This document discusses various immunomodulators used in ophthalmology. It begins by defining immunomodulators as agents that weaken or modulate the immune system's activity, thereby decreasing inflammatory responses. The document then categorizes immunomodulators into classes including corticosteroids, alkylating agents, antimetabolites, signal transduction inhibitors, biologic products, and biological response modifiers. For each class and some individual agents, the document provides details on mechanisms of action, common uses in ophthalmic conditions, dosages, administration routes, and potential side effects.

1. Dr. Sunita Kumawat
DEPTT. Of Ophthalmology
SPMC Bikaner
IMMUNOMODULATORS
in
OPHTHALMOLOGY

2.  As the name implies, immunomodulators
weaken or modulate the activity of the
immune system.
 That in turn,decreases the inflammatory
response.
 Immunomodulators are most often used in
organ transplantation to prevent rejection of
the new organ as well as in autoimmune
diseases which appears to be caused by an
overactive immune system

3. class Type of agent Name of agent
corticosteroids
Alkylating agent Nitrogen mustard cyclophosphamide
chlorambucil
Antimetabolite Folic acid analogs methotrexate
Pyrimidine analogs 5-fluorouracil
Purine analogs Azathioprine
Natural products Antibiotics Cyclosporine
Dapsone
Tacrolimus
Mitomycin
Antibodies Antilymphocyte serum
AntiT cell antibody
Gamma globulin

4. Alkylating agents:
Cyclophosphamide : most potent therapeutic
alkylating agent.
 Converted to active
metabolite(aldophosphamide & 4-
hydroxycyclophosphamide) by liver.
 These active metabolite form DNA crosslinks
between and within the DNA strands,leads to
cell death,which acounts for their predominant
immunosupressive activity.

5. Uses:
1. Cyclophosphamide is the treatment of
choice for any patient with ocular
manifestations of wegner’s granulomatosis
or polyarteritis nodosa.
2. It can be used in Highly destructive form of
inflammation in association with
rheumatoid arthritis.
3. Necrotizing scleritis associated with
relapsing polychondritis.

6. 4.Retinal vasculitis associated with
sarcoidosis;
5.Pars planitis associated with multiple
sclerosis;
6. Severe uveitis associated with ankylosing
spondylitis, with Reiter’s syndrome, or with
inflammatory bowel disease;
7. Idiopathic uveitis; and bilateral
Mooren’sulcer, cicatricial pemphigoid.

7. 8.multifocal choroiditis associated with
progressive systemic sclerosis;
9.Other OID including posterior uveitis or
retinal vasculitis manifestations of Behçet’s
disease,juvenile idiopathic arthritis,
sympathetic ophthalmia;Vogt-Koyanagi-
Harada syndrome; birdshot
retinochoroidopathy; multifocal choroiditis
with panuveitis; retinal vasculitis associated
with systemic lupus erythematosus.

8.  Route : orally, IV
 For controlling ocular inflammation orally is
more effective then intermittent IV pulses.
 DOSE : 2 mg/kg/day orally

9. Side effects:
Potential complications of cyclophosphamide therapy
includes:
 Severe bone marrow depression with resultant
anemia, leukopenia,thrombocytopenia.
 Secondary infections.
 Anorexia, nausea, vomiting, hemorrhagic colitis,
and oral mucosal ulceration;jaundice; hemorrhagic
cystitis.
 Gonadal suppression,alopecia; and interstitial
pulmonary fibrosis.

10. Chlorambucil:
 It interfere with DNA replication and prevent
cellular division of rapidly proliferating cells, such
as inflammatory and neoplastic cells.
Used in retinal vasculitis in Behcet’s ds.
side effects are same as
cyclophosphamide.(except haemmorhagic
cystitis which is a peculiar s/e of
cyclophosphamide and it is not associated
with chlorambucil).
DOSE : 0.1 -0.2 mg/kg single daily dose
orally.

11. Monitoring :
 Careful hematologic monitoring is must for use of
alkylating agents
Avoid depressing:
 WBC<3500 cells/mm3,
 Neutrophil <1500 cells/mm3,
 Thrombocytopenia <75 000 platelets/mm3,
 CBC and urinalys in every 2 weeks, then once in a
month

12. Antimetabolites
Azathioprine:Purine analogue,
Interfere with the synthesis of purine
bases and so with synthesis of DNA,
RNA and protein.
Thus inhibit B &T cell proliferation.
 DOSE : 2-3mg/kg/day, orally

13. Ophthalmic uses:
1. Effective in patients with ocular inflammatory
Manifestations of Behçet’s syndrome
2. sympathetic ophthalmia
3. JIA-associated uveitis that does not respond to
conventional steroid therapy.
 It also can be effective in the treatment of cicatricial
pemphigoid,relapsing polychondritis-associated
scleritis. Multifocal choroiditis with panuveitis,Vogt–
Koyanagi–Harada syndrome, sarcoidosis, pars
planitis, and Reiter’s syndrome-associated
iridocyclitis.

