(O-Med) Lecture 1: Immunosuppressives

  1. which class of immunosupressive acts through broad suppression of cell-mediated, humoral, and innate immunity?
    glucocorticosteroids
  2. List 5 classes of immunosupressive drugs
    • 1. glucocorticoids
    • 2. cytotoxic drugs
    • 3. immunophilin ligands
    • 4. immune modulators
    • 5. DMARDS
  3. which class of immunosuppressive interferes w/ DNA synthesis?
    cytotoxic drugs
  4. What does DMARDS stand for?
    disease modifying anti-rheumatic drugs
  5. which class of immunosuppressive interferes w/ cytokines?
    • immunophlin ligands
    • immune modulators
  6. Glucocorticoids are used for what effect?

    interferes w/ what type of metabolism?
    anti-inflammatory effect 

    - interferes w/ protein, fat and carb metabolism
  7. Name some corticosteroids anti-inflammatory effects
    • - Antagonize histamine release
    • - Inhibit prostaglandin synthesis
    • - Reduce leukocyte migration & adhesion
    • - Reduce macrophage exudation
    • - Decrease fibroblast proliferation (i.e., fluorinated compounds)
  8. Glucocorticosteroids

    - used for what?
    - modifications?
    - used for autoimmune dz

    - similar to natural, endogenous steroids

    - modifications: methylation, fluroination (makes the compound stronger)
  9. Examples of Corticosteroids
    - name 3
    1. Prednisone

    • 2. Prednisolone
    •     - tablet (Medrol)
    •     - syrup (Prelone)

    3. Dexamethasone (Decadron)
  10. Cytotoxic Drugs

    - direct effect on what?
    - used for?
    - side effects?
    - interfere w/ DNA syntesis 

    - direct effect on hyperactive immune cells

    - used in low doses in tx of autoimmune dz (high dose used for cancer tx and for prevention of solid organ transplant rejection)

    - cause bone marrow suppression (risk of infection and malignancies)
  11. Examples of Cytotoxic Drugs

    - name 3
    • 1. Azathioprine
    • 2. Mycophenolate motefil
    • 3. Methotrexate
  12. Azathioprine

    - what class of immunosupressive?
    - brand name?
    - type of cytotoxic drug

    -  conversion to its active form 6-MP, a purine antagonist

    - Imuran (oral tablets)
  13. Mycophenolate motefil

    - what class of immunosupressive?
    - brand name?
    - Cytotoxic drug,  purine antagonist

    - brand name: CellCept (tab or suspension)
  14. Methotrexate

    - what class of immunosupressive?
    - brand name?
    - cytotoxic drug. folic acid antagonist

    - brand name (Rheumatrex)
  15. Immunophilin ligands

    - mode of action?
    - uses?
    - interfere w/ DNA transcription during T-lymphocyte activation (interferes w/ cell-mediated immunity)

    • Uses:
    • @ high dose: prevent GVHD and graft rejection organ transplantation (nephrotoxicity and neurotoxicity)

    @low dose: autoimmune disorders
  16. Examples of Immunophilin Ligands
    • 1. Cyclosporine
    • 2. Tacrolimus
    • 3. Sirolimus
  17. Cyclosporine

    - what type of drug?
    - name 4
    - ex of immunophilin ligands

    • 1. Sandimmune (gel caps, oral and sterile solutions)
    • 2. Neoral (gel caps oral solution)
    • 3. Gengraf (caps and oral solution)
    • 4. Restasis (eye drops)
  18. Tacrolimus

    - what type of drug?
    - name 2
    - ex of immunophilin ligands

    • 1. Protopic ointment
    • 2.  Prograf caps
  19. Sirolimus

    - what type of drug?
    - name 1
    - ex of immunophilin ligands

    1. Rapamune (tabs and oral solution)
  20. Immune Modulators
    - name 2
    • 1. Thalidomide
    • 2. Biological agents
  21. Thalidomide

    - what type of drug?
    - mode of action?
    - effective against?
    - off-label use?
    - immune modulator

    - anti-tumor necrosis factor (TNF) action

    - effective against leprosy, Behcet's, HIV, and GVHD

    - off label use: rheumatic dz
  22. Biolgical Agents

    - type of drug?
    - used in what dz?
    - risk of?
    • - immune modulators
    • - cytokine regulatory function used in rheumatic and CT dz
    • - risk of TB reactivation, lymphoma, and other malignancies
  23. Immune Modulators: Biological Agents
    - name 2 types
    • 1. Anti-TNF agents
    • - Etanercept (Enbrel) SubQ
    • - Adalimumab (Humira) SubQ
    • - Infliximab (Remicade) I.V.

