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Immunomodulators in Ophthalmology


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Immunomodulators in Ophthalmology

  1. 1. Dr. Sunita Kumawat DEPTT. Of Ophthalmology SPMC Bikaner IMMUNOMODULATORS in OPHTHALMOLOGY
  2. 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. 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. 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. 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. 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. 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. 8.  Route : orally, IV  For controlling ocular inflammation orally is more effective then intermittent IV pulses.  DOSE : 2 mg/kg/day orally
  9. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 20.  Leucovorin‘rescue’ may help to reverse some methotrexate induced toxic effects.  Concurrent 1mg/day folate given.
  21. 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. 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. 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. 24. Signal transduction inhibitors Cyclosporine A:  is a fungal metabolite originally isolated from cultures of Tolypocladium inflatum Gams and Cylindrocarpon lucidum.
  25. 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. 26.  Calcineurin inhibition blocks IL-2 trancription, and ultimately result in inhibition ofTcell activation.
  27. 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. 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. 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. 30. Side effects  Renal toxicity,  hypertension.,  Heptotoxicity,  Gingival hyperplasia,  Hypertricosis.  Lid and conjuntival erythema, non specific conjunctivitis.
  31. 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. 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. 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. 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. 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. 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. 37. Side effects:  Nausea, vomiting.  Hepatitis,  Peripheral neuropathy,  Blurred vision,  Psychosis, and  Nephrotic-like syndrome.
  38. 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. 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. 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. 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. 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. 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. 44. Corticosteroids:-
  45. 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. 46.  They act by supressing the formation of arachidonic acid and other inflammatory mediators by inhibition of enzyme phospholypaseA2
  47. 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. 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)
  49. 49.  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.
  50. 50.  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.
  51. 51. 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.
  52. 52.  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.
  53. 53. 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.
  54. 54.  Fuocinolone: Fluocinolone acetonide intrvitreal implant RETISERT is marketed for t/t of chronic non infectious uveitis affecting post. Segment of eye.
  55. 55. Uses:
  56. 56. 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.
  57. 57.  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.
  58. 58. 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
  59. 59. 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.
  60. 60.  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.
  61. 61. 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.
  62. 62. Questions :  Role of immunomodulators in ophthalmology.  Cyclosporine SN.
  63. 63. THANKYOU