14. Side effects:
 Potential drug-induced complications of azathioprine
therapy include hepatotoxicity, severe bone marrow
depression with resultant anemia, leukopenia,
thrombocytopenia.
 Anorexia, nausea, vomiting, gastrointestinal distress
diarrhea, rash, fever, and arthralgia. and
 Secondary infections.

15. Mycophenolate mofetil:
It Converted to mycophenolic acid, inhibits
inosine monophosphate dehydrogenase,
which is critical to de novo purine
synthesis.thus it enterfere with synthesis of
DNA, RNA, and protein.thus inhibitT&B
cell proliferation
 It is administered orally as1–3 g/day

16. Uses:
 Mycophenolate mofetil has been shown to be
effective in the care of patients with ocular
cicatricial pemphigoid,
 scleritis,
 uveitis and
 orbital pseudotumor.
Side effects:
 The most notable potential adverse effect of
mycophenolate mofetil is secondary infection
and other are same as azathioprine.

17. Methotrexate :
It is a folic acid analog also known as
amethopterin, binds to folic acid reductase,
thus blocking the conversion of dihydrofolic
acid to tetrahydrofolic acid.
This interferes with thymidine synthesis and,
so, with DNA synthesis and cell division.
It has little effect on resting cells but
pronounced effects on rapidly proliferating
cells.

18.  It affects both B andT lymphocytes and can inhibit
humoral and cellular immune responses.
 Folinic acid can reverse the metabolic block produced
by methotrexate, thus rescuing viable cells.
 The suggested regimen of methotrexate is 2.5–7.5 mg
once a week, with gradual escalation of the dose, as
indicated by the clinical response, to a maximum of
50mg/week.
 Route : orally , IM, IV, SC,intravitreal.
 Mtx may take 6 months to produce its full effect .

19. Uses:
 It cab be used in Idiopathic cyclitis,sympathetic
ophthalmia, ocular manifestations of
rheumatoid arthritis, JIA, Reiter’s syndrome,
ankylosing spondylitis,inflammatory bowel
disease, and psoriasis.
 400 microgm intravitreal Mtx is given as aTt
of ref. uveitis and Cystoid Macular Edema.

20.  Leucovorin‘rescue’ may help to reverse
some methotrexate induced toxic effects.
 Concurrent 1mg/day folate given.

21.  S/E : GI distress,anorexia , reversible
hepatotoxicity , cirrhosis, teratogenicity,
and myelosuppression.
 Thus Proper monitoring is important; this
obviously requires the involvement of an
additional specialist and regular laboratory
testing in these patients.
 CBC, LFT should be done in every 4-6wk.

22. 5-fluorouracil :
 Pyrimidine analogue, mimics uracil after
intracellular conversion to nucleotide and
subsequent incorporation to RNA.
 Thus it is toxic to rapidly dividing cells.

23. Uses:
 The sole opthalmic application of 5-FU is
subconjunctival injection after glaucoma
filtering surgery in an effort to prevent
subconjunctival fibrosis and bleb failure.
 The primary toxic effect of subconjunctival 5-
FU consists of superficial punctate
keratopathy and persistent corneal epithelial
defect, and wound leak.

24. Signal transduction inhibitors
Cyclosporine A:
 is a fungal metabolite originally isolated
from cultures of Tolypocladium inflatum
Gams and Cylindrocarpon lucidum.

25.  It inhibit calcineurin,
 Calcineurin is a enzymatic protein that
normaly dephosphorylates the cytoplasmic
subunit of nuclear factor of activated
Tcells(NFAT). By doing so it augment
trancription of numerous cytokines including
IL2. which inturn activate toT cells

26.  Calcineurin inhibition blocks IL-2 trancription,
and ultimately result in inhibition ofTcell
activation.

27. Uses:
 CsA may be particularly useful in the treatment of
various forms of posterior uveitis, especially when
both retina and choroid are involved in the
inflammatory process in: sympathetic ophthalmia,
Vogt–Koyanagi–Harada syndrome, multifocal
choroiditis with panuveitis, posterior uveitis
associated with Behçet’s syndrome.
 Oral (usual initial dose) 2.5mg/kg/day in two
divided doses. Can be increased upto .
5-7mg/kg/day

28.  In 2003 an ophthalmic formulation,
cyclosporine 0.05% emulsion, was approved
by the FDA to treat dry eye disease.. It is
effective for keratoconjunctivitissicca.
 Topical cyclosporine emulsion has also been
investigated for treatment of other ocular
surface disorders that may have an immune-
based inflammatory component.

