IMMUNOSUPPRESSANTS IN OPHTHALMOLOGY.DP.pptx

Ophthmology
Medicine
Immunosuppressant
Disease

1. IMMUNOSUPPRESSIVE DRUGS IN OPHTHALMOLOGY DR. DEEPTI POUDEL 2 ND YEAR RESIDENT TILGANGA INSTITUTE OF OPHTHALMOLOGY

2. INTRODUCTION Immunosuppressants are the class of drugs which inhibit or prevent the activity of immune system Inhibit or decrease the intensity of the immune response in the body

3. INDICATIONS OF IMMUNOMODULATORY THERAPY (IMT) IN TREATMENT OF UVEITIS Vision-threatening intraocular inflammation or necrotizing scleritis Inadequate response to corticosteroid treatment Cases in which systemic or local corticosteroids are contraindicated or intolerable because of systemic or local adverse effects ( eg : glaucoma, cataract) Cases in which systemic corticosteroid cannot be tapered below 7.5 mg/day.

4. Following things should be assessed before initiation of IMT: Infection Recent live vaccine administration Hepatic, renal and hematologic contraindications Pregnancy or breastfeeding Status of family planning and contraception Objective longitudinal evaluation of the disease process

5. CLASSIFICATION BIOLOGIC AGENTS NONBIOLOGIC AGENTS ANTIMETABOLITES ALKYLATING AGENTS T-CELL INHIBITORS TNF INHIBITORS DRUGS INHIBITING OTHER PROINFLAMMATORY IMMUNE MEDIATORS

6. ANTIMETABOLITES METHOTREXATE AZATHIOPRINE MYCOPHENOLATE MOFETIL NON-BIOLOGIC IMT

7. METHOTREXATE A folic acid analogue MECHANISM OF ACTION: Inhibits dihydrofolate reductase

8. Routes of administration : oral, intravenous, intramuscular, subcutaneous, intravitreal Absorption : 70% after oral administration Half life: 6-9 hours(may last upto 24 hours in some) Metabolism : Metabolized in liver as well as in other tissues Methotrexate Methotrexate polyglutamate Elimination : Kidney(major), Liver( upto 30%): excreted as 7-hydroxy methotrexate in bile Folylpolyglutamate synthase

9. Dose : 0.15mg/kg/week Folic acid : 1-2 mg/day to reduce adverse effects (OR, 5mg twice a week) Time taken to control ocular inflammation : up to 6 months to produce full effect

10. CLINICAL APPLICATIONS J uvenile idiopathic arthritis (JIA)–associated anterior uveitis Sarcoidosis, panuveitis, and scleritis Psoriasis, psoriatic arthritis Ankylosing spondylitis Polymyositis, dermatomyositis Wegener’s granulomatosis, giant cell arteritis Systemic lupus erythematosus and vasculitis.

11. ADVERSE EFFECTS: Gastrointestinal distress, anorexia, nausea, vomiting, fatigue Mucosal ulcers, stomatitis, alopecia Hepatotoxicity Leukopenia, anaemia Nephrotoxicity Pneumonitis Bone marrow suppression Liver cirrhosis (<0.1%) Teratogenic Monitoring : CBC, LFT, RFT (initially at weekly for 4 weeks then every 2-3 months)

12. AZATHIOPRINE Purine nucleoside analogue A pro drug of mercaptopurine Mechanism of action :

13. Evaluation of TPMT activity has revealed 3 groups of patients: • Low/no TPMT activity (0.3% of patients); azathioprine therapy not recommended • Intermediate TPMT activity (11% of patients); azathioprine therapy at reduced dosage • Normal/high TPMT activity (89% of patients); azathioprine therapy at higher doses than in patients with intermediate TPMT activity

14. Pharmacokinetics : well absorbed from gastrointestinal tract with bioavailabilty of 80% Half life : less than 2 hours (but active 6-thioguanine nucleotides can remain concentrated in cells for few days) Elimination : Kidney

15. Route of administration : Oral Dose : up to 2-2.5 mg/kg/day Time taken to control ocular inflammation : After 3-6 months of initiation of therapy 50-60% of patients achieve remission CLINICAL APPLICATIONS : Behcet disease Intermediate uveitis VKH syndrome Sympathetic ophthalmia Necrotizing scleritis RA, psoriatic arthritis, reactive arthritis, SLE

16. ADVERSE EFFECTS: Nausea Vomiting Gastrointestinal upset Bone marrow suppression (leukopenia, anemia and thrombocytopenia) Hepatic toxicity Rarely hypersensitivity reactions(5%): fever, skin rashes, diarrhea, pancreatitis, hepatitis Obstetric complications: minimal risk of preterm birth, IUGR Monitoring : CBC and LFT-initially weekly for first 4-8 weeks, then every 3 monthly

17. MYCOPHENOLATE MOFETIL Isolated from Penicillium glaucus Mechanism of action :

18. Pharmacokinetic : good oral bioavailability Metabolism: In liver Mycophenolate mofetil Mycophenolic acid (active form) Elimination : Kidney Available forms : Oral and intravenous In vivo hydrolysis

