Immunomodulatory therapy (IMT) for ocular inflammation

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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[1] 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[2] 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

IMT therapy should be considered in[1][3]

  • 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


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.[3]

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[4] and adalimumab[5] (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[3]
  • 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.[6][7][8] 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.[9] 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'[10] The study also noted that cyclophosphamide did not increase overall mortality, but a nonsignificant increase in cancer mortality was noted.[10] However, the study found that TNF inhibitors significantly increased overall and cancer-related mortality.[10]

Types of IMT

Group Drug Mechanism of action Dose Maximum dose Major indications Side effects Strategies to prevent side effects Information
Antimetabolites Methotrexate (MTX)[11]
  • Inhibits Dihydrofolate reductase enzyme- prevents synthesis of purine nucleotides and thymidylate--> interferes with DNA synthesis, repair, and cellular replication
  • Anti-inflammatory actions may be related to extracellular release of adenosine
  • Inhibition of T-cell activation and production of cytokines and intercellular adhesion molecules[12]
  • Inhibition of purine metabolism
  • Inhibition of IL-1β receptor binding.
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),[1]

Uveitis associated with arthritis: JIA, AS, RA, psoriatic arthritis, reactive arthritis

OCP

VKH

Sympathetic Ophthalmia

SC

  • Fatigue
  • Nausea, vomiting, ulcerative stomatitis,
  • Hepatotoxicity/cirrhosis/fibrosis/elevated liver enzyme (usually asymptomatic and transient)
  • Pneumonitis
  • Mild hair loss, photosensitivity
  • Bone marrow toxicity (leucopenia, thrombocytopenia),
  • Fetal loss/congenital malformation,
  • Rare mood swings in children
  • Malignant lymphoma (may regress after discontinuation of MTX, if not needs appropriate therapy)
  • Opportunistic infection including Pneumocystis carinii pneumonia
Folic acid 1mg qD reduces mouth sores but can potentially reduce effect.

Use sunscreen with SPF 35 or greater for outdoor.

Avoid alcohol.

Diarrhea and ulcerative stomatitis need interruption of therapy, otherwise hemorrhagic enteritis/death from intestinal perforation may occur.[11]

Dry nonproductive cough may require evaluation/cessation of therapy.[11]

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

nonresponsive

noninfectious uveitis

in adults and children,

adjuvant to cyclosporine

in ABD and BSCR'[2]

OCP

  • Diarrhea, nausea, GI ulceration
Azathioprine/AzoranⓇ/ImuranⓇ Purine analogue 1mg/kg/day PO (100-250mg qD) 3mg/kg/day Scleritis in RP, GPA

iridocyclitis in JIA, reactive arthritis

VKH

SO

OCP

ABD

Pars planitis

uveitis in sarcoidosis, SLE

  • GI upset
  • Bone marrow toxicity (leucopenia, thrombocytopenia)
  • Hepatitis
  • Pancreatitis
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

graft rejection[1]

  • Hypertension
  • Nephrotoxicity
  • Hyperlipidemia/hypercholesterolemia
  • Hirsutism
  • Hyperplasia of gum
  • Hyperuricemia
  • Hyperglycemia/diabetes
  • GI upset
  • Neurotoxicity- paresthesias
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

BSCR

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.[13]

Absorption is not dependent on bile.[13]
Voclosporine Calcineurin inhibitor 0.4mg/kg/day in divided dose PO Noninfectious sight threatening uveitis[14]Evaluated in LUMINATE trial Similar to cyclosporine.
Sirolimus (Rapamycin) mTOR inhibitor Loading dose 6 mg/day, followed by

Maintenance 2 mg/day, PO

6mg/day [1] Recalcitrant non-infectious uveitis

[the intravitreal form is evaluated in SAVE and SAKURA study[15]]

  • GI distress
  • Skin disorders
Alkylating agent Cyclophosphamide/CytoxanⓇ Causes DNA cross linking 1 mg/kg/day PO or

1 g/m2 (BSA) infusions

q1-2 weeks (IV pulse)[1]

3mg/kg/day PO[1] Necrotizing scleritis/PUK in GPA, RP, PAN, RA

Bilateral Mooren ulcer

ABD

OCP

SO

  • Alopecia
  • Hemorrhagic cystitis (due to a metabolite acrolein)
  • Bone marrow toxicity (anemia, leucopenia)
  • Sterility
  • Secondary malignancy
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

ABD

SO

Uveitis in JIA

  • Bone marrow toxicity which may be reversible or irreversible
  • Sterility
  • Malignancy
  • Opportunistic infection
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

variable region

5-20 mg/kg/day (IV infusion)

Loading dose 0,

2, 4 weeks, then q4Wk for

6 months after

steroid-free remission

has been achieved.