29.  In these trials, cyclosporine 0.05% emulsion
has shown efficacy for management of
posterior blepharitis, ocular rosacea, post-
LASIK dry eye, contact lens intolerance,
atopic keratoconjunctivitis, graft-versus-host
disease, and herpetic stromal keratitis.
 It was also investigated for the treatment of
corneal graft rejection and the results were
disappointing.

30. Side effects
 Renal toxicity,
 hypertension.,
 Heptotoxicity,
 Gingival hyperplasia,
 Hypertricosis.
 Lid and conjuntival erythema, non specific
conjunctivitis.

31. Biologic products:
 Mytomycin C: Isolated from Streptococcus
calspitosus.
 Is an antibiotic with antineoplastic action.
 Reacts with DNA in ways similar to
alkylating agents. It cross-links DNA and
inhibits its synthesis and thus acts as highly
effective antimitotic agent.

32.  The ocular indications for mitomycin C are
recurrent pterygium and glaucoma filtering
surgery.
 It is clearly simpler and cheaper than either
conjunctival transplantation or b-irradiation.

33.  It can be applied to the scleral bed of the
guarded trabeculectomy site, as 0.4 mg/mL
in saturated cellulose sponges, with
conjunctiva draped over the sponges for 4
min, and then vigorously irrigate the area
with 45 mL of balanced salt solution after
removal of the sponges.

34.  Mitomycin can be used to reduce the risk of
corneal scarring after certain procedurs like
photorefractive and photo therapeutic
keratectomy.
 It also is used to treat conjunctival and corneal
squamous cell neoplasia.
 Potential complications of topical mitomycin C is
scleral or corneal ulceration, scleral calcification,
conjuctival irritation, burning pain in eye, and
secondary glaucoma.

35.  Dapsone:
 Dapsone is a sulfa drug.
 Used for the antibiotic treatment of leprosy. In
addition to its antibacterial activity, it is a
myeloperoxidase inhibitor and stabilizes
lysosomal membranes.
 Its antiinflammatory and immunosuppressive
effects are most dramatic in dermatitis
herpetiformis and cicatricial pemphigoid.

36.  Dapsone may produce profound hemolysis in
patients deficient in glucose-6-phosphate
dehydrogenase, so any patient considered for
dapsone therapy must first be evaluated for
glucose-6-phosphate dehydrogenase level.
 Dose 25 mg twice daily, can be increased
upto150 mg/day if needed and if tolerated.

37. Side effects:
 Nausea, vomiting.
 Hepatitis,
 Peripheral neuropathy,
 Blurred vision,
 Psychosis, and
 Nephrotic-like syndrome.

38. Biological response modifiers:
 Inflammation is driven by a complex series of
cell-cell and cell cytokine interactions.
 Inhibitors of various cytokines have been
labelled as biologic response modifiers.
 These drugs results in targeted
immunomodulation.

39. Gamma immunoglobulin:
 Has been used in several patients whose severe
atopic keratoconjunctivitis did not respond
adequately to strict environmental controlls
and systemic antihistamine therapy.
 It must be given each week, iv or im.
 It has also been used with great effect in ocular
cicatricial pemphigoid which was inadequately
responsive to more conventional
immunomodulatory agents.

40.  Daclizumab:
 Daclizumab is a humanized monoclonal antibody to
IL-2 receptor.
 is approved and marketed for the treatment of solid
allograft rejections.
 It has been found safe and effective in treatment-
resistant ocular inflammation, particularly uveitis,
scleritis, atopic disease and cicatricial pemphigoid.
 dose 1 mg kg–1, iv, in every2 weeks .

41.  Infliximab :
 Infliximab is a mouse–human monoclonal
antibody which neutralizes TNF-a.
 It has been used to treat various forms of uveitis.
 dose 5–10 mg kg–1 every 2–4 weeks, through iv
infusion
Adverse effects:
 it has been associated with development of
malignancies in some instances and with increased
susceptibility to infection and to reactivation of
latent tuberculosis.

42.  Adalimumab : is a fully humanized
monoclonal IgG antibody directed against
TNF-α .
 It is under investigation for the treatment
of refractory ocular inflammatory diseases
like behcet’s ds.
 Dose : 40mg : Subcutaneous in every 2wk

43. some other newer agents:
 Rituximab : a chimeric monoclonal antibody against
CD-20 positive cells (mainly B lymphocyte)
 Anakinra : a recombinant IL-1 receptor antagonist
 Abatacept : a soluble fusion protein composed
CTLA-4 and a Fc fragment of human Ig G.
 Tocilizumab : recombinant human antibody against
IL6
 Interferon alfa-2a/2b .

44. Corticosteroids:-

45.  Steroidal medications are the most frequently
used “immunonotherapy” medication in
ophthalmology.
 Their antiinflammatory and antiallergic
activities are most important reason for their
clinical use.
 It must be remembered that the
antiinflammatory and immunosupressive
qualities are nonspecific & palliative and they
are never curative.