    • 2. IL-1 receptor
    • - Anakinra (Kineret) SubQ
  24. DMARDS

    - used for what?
    - limited to tx of what?
    - RA and other autoimmune conditions

    - limited in tx of oral mucosal conditions
  25. DMARDS

    - name 5
    • 1. Gold
    • 2. Penicillinamine
    • 3. Sulfasalazine
    • 4. dapsone
    • 5. Chloroquine
  26. Gold

    - class of immunosupressive drug?
    - Brand name?
    - mech of action?
    • - ex of DMARDS
    • - brand name: Auranofin
    • - interferes w/ macrophage fxn
  27. Penicillinamine

    - class of immunosupressive drug?
    - Brand name?
    - mech of action?
    - also used in what dz?
    • - ex of DMARDS
    • - brand name: Cuprimine

    • Mech.
    • - reduces macrophages and T cells fxn
    • - chelating agent used in tx of Wilson's Dz
  28. Sulfasalazine

    - class of immunosupressive drug?
    - Brand name?
    - mech of action?
    - tx of what?
    • - ex of DMARDS
    • - brand name: Azulfidine
    • - anti-prostaglandin synthesis
    • - tx of ulcerative colitis
  29. Dapsone

    - class of immunosupressive drug?
    - Brand name?
    - mech of action?
    - tx of what?
    - prophylaxis for what?
    • - ex of DMARDS
    • - (Dapsone)
    • - antibiotic
    • - tx of: leprosy, malaria, dermatitis herpetiformis
    • - prophylaxis against PCP and Toxoplasmosis in AIDS
  30. Chloroquine and hdyrochloroquine

    - class of immunosuppressive drug?
    - mech of action?
    - used for?
    - inhibits what?
    • - ex of DMARDS
    • - abx
    • - used against malaria 
    • - inhibits lyphocyte proliferation
  31. Before deciding on tx of an oral lesion, what are the 5 most important questions?
    1. What is the lesion’s clinical presentation?

    2. Can you develop a differential Dx list based on the lesion’s clinical behavior & characteristics?

    3. Is a biopsy necessary?

    4. Are there any precipitating factors to be identified and managed?

    5. Is there an evidence-based or targeted treatme
  32. Recurrent Apthouse Stomatitis (RAS): Clinical presentation 

    - name 3
    • - minor aphthae
    • - major aphthae
    • - herpetiform ulcers
  33. Recurrent Apthouse Stomatitis (RAS): Clinical behavior and characteristics
    • - recurring oral ulcers
    • - painful on eating, swallowing and speaking
    • - onset during childhood, frequency and severity decreases w/ age
    • - 80% of cases develop before age 30
    • - There may be positive family hx
    • - onset in later age suggests not simple RAS but part of a more complex disorder
  34. RAS Behavior and Characteristics

    - associated w/ what type of pain?
    - describe lesion?
    - associated w/ a prodrome of burning or pain 24-48 hrs before

    - lesions are clearly defined, round, or oval

    - shallow necrotic center covered w/ a yellow-grayish pseudomembrane

    - raised margins w/ erythematous haloes
  35. RAS - is a biopsy necessary?
    NO
  36. RAS Precipitating Factors
    • - emotional stress
    • - mechanical trauma
    • - dietary deficiencies
    • - food allergies
    • - habits
    • - local factors (pathogens, chemicals & foods)
  37. Name some allergies that might cause RAS?

    - name 2
    1. cinnamic aldehyde: Very common artificialcinnamon flavoring agent in many toothpastes, and foods

    2. sodium lauryl sulfate:A foaming agent found in most toothpastes & shampoosMay cause denaturing of the oral mucin layer, causing an increased incidence of RAU
  38. Name a bacteria that might cause RAS?
    strep. sanguis
  39. Name some viruses that might cause RAS?

