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Article initiated by:
Koushik Tripathy, MD (AIIMS)
All contributors:
Ghazala D. O'Keefe, MD,Dan Thomas G,Koushik Tripathy, MD (AIIMS),Harikrishnan Vannadil, MD, MS (Ophthal),WikiWorks2,Alan Palestine, MD,Edmund Tsui, MD
Assigned editor:
Olena Hurzhii, MD
Review:
Assigned status Update Pending
by Edmund Tsui, MD on September 19, 2023.
The Merriam-Webster's dictionary defines immunomodulator as 'a chemical agent (as methotrexate or azathioprine) that modifies theimmuneresponse 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 'anydrugorsubstancethatsuppresses theimmuneresponse'. 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.
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:
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]
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]
- 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.
SQ is preferred for higher dosage and may prevent
GI side effects.
Splitting the dose in 2 days may also reduce side effects.
50 mg/week (SQ),[1]
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
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.[11]
Dry nonproductive cough may require evaluation/cessation of therapy.[11]
Folinic acid/leucovorin treats MTX toxicity.
nonresponsive
noninfectious uveitis
in adults and children,
adjuvant to cyclosporine
in ABD and BSCR'[2]
OCP
- Diarrhea, nausea, GI ulceration
iridocycl*tis in JIA, reactive arthritis
VKH
SO
OCP
ABD
Pars planitis
uveitis in sarcoidosis, SLE
- GI upset
- Bone marrow toxicity (leucopenia, thrombocytopenia)
- Hepatitis
- Pancreatitis
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
BSCR
Idiopathic posterior uveitis
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]
Maintenance 2 mg/day, PO
[the intravitreal form is evaluated inSAVE and SAKURA study[15]]
- GI distress
- Skin disorders
1 g/m2 (BSA) infusions
q1-2 weeks (IV pulse)[1]
Bilateral Mooren ulcer
ABD
OCP
SO
- Alopecia
- Hemorrhagic cystitis (due to a metabolite acrolein)
- Bone marrow toxicity (anemia, leucopenia)
- Sterility
- Secondary malignancy
Cryopreservation of sperm/eggs before using.
Filgrastim may be used for severe leucopenia.
ABD
SO
Uveitis in JIA
- Bone marrow toxicity which may be reversible or irreversible
- Sterility
- Malignancy
- Opportunistic infection
Chimeric IgG1k anti-TNFa
monoclonal antibody with a
human constant and mouse
variable region
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]
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
Quantiferon TB Gold (interferon gamma release assay) before starting. Rule out active tuberculosis/infection before initiating treatment.
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
anti-TNFa antibody
Fab’ fragment
- 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
Not indicated in children[18]
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
[chimericanti-CD20 monoclonalantibodywith mouse variable and human constant regions]
'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.'
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
IL1
receptor monoclonal
IgG antibody
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
antieIL-2 receptor
(CD25) monoclonal
antibody
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
and bilirubin levels before initiation
Stop in severe liver injury/ severe immune mediated disorder/severe infection.
IgG1k anti IL-6 receptor
monoclonal antibody
8mg/kg q4wk[29]
- 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,
, platelet countbelow 100,000 per mm3, or who have ALT or AST above 1.5 times theupper limit of normal
Inhibition of neutrophil adherence[30]
- 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
Avoid in sulfa allergy.
- 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]
- 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
Avoid when patient is on CYP34A inhibitors- life-threatening drug interaction may occur.
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]
or 1-2g/kg/cycle over 3 days[1]
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
Monitor for hemolysis.
Maintenance: 3.0 or 4.5 million units 3 times qWeek[38][39]
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
or
30ug qWk (Avonex®) IM[41]
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
infusion at weeks 0, 2, and 4, and was thencontinued monthly[45]
- 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
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 3months 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 QuantiFERON TB gold test must be done before starting the drug. Hepatitis B surface antigen should be done in high risk cases.[1]
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]
The IMTs usually take time (2 - 3 months) to start acting, thus for the acute control of inflammation use of systemic and/or topical corticosteroids is needed. Early onset of action may be noted at 1-2 weeks[1] in especially the biologic drugs including
However, rituximab (IV) may take 3 months to show clinically obvious activity.
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.
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.
