition of neutrophil adherence
|50mg/day PO||150- 300 mg/day PO||
||The patient should contact the doctor urgently in case of sore throat, fever, pallor, purpura or jaundice.
Avoid in sulfa allergy.
|The FDA Dermatology Advisory Committee recommended that, when feasible, counts should be done weekly for the first month, monthly for six months and semi-annually thereafter|
|Colchicine||Inhibits microtubule formation
||0.5-1mg/day PO||1.8mg/day PO||ABD||
||Modify dose in renal impairment.
Avoid when patient is on CYP34A inhibitors- life-threatening drug interaction may occur.
|Consider temporary discontinuation/stopping in severe blood dyscrasia, and neuromuscular toxicity|
|IVIG||Suppression of IgG production, accelerated
catabolism of IgG, neutralization of complement-mediated reactions,
neutralization of pathogenic antibodies, downregulation of inflammatory
cytokines, inhibition of autoreactive T lymphocytes, inhibition of
immune cell trafficking, and blockage of Fas-ligand/Fas-receptor interactions'
|0.5g/kg/day for 3 consecutive days q4week
or 1-2g/kg/cycle over 3 days
demyelinating optic neuropathy
Monitor for hemolysis.
|Interferon (IFN) α2a (Pegasys®)||Immunomodulatory cytokine||Induction: 3.0 or 4.5 million units SQ qD for 14 days, then||6 million units/day||ABD
||Stop in case of severe neuropsychiatric disorder, low blood counts and other serious adverse events.|
|IFN β1a||Immunomodulatory cytokine||22ug or 44ug three times/wk SQ (Rebif®)
30ug qWk (Avonex®) IM
|intermediate uveitis associated with MS,
optic neuritis associated with MS (CHAMPS and PRISMS study)
|Abatacept (Orencia®)||Fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4||10 mg/kg (up to a maximum of 750 mg) by 30-min intravenous
infusion at weeks 0, 2, and 4, and was then continued monthly
|Refractory JIA uveitis||
Baseline tests and follow-up tests for IMT
For most of the drugs in IMT, minimum baseline tests comprise of:
- CBC (hemoglobin, total red blood corpuscular count, total leucocyte count, thrombocyte count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration) with differential count
- LFT (at least alanine transaminase, aspartate transaminase, gamma glutamyl transferase),
- BUN, Cr
At follow-up, these tests should be repeated every 4-6 weeks.
For cyclophosphamide, urine analysis should also be added in the baseline and follow up every monthly along with the other blood tests
For cyclosporine baseline tests should also include Blood pressure, lipid profile, serum magnesium, potassium, and uric acid. 'CBC, uric acid, potassium, lipids, and magnesium should also be monitored every 2 weeks for the first 3 months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments are made.'
For azathioprine, thiopurine methyltransferase (TPMT) must be assessed before starting the drug.
For anti-TNF therapy, tuberculin test or Quantiferin TB gold test must be done before starting the drug. Hepatitis B surface antigen should be done in high risk cases.
For tocilizumab, lipid profile should be done at baseline and at the follow-ups.
Before starting interferon, do pregnancy testing, other routine blood labs (platelet > 90,000/ul, ANC >= 1500/ul), thyroid stimulating hormone, thyroxine hormone, electrocardiogram in patients with previous heart disease.
Expected onset of anti-inflammatory action
The IMTs usually take time (2 weeks- 3 months) to start acting, thus for the acute control of inflammation steroids systemic and topical is needed. Early onset of action may be noted at 1-2 weeks in especially the biologic drugs including
However, rituximab (IV) may take 3 months to show clinically obvious activity.
Pregnancy and IMT
Although most of the IMT drugs should be avoided when pregnancy/conception is planned, some IMT drugs have a class B status ("Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.") in pregnancy.
These class B drugs include
Duration of the IMT
The goal of IMT is durable remission while off steroids. These are thought to retrain the immune system so that the recurrent sight threatening inflammation is prevented. For ocular inflammation, the patient may need a longer duration of IMT.
After some time (usually 2 years) when the eyes have responded well to the immunomodulatory therapy (IMT) and have remained quiet for 2 years, these drugs may be tapered off. Eyes should be without active inflammation when the patient is off steroids, and systemic disease should also be controlled before the consideration of tapering off IMT. Provided no recurrence is noted during the taper, the drug can be stopped. These drugs are supposed to create an immune tolerance or retrain the immune system, so that recurrences can be prevented.
- ABD- Adamantiades-Behçet disease
- ANC- absolute neutrophil count
- AS- ankylosing spondylitis
- BSA- body surface area
- BSCR- Birdshot Chorioretinopathy
- BUN- blood urea nitrogen
- CBC- complete blood count
- CD- cluster of differentiation
- CINCA- Chronic infantile neurological cutaneous articular
- Cr- creatinin
- DLC- differential leucocyte count
- DNA- deoxyribonucleic acid
- GI- gastrointestinal
- GPA- granulomatosis with polyangiitis
- IFN- interferon
- IL- interleukin
- IM- intramuscular
- IMT- immunomodulatory therapy
- IU- intermediate uveitis
- IV- intravenous
- JIA- juvenile idiopathic arthritis
- LFT- liver function test
- MS- multiple sclerosis
- mTOR- mammalian (or mechanistic) target of rapamycin
- MTX- methotrexate
- NS- necrotizing scleritis
- OCP- Ocular cicatricial pemphigoid
- PO- per orally
- qD- every day
- qWk- every week
- RA- rheumatoid arthritis
- RP- relapsing polychondritis
- SC- Serpiginous choroiditis
- SLE- systemic lupus erythematosus
- SQ- subcutaneous
- SO- Sympathetic Ophthalmia
- TB- tuberculosis
- TNF- tumor necrosis factor
- TPMT- thiopurine methyltransferase
- VKH- Vogt-Koyanagi-Harada syndrome
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