19. CLINICAL APPLICATION : Effective in cases of chronic uveitis ( effective corticosteroid- sparing agent in up to 85% of patients) Efficacy in children (88%) and can be a safe alternative to methotrexate in patients with pediatric uveitis

20. Dosage : 1-1.5 gram twice daily in adults orally Time taken to control ocular inflammation : approximately 4 months

21. Adverse effects : Gastrointestinal distress (nausea, vomiting, abdominal pain) and diarrhea (<20%) Leukopenia, thrombocytopenia and anemia Increase incidence of infections Hepatotoxicity Monitoring : CBC: once in 2 weeks for first 2-3 months, then monthly for 1 st year Liver function test : at 1 month and every 3 months. Surjushe A, Saple D G. Mycophenolate mofetil. Indian J Dermatol Venereol Leprol 2008;74:180-184

22. T CELL INHIBITORS Cyclosporine Tacrolimus

23. CYCLOSPORINE A macrolide product of fungus Beauveria nivea

24. Cyclosporine is available in 2 oral preparations One is a microemulsion ( Neoral , Novartis) and has better bioavailability than the standard formulation ( Sandimmune , Novartis) The microemulsion is initiated at 2 mg/kg/day, and the standard formulation at 2.5 mg/kg/day in adults Pharmacokinetic: incompletely absorbed, has 20-30% of bioavailability Metabolism: Liver

25. CLINICAL APPLICATION Effective in intermediate uveitis, posterior uveitis, Behcet disease, and VKH syndrome. Topical cyclosporine 0.05% and 0.1% can be used in cases with severe dry eye and VKC Dosage : 1-5 mg/kg/day divided in 2 doses Time taken to control ocular inflammation : approximately 6 months- 12months

26. ADVERSE EFFECTS Systemic hypertension Nephrotoxicity GI upset Gingival hyperplasia, paresthesia, fatigue Hypertrichosis Hyperlipidemia, hyperglycemia, hyperuricemia Monitoring : Blood pressure, serum creatinine levels, CBC monthly

27. TACROLIMUS It is a product of Streptomyces tsukubaensis

28. CLINICAL APPLICATION : Used in intermediate uveitis and posterior uveitis with greater safety than cyclosporine (less chance of hypertension and hyperlipidaemia ) Routes : Oral, intravenous Metabolism : Liver Dosage : 0.10-0.15 mg/kg/day

29. ADVERSE EFFECTS: Nephrotoxicity (less common than cyclosporine because of low dose) Hypertension, tremor, paresthesia, hypomagnesemia Monitoring : Serum creatinine levels, CBC, blood glucose monthly

30. ALKYLATING AGENT Cyclophosphamide Chlorambucil

31. CYCLOPHOSPHAMIDE An alkylating agent Major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication Alkylate purines in DNA and RNA, resulting in impaired DNA replication and cell death Suppresses T-cell and B-cell function

32. Treatments of choice for patient with ocular manifestation of W egeners granulomatosis or polyarteritis nodosa. Pharmacokinetic : has high bioavailability orally and metabolized in liver into its active metabolites Elimination : Kidney Dosage : 1-2 mg/kg/day

33. ADVERSE EFFECTS Nausea and vomiting Hemorrhagic cystitis, myelosuppression S terility, reversible alopecia, teratogenic Increased risk of leukemia or lymphoma Gross hematuria is indication to discontinue therapy

34. Leucocyte count<2500cells/ µL -discontinued till cell count recovers Opportunistic infections such as pneumocystis pneumonia occur more commonly- trimethoprim-sulfamethoxazole prophylaxis Time taken to control ocular inflammation : within 12months (3/4 th of pts) Complete blood counts and urinalysis are monitored weekly to monthly

35. CHLORAMBUCIL It is a very long acting alkylating agent that interfere with DNA replication Effective in providing long-term drug free remission in 66%-75% of patients with sympathetic ophthalmia, Bechet disease.

36. Dosage : A single daily dose of 0.1–0.2 mg/kg in adults. Side effects : sterility, increased risk of hematologic malignancy, teratogenic, myelosuppression Monitoring: CBC weekly

37. MITOMYCIN C It is antineoplastic/antibiotic agent isolated from soil bacterium Streptomyces caespitosus . MECHANISM OF ACTION: Undergoes metabolic activation through an enzyme-mediated reduction to generate an alkylating agent and cross-links with DNA.

38. Clinical application Pterygium surgery Glaucoma filtering surgery Ocular surface squamous neoplasia DCR Dosage :0.02-0.04%

39. COMPLICATIONS: Pain, photophobia, watering, lid edema, scleral thinning, scleral melt, ulceration and symblepharon formation

40. 5- FLUOROURACIL (5-FU) It is fluorinated pyrimidine analogue antimetabolite, which blocks DNA synthesis through the inhibition of thymidylate synthesis. It has been shown to inhibit fibroblast proliferation Reduces fibroblast proliferation and subsequent scarring.