    - name 2
    • - Adenovirus
    • - HSV-1
  40. RAS Management

    - describe different types and managment
    • Type A: episodes last a few days
    • - ID precipitating factors

    • Type B: painful RAS lasting 3-10 days causing pt to alter diet and OH habits
    • - ID precipitating factors
    • - use topical prophylaxis

    • Type C: painful chronic courses of RAS- one ulcer heals and another starts
    • - refer to OM specialist
    • - need systemic mngmt w/ potent compounds
  41. RAS mngmt--Evidence
    Dictated by dz severity, pt’s med hx, frequency of flare ups, and pt’s ability to tolerate medications

    Palliative tx is always an option (discussed under OTC lecture)

    Very few randomized clinical trials available:Topical chlorohexidine gluconate and topical corticosteroids are both effective in reducing pain & severity but ineffective in frequency of eruptions

    Topical treatment in the prodromal stage may prevent ulcer development
  42. RAS Prevention
    - toothpaste w/out sodium lauryl sulfate:

    • Biotene dry mouth toothpaste
    • Rembrandt whitening toothpaste for canker sore sufferers
    • Squigle enamel saver
    • TheraBreath toothpaste
    • CloSYSII toothpaste
  43. When RAS is associated w/ systemic, tx of oral lesion is secondary. 

    - Name 3 systemic dz
    1. Behçet’s syndrome (eyes, joints, neurological systems and skin)

    • 2. Chronic GI absorption problems
    • - Crohn’s disease & ulcerative colitis
    • - Celiac Disease; gluten sensitive enteropathy (4% of some RAS)

    • 3. Immune disturbances
    • - Agranulocytosis
    • - Cyclic neutropenia
    • - HIV positive patients especially when CD4      T-lymphocyte count is fewer than 100/mm3
  44. Oral LP: Clinical Presentation
    Reticular Lichen Planus - Wickham's striae on the buccal mucosa & lips

    Erosive Lichen Planus - epithelial sloughing and erosion

    Plaque-form Lichen Planus - thick adherent plaques associated with the classic reticular LP on the buccal mucosa
  45. LP in other sites
    • - skin lesions
    • - vulvovaginal lesions
    • - penile and anal lesions
    • - scalp lesions
    • - nail involvement
  46. LP Lesion Characteristics

    - etiology?
    - process?
    - what happens to epithelium?
    Etiology unknown

    • A cell-mediated  cytotoxic process
    • - Langerhans cells recognize unknown antigen and stimulate T-lymphocytes
    • - Lymphocytes cytotoxic to epithelial cells are produced

    - Epithelium undergoes degeneration
  47. LP: Biopsy needed?
    - biopsy almost ALWAYS needed

    - Direct IF:All clinical types test negative for IgG, IgM & IgA antibodies and positive for fibrinogen along the basement membrane zone
  48. Oral LP Precipitating Factors
    • Stress
    • Trauma
    • Environmental exposures
    • - Diet
    • - Medications
  49. Oral LP Management

    - tx reserved for?
    Treatment reserved for atrophic & ulcerated lesions
  50. Oral LP Managment
    Identify triggers – certain foods, stress, xerostomia, etc

    • Use an immunosuppressant – corticosteroids are preferred for their targeted anti-inflammatory effects
    • - For limited disease, topical treatment is adequate
    • - For widespread disease combine systemic & topical tx

    • Other immunosuppressants are used for refractory cases in combination with or in lieu of corticosteroids
    • - Also used for patients who cannot tolerate corticosteroids (e.g., severe DM)

    • Maintenance may be necessary
    • - Topical or systemic agents

    Careful clinical and histologic follow up - malignancy?
  51. Pemphigoid (MMP) Clinical Presentation

    - 2 clinical variants
    - untreated can progress to?
    A chronic bullous mucocutaneous disease w/ two clinical variants:

    - Cicatricial Pemphigoid (MMP) mostly affecting mucous membranes

    - Bullous Pemphigoid (BP) usually affecting the skin

    - Untreated cases may progress to involve other mucosal sites such as the eyes
  52. Pemphigoid: Disease Characteristics
    IgG autoantibodies against at least 10 components of hemidesmosome apparatus n

    - Bullous pemphigoid antigen 2 (BPAG2), epiligrin (laminin-5), type VII collagen

    Possible malignant potential for antiepiligrin MMP
  53. Pemphigoid: Biopsy necessary?
    - ALWAYS necessary!