Then taper

off with 3 infusions

at 6, 8, 10, 12 week

interval each, before

withdrawal.[1]

20 mg/kg/IV infusion Refractory ABD,

uveitis and scleritis

secondary to JIA, AS,

GPA, sarcoidosis,

Crohn’s disease,

conventional immunomodulator therapy-resistant uveitis[1]

BSCR

OCP

  • Reactivation of infections (tuberculosis, fungal infection) which may be fatal
  • Infusion reaction/ 'Remicade reaction' (pruritus, flushing, dyspnea, chest pain/tightness/discomfort, hypertension, myalgia, nausea, urticaria, headache, dizziness)[16]
  • Malignancy/lymphoproliferative disease/nonmelanoma skin cancers
  • Lupus like syndrome
  • Congestive cardiac failure
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

pseudotumor

  • Pain at injection site
  • Headache
  • Nausea, stomach upset
  • Rash, anaphylaxis
  • Sepsis
  • Drug induced lupus
  • Secondary malignancy
  • Demyelinating disorder
Stop in serious infection or sepsis.
Certolizumab/CimziaⓇ Recombinant human

anti-TNFa antibody

Fab’ fragment

400mg/wk IV[1] 1000mg/wk IV[1] To reduce anterior uveitis (AU) flares in subjects with active axial Spondyloarthritis (axSpA) in trial[17]
  • Serious infections[18] including TB, fungus (histoplasmosis), bacterial sepsis, reactivation of hepatitis B virus, other opportunistic infections
  • Secondary malignancy like lymphoma in children and adolescent- avoid in children
  • Anaphylaxis, rash
  • Heart failure
  • Demyelinating disease
  • Lupus like syndrome
  • Bone marrow toxicity- cytopenias/pancytopenia
Stop in serious infection or sepsis.

Not indicated in children[18]

Golimumab/SimponiⓇ Fully human anti-TNF-alpha monoclonal antibody 50mg SQ q4wk[19] JIA associated uveitis[19]

idiopathic retinal vasculitis[20]

  • Serious infections[21] including TB, invasive fungal infection, bacterial sepsis, reactivation of hepatitis B virus, other opportunistic infections
  • Secondary malignancy like lymphoma in children and adolescent
  • Anaphylaxis, rash
  • Heart failure
  • Demyelinating disease
Stop in serious infection or sepsis.
Anti-CD20 Rituximab/RituxanⓇ

[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[22] or based on clinical evaluation, but not sooner than every 16 weeks.' 

'Foster protocol'[9], 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

OCP

ABD,

orbital inflammatory syndrome

  • Infusion reactions- which may even be fatal approximately 80% of fatal reactions occurred with first infusion'[22]
  • Neutropenia
  • Progressive multifocal leukoencephalopathy (PML)
  • Serious infections, sepsis, reactivation of hepatitis B or fulminant hepatitis
  • Cardiac arrhythmia/angina- may be fatal
  • Bowel obstruction and perforation
  • Upper respiratory tract infection, nasopharyngitis
  • Severe mucocutaneous reaction including Stevens Johnson syndrome
IL 1 receptor antagonist Anakinra/KinretⓇ Humanized anti

IL1

receptor monoclonal

IgG antibody

100mg/day SQ[23] CINCA associated panuveitis (anterior uveitis, disc edema, vitritis)[24]

ABD[25]

  • Infusion site reaction
  • Headache
  • Upper respiratory infection/nasopharyngitis
  • Nausea, diarrhea, vomiting
  • Serious infections/sepsis
  • Hypersensitivity reaction- anaphylaxis
  • Neutropenia especially when used to anti-TNF agents
Use with TNF blocking agents is not recommended- higher rate of infection when used in combination.[23]
IL 2 receptor antagonist Daclizumab/ZinbrytaⓇ Humanized IgG1

antieIL-2 receptor

(CD25) monoclonal

antibody

150mg q4Wk SQ[26]

1 mg/kg q2Wk for 5 doses IV (renal transplant dosage)[1]

  • ABD
  • IU
  • Sarcoidosis
  • BSCR
  • VKH
  • Idiopathic noninfectios intermediate/posterior uveitis[27]
  • Hepatic injury including autoimmune hepatitis leading to life threatening events and liver failure (contraindicated in preexisting liver disease/impairment including ALT or AST > 2 times normal upper limit, and autoimmune hepatitis/ autoimmune conditions involving liver)
  • Hypersensitivity reaction/anaphylaxis
  • Serious infections
  • Severe depression/suicidal ideation
  • Serious immune mediated disorders including skin reaction, lymphadenopathy, non infectious colitis colitis
Obtain transaminase

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[26]
IL 6 receptor antagonist Tocilizumab /ActemraⓇ Recombinant humanized

IgG1k anti IL-6 receptor

monoclonal antibody

4 mg/kg q4wk followed by an increase to 8 mg/kg q4wk based on clinical response.[28]

8mg/kg q4wk[29]

8 mg/kg q4wk
  • Refractory uveitis related macular edema[29] in
    • JIA
    • BSCR
    • SO
    • Idiopathic panuveitis
    • AS
  • Serious infections which may be life-threatening/needing hospitalization including TB, bacterial, invasive fungal, viral, and other opportunistic infection[28]
  • Neutropenia
  • GI perforation
  • Hypersensitivity/anaphylaxis
  • Monitor neutrophils, platelets, lipids, and liver function tests,
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[30]