41. CLINICAL APPLICATION Pterygium surgery Ocular surface squamous neoplasia

42. COMPLICATIONS: Pain, pruritus, burning sensation P hotophobia, watering, lid edema S cleral thinning, scleral melt, ulceration and symblepharon formation Tenderness and residual post inflammatory hyperpigmentation

43. BIOLOGICAL AGENTS Inhibitors of various cytokines and inflammatory mechanisms Result in targeted immunomodulation, thereby theoretically reducing the short- term systemic adverse effects that are common with the non-biological agents More expensive and may carry higher long- term risks of serious infections or secondary malignancies Are reserved for specific conditions, such as Behcet disease or situations in which nonbiologic- IMT agents have failed.

44. TUMOR NECROSIS FACTOR (TNF- α ) INHIBITOR Infliximab Adalimumab Certolizumab Golimumab

45. INFLIXIMAB A mouse/human- chimeric, immunoglobulin G1 kappa (IgG1 κ) monoclonal antibody directed against TNF- α DOSAGE : 3-10 mg/kg Infusions at weeks 0, 2, and 4 and every 4–8 weeks thereafter for maintenance

46. CLINICAL APPLICATION: Effective in controlling current inflammation and decreasing the likelihood of future attacks in Behcet uveitis, undifferentiated uveitis, sarcoidosis, VKH syndrome, and many other entities in more than 75% of patients Favorable effects have been reported in patients with HLA- B27– associated anterior uveitis

47. Side effects : I nfections (TB reactivation) Drug- induced lupus, systemic vascular thrombosis , congestive heart failures D emyelinating disease Vitreous hemorrhage Low dose methotrexate (5 - 7.5mg/week) may be administered concomitantly to reduce the risk of drug induced lupus syndrome and the formation of human antichimeric antibodies, which can lead to reduced efficacy of infliximab

48. ADALIMUMAB It is a full humanized monoclonal antibody which is a TNF – alpha inhibitor Dosage and Route: Administered via subcutaneous injection, the initial dosage is 80 mg, followed by maintenance dose of 40 mg/0.8 mL every other week starting 1 week after the initial dosage.

49. Effective in pediatric patient with uveitis (success 88%) and in adult posterior uveitis, panuveitis, behcet uveitis Side effects: Increased risk of bacterial infections( including TB and opportunistic infections) Headache, nausea Rash, stomach upset (less common than infliximab) L eukopenia and vasculitis Less expensive than infliximab, can be injected subcutaneously at home every 2 weeks

50. OTHER BIOLOGIC AGENTS

51. RITUXIMAB MECHANISM OF ACTION : Chimeric monoclonal antibody which binds CD 20 positive lymphocytes (mainly B lymphocytes) Dosage: Two infusions 1.0 g IV given 2 weeks apart CLINICAL APPLICATION : Used in treatment of B ehcet retinal vasculitis and granulomatosis with polyangiitis- associated necrotizing scleritis or other scleritis, and mucous membrane pemphigoid . Side effects: rash, late onset neutropenia, few case reported

52. INTERFERON ALPHA 2a/2b (INF- α 2a/2b) IFN- α2a has antiviral, immunomodulatory, and antiangiogenic effects. Administered subcutaneously, has been reported to be beneficial in some patients with uveitis Reports in the European literature indicate that IFN- α2a is efficacious and well tolerated in patients with Behcet uveitis, controlling inflammation in almost 90%; it is somewhat less effective in non- Behcet uveitis, with inflammation control in 60%.

53. IFN- α2b is used in the treatment of Ocular surface squamous neoplasia. Dose: 1million IU/ml Side effects : Flu like symptoms L eukopenia and thrombocytopenia D epression

54. TOFACITINIB Molecule that inhibits Janus associated kinases (JAKs) with some selectivity for JAK1 and JAK3 Several inflammatory cytokines that have been implicated in pathogenesis of ocular inflammation are known to utilize the JAK/STAT signaling pathway, including interleukin-2 (IL-2) and IL-6 Used for patients with rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

55. In a study done by Gupta et al. (2022) which included refractory anterior uveitis patients: Those patients of uveitis who failed topical therapy, were given steroids (1 mg/kg prednisolone) along with steroid sparing immunosuppressant including methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide or azathioprine. T ofactinib (5mg BD) was given to patients who failed topical and oral therapy in form of combination of prednisone (failure to maintain 7.5 mg or below after 3 months of initiation) and at least 1 other systemic immunosuppressive drug (given in combination with steroids for atleast 3 months) 

56. T ofactinib 5 mg twice a day dose can be used as an immunosuppressant in refractory uveitis in reducing inflammation and reducing steroid dosage.

57. REFERENCES Uveitis and ocular inflammation, AAO(2022-2023) Katzung , Basic and Clinical Pharmacology, 12 th edition, 2012 Hanoodi M, Mittal M. Methotrexate. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Jun 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK556114/ Mohammadi O, Kassim TA. Azathioprine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Jun 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK542190/ Surjushe A, Saple DG. Mycophenolate mofetil. Indian J Dermatol Venereol Leprol . 2008 Mar 1;74:180.

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