46.  They act by supressing the formation of arachidonic
acid and other inflammatory mediators by
inhibition of enzyme phospholypaseA2

47.  Steroid use in clinical ophthalmic practice
may be divided into 3 classes of therapy:
1. In post traumatic controll of inflammation
after surgery.
2. In Disorders of immune hyperreactivity.
 Iritis, posterior uveitis,
 Allergic disorders, such as allergic
conjunctivitis, atopic and vernal
keratoconjunctivitis,and graft rejection.

48.  3. For t/t of diseases that have combined immune
and infectious processes:
 Such as disciform herpes and bacterial corneal
ulcers,& retinal vasculitis associated with some
infective diseases.
 These should be treated very cautiously and
judiciously with steroids for immune mediated
damage, whereas the infection is treated or
controlled with antibiotics.( thus a combined
approach should be there)

50.  It must be recognized that even in the
absence of an infectious agent, whenever
complete immunosuppression is established
by the use of steroids, prophylactic
antimicrobial therapy should be considered.

51.  The sensitivity of treating such serious
problems with steroids must be emphasized,
because often only certain phases of these
diseases respond to steroids, and in other phases
steroids may be contraindicated.
 Steroids are at first administered in medium- or
large-size doses to adequately suppress
inflammation. then tapered gradually to prevent
rebound inflammation.

52. Routes
 Topical steroids are used to prevent or
suppress ocular inflammation in trauma and
uveitis and after most surgical procedure.
 Subconj and retrobulbar inj.Are used for
more severe inflammations.
 Systemic therapy is used to treat sys
immune disease like giant cell arteritis, and
vision threatening capillary hemangiomas in
childhood.
 IV methylprednisolone is used for
demylinating optic neuritis.

53.  Steroids can be delivered from a drug depot:as
cotton pledgets and collagen shields.
 Intravitreal steroid: is being used to treat variety of
retinal conditions including-
ARMD,
Diabetic retinopathy,
Cystoid macular edema.
 Two intravitreal triamcinolone formulations:
Trivaris andTriesence are approved for ocular
inflammatory conditions and visualization
during vitrectomy, respectively.

54. Weaker corticosteroid:
1. Fluoromathanolone( FML) 0.1%
2. Medrysone (HMS) 1%
 Used for corneal inflammation with moderate
efficacy and lesser side effects.
Soft steroids:
1. Loteprednol etabonate: for seasonal and
pernnial conjuctivitis.
2. Rimexolone : post operative inflammation, ant.
Uveitis.
 These Both are with decreased propensity to
raise IOP.

55.  Fuocinolone:
Fluocinolone acetonide intrvitreal implant RETISERT
is marketed for t/t of chronic non infectious uveitis
affecting post. Segment of eye.

57. Uses:

60. Ocular side effects of steroids
 Corticosteroids may cause glaucoma or
cataracts, may enhance secondary herpetic
or bacterial infections of the ocular surface,
or inhibit corneal epithelial and stromal
healing, resulting in further corneal melting
and perforation.
 Complications of prolonged corticosteroid
therapy can be devastating and sight
threatening.

61.  The steroid inhibits fibroblasts proliferation
and results in delayed collagen synthesis,
which can cause or exacerbate corneal
melting.And delay healing of postoperative
wound, stromal or epithelial defect.

62. Systemic side effects:
 Suppression of the pitu-adr axis
 Cushingoid habitus
 Hyperglycemia,muscle wasting, osteoporosis
 Trunkal obesity
 CNS effects eg. euphoria
 Insomnia
 Aseptic necrosis of the hip
 Peptic ulcer
 DM
 Psychosis

63. special consideration in immunomodulation
 • Immunomodulators reduce the activity of the
immune system.
 In so doing, they also decrease the body’s ability
to combat infection. so Be aware for any
incidence of fever, chills, or sore throat of any
patient receiving this therapy.
 Blood tests should be performed frequently to
check for effects on the bone marrow.
 Blood pressure and liver and kidney functions
need to be closely monitored.

64.  Women who are pregnant or wish to become
pregnant should not to be start with these
drugs.
 Methotrexate use should be avoided (by
pregnant women and by both men and
women for several months before conception)
because it may lead to pregnancy loss or
possible birth defects.

65. References :
 Albert Jakobiec’s principles and practice of
ophthalmology (3rd edition).
 Goodman & Gilman’s pharmacological basis of
therapeutics (12th edition).
 Parson’s disease of the eye (21st edition).
 Kanski Brad Bowling clinical ophthalmology (7th
edition).
 Internet resources.

66. Questions :
 Role of immunomodulators in
ophthalmology.
 Cyclosporine SN.

67. THANKYOU