50mg/day PO[1] 150[1]- 300 [31]mg/day PO
  • OCP
  • Scleritis associated with RP
  • Agranulocytosis, aplastic anemia potentially leading to death
  • Hemolytic anemia (avoid in glucose 6 phosphate dehydrogenase deficiency)
  • Cutaneous reactions including Stevens Johnson syndrome
  • Peripheral neuropathy
  • Nausea, vomiting, pancreatitis
  • Headache, insomnia, psychosis
  • Vertigo, tinnitus
  • Pulmonary eosinophilia
  • Renal papillary necrosis, nephrotic syndrome, albuminuria, hypoproteinemia without proteinuria
  • Drug induced lupus, infectious mononucleosis like syndrome
  • Non-arteritic anterior ischemic optic neuropathy
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[31]
Others
Colchicine Inhibits microtubule formation
  • inhibits activation, degranulation and migration of granulocytes
  • antimitotic- causes metaphase arrest
  • may interfere with formation of inflammasome in neutrophils and monocytes which mediate IL1 activation[32]
0.5-1mg/day PO[33] 1.8mg/day PO[1] ABD
  • Myelosuppression- leucopenia, granulocytopenia, thrombocytopena, aplastic anemia
  • Myotoxicity especially rhabdomyolysis may occur especially with other drugs known to cause this (statins)
  • Abdominal pain, diarrhea, nausea, and vomiting
  • Pharyngolaryngeal pain
  • Elevated liver enzymes
  • Azoospermia
  • Alopecia, rash
  • Sensory motor neuropathy
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'[12]

0.5g/kg/day for 3 consecutive days q4week[34]

or 1-2g/kg/cycle over 3 days[1]

2.5g/kg/cycle[1] OCP[35]

Graves' ophthalmopathy

demyelinating optic neuropathy

scleritis

refractory uveitis[36]

  • Thromboembolism[37] especially in patients with other risks factors
  • Renal dysfunction, acute renal failure, osmotic nephrosis - more common in IVIg products containing sucrose.
  • Aseptic meningitis syndrome especially with rapid infusion/ high dose
  • Transmission of viruses/prion disease- as it is prepared from human blood
  • Hemolytic anemia
  • Headache, fatigue
  • Nausea, vomiting, abdominal pain
  • Increased body temperature, chills
  • Hypertension
  • Leukopenia
  • Hypersensitivity
Ensure hydration.

Monitor for hemolysis.

Interferon (IFN) α2a (Pegasys®) Immunomodulatory cytokine Induction: 3.0 or 4.5 million units SQ qD for 14 days, then

Maintenance: 3.0 or 4.5 million units 3 times qWeek[38][39]

6 million units/day[1] ABD

SO

  • Life threatening neuropsychiatric disease including depression, suicidal tendency, homicidal ideation, psychosis
  • hemolytic anemia
  • Autoimmune endocrine disorders including thyroid disorders; hyperglycemia
  • Autoimmune disease including myositis, hepatitis, systemic lupus erythematosus, thrombotic thrombocytopenic parpura
  • Infection- bacterial, fungal, viral
  • Bone marrow toxicity
  • Colitis and pancreatitis
  • Hypersensitivity reaction including Stevens Johnson syndrome
  • Peripheral neuropathy when used in combination with telbivudine
  • When used with Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients[40]
  • Eye diseases including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment
  • Cerebrovascular accidents, pulmonary disorders, peripheral neuropathy, myocardial infarction
  • Hepatic failure/exacerbation of hepatitis
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®)

or

30ug qWk (Avonex®) IM[41]

intermediate uveitis associated with MS,

optic neuritis associated with MS (CHAMPS and PRISMS study)[42]

  • Flu like symptoms
  • Depression, suicide[43], psychosis,
  • Hepatic injury
  • Hypersensitivity reaction including anaphylaxis
  • Congestive cardiac failure
  • Reduced blood counts
  • Autoimmune disorder- idiopathic thrombocytopenia, hyper- and hypothyroidism, and rare cases of autoimmune hepatitis
  • Spread of blood-borne infection/prion disease (Rebif contains albumin)[44]
  • Seizures
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[45]

Refractory JIA uveitis
  • Avoid with anti-TNF drugs- high risk of infection
  • Headache
  • Upper respiratory tract infection
  • Hypersensitivity including anaphylaxis
  • Nausea
  • May blunt the effectiveness of some vaccines[46]
  • Lymphoma

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.'[47]

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.[1]

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.[40]

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[1] in especially the IV drugs including

  • adalimumab
  • infliximab

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[34]

  • infliximab
  • adalimumab
  • certolizumab
  • etanercept
  • golimumab
  • anakinra
  • basiliximab

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[1]) 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.

Abbreviations

  • ABD- Amantiades-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- Serpigineous 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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