immunomodulatory therapy in opthalmology

1. Dr. Rakshya Basnet
1st year resident
LEIRC,NAMS
Immunosuppresants in Ophthalmology

2. Contents
• Introduction
• Classification
• Antimetabolites
• Alkylating agents
• Antibiotics
• Biological response modifiers
• Conclusion
2

3. Introduction
• 1st described- Hektoen L, Corper JH: Effect of mustard gas on
antibody formation. J Infect Dis 1921
• Immunomodulatory therapy (IMT) is playing an increasingly important
role in care of patients with neoplastic and autoimmune diseases
3

4. In any case of ocular inflammatory disease(OID)
Stepladder approach
use steroid first aggressively
all routes(topical, periocular,intraocular,systemic)
in larger doses
If relapse add oral NSAIDs
immunomodulatory therapy

5. When to use??
• A) Early/Absolute-vision threatning intraocular inflammation
-disease process that is likely reversible
• B) steroid sparing –inadequate response to steroid
-failed therapy of steroid
-side effects
-unacceptable adverse effects
-long term steroid dependence
-requiring repeat steroid injection

6.  early initiation in:
• Behçet’s with posterior segment
• Sympathetic ophthalmia
• Necrotizing scleritis with systemic association
• Serpiginous choroidopathy with vision threatening involvement
 Some consider early initiation for :
• Birdshot chorioretinopathy
• JIA associated chronic uveitis
• Multifocal Choroiditis with Panuveitis
• Vogt Koyanagi Harada Disease
Initiation of steroid sparing
immunomodulatory therapy(IMT)

7. Before starting immunosuppresants..
• Absence of infection
• Hepatic & hematologic contraindication
• Pregnancy testing
• F/U from physician
• Longitudinal evaluation of disease process
• Informed consent

8. Ophthalmologist
ImmunologistWho ?
Infectious dis. spl.

9. Classification 9
C)Alkylating agents
Cyclophosphamide
Chlorambucil
B)Transcription factor inhibitors
Antibiotics
 Cyclosporine
 Tacrolimus
 Mitomycin
D)Biologic Response Modifiers
 Infliximab
 Adalimumab
 Rituximab
 daclizumab
 Intravenous Immunoglobulin
 Interferon Alpha- 2a
A)Antimetabolites
 Azathioprine
 Mycophenolate mofetil
 Methotrexate
 5-Fluorouracil

10. ANTIMETABOLITES 10

11. Antimetabolites
• Inhibits use of a metabolite
11

12. azathioprine
• Purine analog
• Route: oral
• Dose: 2-3 mg/kg/day
12

13. 13

14. Azathioprine; Ophthalmic indications
• Used in combination with steroids
• Corneal graft rejection
• Behçet’s syndrome
• Sympathetic ophthalmia
• JIA-associated uveitis that does not respond to conventional steroid therapy
• Cicatricial pemphigoid
• Relapsing polychondritis-associated scleritis
• Multifocal choroiditis with panuveitis
• VKH, sarcoidosis, pars planitis, and Reiter’s syndrome-associated iridocyclitis
15

15. Azathioprine; Monitoring
• TPMT (Thiopurine methyltransferase)  pretreatment
1. low/no TPMT activity (0.3% of patients)- not recommended
2. Intermediate TPMT activity (11% of patients)-at reduced dosage
3. Normal/high TPMT activity (89% of patients)-higher doses than in
patients with intermediate TPMT activity
• CBC weekly (1-2 months) then 3 monthly
• LFT
16

16. Azathioprine; Side effects 17
A B C

17. Mycophenolate mofetil
• Derived from fungus Penicillium stoloniferum or P. echinulatum
• Route: oral
• Dose: 1-3 g/day
18

18. 19

19. Mycophenolate mofetil; INDICATIONS
• Ocular cicatricial pemphigoid
• Scleritis
• Chronic Uveitis
• Orbital pseudotumor
• Corneal graft rejection
20

20. Mycophenolate mofetil; Side effects 21
A B C

21. Mycophenolate mofetil; Monitoring
• CBC
• LFT
22
Stat, weekly for 4 weeks then in every 4-6 weeks

22. Methotrexate (amethopterin)
• Folic acid analog
• Route: oral, intramuscular or intravenous
• Dose: 2.5–7.5 mg once a week, with folic acid 1 mg daily
23

23. 24

24. Methotrexate;Ophthalmic Indications
• Idiopathic orbital inflammatory disease
• Metastasis to choroid from choriocarcinoma
• Idiopathic cyclitis
• Sympathetic ophthalmia
• uveitis rheumatoid arthritis,JIA,Reiter’s syndrome, ankylosing spondylitis,
inflammatory bowel disease & psoriasis
• Scleritis in collagen dz. As Reiter’s syndrome, RA, cicatricial pemphigoid
26

25. Methotrexate; Side effects 27
A
B C

26. Prevention of complications
• Use of folic acid
• Alcohol abstinence
• Avoid medications affecting liver
• Appropriate contraception for women
• Potential for sperm mutation

27. Methotrexate; Monitoring
• CBC
• RFT
• LFT
29
Stat, then weekly until dose stable, then every 2-3 months

28. 5-fluorouracil
• Synthetic pyrimidine analogue
• Potent inhibitor of fibroblast proliferation
• Route: subconjuctival
• Dose: 5mg for 7-14 days twice-daily
30

29. 5-FU; Ophthalmic Indication
• Primary glaucoma filtering surgeries in reviving failing filtering blebs
• Dacryocystorhinostomy
• Pterygium surgery
• Vitreoretinal surgery to prevent proliferative vitreoretinopathy
• ocular surface squamous neoplasia
• Topical is used to treat BCC
31
.

30. 5-FU;contraindications
• Severely debiliated disease
• Pregnancy
• breastfeeding

31. 5-FU;Side effects
• Superficial punctate keratopathy
• Persistent corneal epithelial defect
• Filamentary keratopathy
• Wound / suture track leaks
33

32. Alkylating agents
34
Cyclophosphamide
Chlorambucil
Nitrogen mustards
nucleophilic substitution reactions

33. Cyclophosphamide
35
Most potent of therapeutic alkylating agents
Dose is 1–2 mg/kg
Half-life is 7 h

34. 36
Route- oral/ IV(intermittent intravenous pulses)
P 450 Phosphoamidase
aldophosphamide
4-OH
cyclophosphamide

35. Cyclosphosphamide;Mechanism
• Alkylation of DNA
• Breaks in DNA
• Repair with phosphodiester bond
• Cross-linking betwn DNA,dna & rna,these molecules and proteins
• Death of cell
37

36. Cyclosphosphamide; Indications
• Ocular manifestations of Wegener’s granulomatosis,PAN
• Necrotizing scleritis
• Cicatricial pemphigoid
• JIA associated iridocyclitis
• RETINOBLASTOMA
• RHABDOMYOSARCOMA
• B/L Mooren’s ulcer
38

37. Cyclosphosphamide; Side effects
• Severe bone marrow depression
• Hemorrhagic cystitis
• Anorexia, nausea, vomiting
• Hemorrhagic colitis
• Oral mucosal ulceration
• Jaundice
• Gonadal suppression
• Alopecia
• Interstitial pulmonary fibrosis
39

38. Hemorrhagic cystitis
• 5–10% of patients
• Chemical irritation of lining of bladder – acrolein
• Can lead to bladder carcinoma
PREVENTION
• Restricting consumption early hrs of day
• Forcing fluid intake during remainder of day
• Acetylcysteine or mesna (sodium 2-mercaptoethanesulfonate )
40

39. Cyclosphosphamide; Contraindications
• Hypersensitivity
• Severely depressed bone marrow function
• Pregnancy
41

40. Cyclosphosphamide; Monitoring
• Twice a week ( CBC and Urine analysis) initially,then once a month
• Avoid depressing
• WBC < 3500cells/mm3
• Neutrophils <1500cells/mm3
• Platelets <75,000/mm3
42

41. Chlorambucil
• Slowest acting of nitrogen mustard
• Route- oral
• Dose- 0.1 mg/kg/day
• short-term and high dose therapy 3-6 months
43

42. Mechanism of action
• Similar to cyclophosphamide
44

43. Chlorambucil; Indications
• Used in retinal vasculitis in Behcet’s disease
• Sympathetic opthalmitis
• Idiopathic orbital inflammation(IOI)
45

44. Chlorambucil; Side effects
• Bone marrow suppression
• Sterlity (male> female) -> pretreatment sperm banking
• Mutagenic
46

45. Transcription factorinhibitors
Antibiotics
Cyclosporine
Tacrolimus
Mitomycin
47

46. Cyclosporin A & TACROLIMUS
• Fungal -Tolypocladium inflatum Gams,Cylindrocarpon lucidum
• Tacrolimus -fungus Streptomyces tsukubaensis
• Route: oral, topical (OSD)
• Dose: starting 2.5 mg/kg/day to maximum of 5mg/kg/day
• Tacrolimus;0.10-0.15mg/kg/day in adults
48

47. Mechanism 49

48. Cyclosporine; Indications
• Sympathetic ophthalmia
• Vogt–Koyanagi–Harada syndrome
• Multifocal choroiditis with panuveitis
• Posterior uveitis associated with Behçet’s syndrome
• Corneal graft rejection
50

49. Cyclosporine; Side effects 51
A B C

50. Cyclosporine; Monitoring
• CBC
• Serum creatinine
• BUN
• Urine analysis
• Blood pressure
• Fasting lipid profile
52
4-6 weekly
3 monthly

51. MytomycinC
• Isolated from Streptococcus calspitosus
• Route: topical
• Dose: 0.02-0.04% Drops
• Inhibits DNA dependent RNA synthesis reduce collagen formation by
inhibiting fibroblast proliferation
53

52. CLINICAL USES OF MITOMYCIN C IN
OPHTHALMOLOGY
 Pterygium surgery
 Glaucoma filtering surgery
 Refractive surgeries
 Ocular surface tumors
 Squint surgeries
 Dacryocystorhinostomy (DCR)
 Allergic conjunctivitis

53. Adverse effects OF TOPICAL MITOMYCIN C
• Conjunctival hyperemia
• Blepharospasm
• Corneal punctate erosion
• Punctal stenosis
• Limbal stem cell deficiency

54. Biological response modifiers
• Inhibitors of cytokines
• Results in targeted immunomodulation
71

55. Biologic Response Modifiers
•Most uveitis specialists would not manage administration of
these agents but would refer patient to a rheumatologist
•Must be sure that inflammation is non-infectious

56. Daclizumab
• Monoclonal antibody against IL-2 receptor of activated lymphocytes
• Route: IV
• Dose: 1-4 mg/kg, in every2 weeks
INDICATIONS
• Resistant ocular inflammation- uveitis, scleritis, atopic disease and
cicatricial pemphigoid
73

57. Infliximab
• IgG monoclonal antibody against TNF-a
• Route: IV
• Dose: loading dose 5mg/kg at day 0 and 2 followed by infusion 4
weekly
74

58. Infliximab; Indications
• Ocular complication of Bechets disease
• Refractory uveitis associated with JIA, ankylosing
spondylitis,sarcoidosis,VKH syndrome
75

59. Infliximab; Side effects
• Drug induced lupus,systemic vascular thrombosis,
• Increase susceptibility:Mycobacterium,Aspergillus,Histoplasmosis,Toxoplasma,Candida
• Reactivation of latent tuberculosis
MONITORING
• CBC and LFT stat and 4-6 weekly
• Tuberculin skin test stat and yearly
76

60. ADALIMUMAB
• Human monoclonal immunoglobulin against TNF-alpha
• Used in pediatric uveitis and adult behcet uveitis,posterior and
panuveitis
• Can be self administered by subcutaneous injection every 2 weeks

61. some other newer agents
• Rituximab : Monoclonal antibody against CD-20 positive cells
• Anakinra : IL-1 receptor antagonist
• Tocilizumab : Recombinant human antibody against IL6
• Interferon alfa-2a/2b-alternative to anti-TNF
antiviral, immunomodulatory, antiangiogenic
78

62. Intravenous immunoglobulin
• Effective in uveitis otherwise refractory to IMT
• Useful in mucous membrane pemphigoid

63. Conclusion;
• No therapeutic response may occur for several weeks after initiation of IMT
• maintain on corticosteroids until IMT begins effect
• monitor closely
• Serious complications include renal& hepatic toxicity, bone marrow
suppression, increased susceptibility to infection
• In addition, alkylating agents may cause sterility,future malignancies
81

64. • Alkylating agents-trimethoprim-sulfamethoxazole prophylaxis
• Potentially teratogenic-methotrexate,cyclosphosphomide
82

65. Bibliography
 Jakobiec’s principles and practice of ophthalmology.3rd edition
(vol 1)
 AAO.Intraocular inflammation and uveitis.2016-1017
 Ocular therapeutics and pharmacology-Philip P.Ellis-6th edition
 Ocular pharmacology-William H.Havener -5th edition
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66. Thank you