    - Although lesions are Nikolsky positive, histologic assessment is required for diagnosis:

    • - Light Microscopy on oral biopsies to detect the area of epithelial separation
    • - Direct immunofluorescence (DIF) on tissue sample to distinguish from other types of bullous diseases

    - Indirect IF to detect autoantibodies in serum are usually negativenMay be present in 25% of cases
  54. Pemphigoid Precipitating Factors
    Although flare ups may be unpredictable, some factors may increase frequency:

    • - Stress
    • - Trauma (Dry mouth??)
    • - Environmental factors (Diet, Medications, Oral hygiene)
  55. Pemphigus Clinical Presentation
    Pemphigus Vulgaris – Most common, almost always start in the mouth. Positive Nicolsky sign

    Pemphigus Foliaceus – Crusted sores or fragile blisters on face and scalp. Not as painful

    Paraneoplastic Pemphigus – Least common seen in patients with hematologic malignancies; features oral painful ulcers
  56. Pemphigus Diseases Characteristics

    - Autoantibodies against which epithilial adhesion components?
    Autoantibodies against epithilial adhesion components:

    - Desmoglein 3 in the mucosal dominant type

    - Desmoglein 1 mostly in mucocutanoeus variant
  57. Pemphigus: Biopsy necessary?
    - Light microscopy (H&E) to detect the epithelial cells separation c/w pemphigus

    - Direct immunoflourescence to detect autoantibodies in the tissue

    - Indirect immunofluorescence to detect circulating autoantibodies

    - Antibody titer test to measures levels of serum autoantibodies (Used to obtain a more complete understanding of the course of the disease)

    - ELISA serum assay for identification of desmoglein antibodies (most accurate)
  58. Pemphigus Precipitating Factors
    Flare ups are persistent and unpredictable, some factors may increase frequency:

    • - Stress
    • - Trauma (Dry mouth??)
    • - Environmental factors (Diet, Medications, Oral hygiene)
  59. Toical tx are most likely used for?
    skin conditions
  60. Topical Dermatologic Glucocorticoids

    In the order of decreasing potency*
    Clobetasol Propionate (Temovate 0.05%)   Halobetasol (Ultravate 0.05%)

    Fluocinonide (Lidex 0.05%) Halcionide (Halog 0.1%)                                    

    Betamethasone dipropionate                                           (Diprosone 0.05%)

    Triamcinolone acetonide (Kenalog 0.1%)       Betamethasone valerate (Valisone 0.1%)

    Hydrocortisone (several 1% preparations; i.e., Anusol)
  61. Inactive Ingredients of Dermatologic Preparations

    - ointment contains what?
    Ointments contain emollients and occlusive pastes are not suitable for oral mucosal use

    • - Emollients (glyceryl monosterate)
    • - Occlusive pastes (white petroleum and white wax)

    • Gels and creams are easier to apply to wet mucosa
    • - Some gels contain alcohol!
    • - Use the cream alternative

    Trick: orabase is for intraoral use. Mix with an equal amount of a potent corticosteroid to improve efficacy
  62. Topical Steroids (Intermediate)
    • Triamcinolone acetonide (0.1%)
    • - Kenalog® in Orabase®; Kenalog® Topical, Aristocort® Topical
    • - Kenacort® (Mexico); Ledercort (Mexico

    • Rx:
    • Kenalog in Orabase Dental
    • Paste 0.1%
    • Disp: 15 gr
    • Sig: apply to oral lesions tid
  63. Topical Steroids (Potent)
    Fluocinonide (0.05% G, C, O)

    • - Lidex®; Lidex-E®
    • - Canadian/Mexican Brand Names:  Gelisyn (Mexico); Lyderm (Canada); Topactin® (Canada); Topsyn (Canada) 

    • Rx: 
    • Lidex 0.05% gel 
    • Dis: 15 gr (15, 30, 60 gr tubes) 
    • Sig: apply to oral lesions tid
  64. Topical Steroids (Intermediate)
    Betamethasone

    - Alphatrex® Topical; Betalene® Topical; Betatrex® Topical; Diprolene® Topical; Diprosone® Topical; Maxivate® Topical; Psorion® Topical; Teladar® Topical; Valisone®

    - Canadian/Mexican Brand Names: Taro-Sone® (Canada); Topilene® (Canada); Topisone® (Canada) ethasone or Decadron cream 0.1% (Mexico) 

    • Rx: 
    • Valisone cream 0.1% 
    • Disp: 15 gr 
    • Sig: apply to oral lesions tid
  65. Topical Steroids (Ultra Potent)
    Clobetasol propionate (0.05% G, C, O)

    - Cormax®; Temovate®

    - Canadian/Mexican Brand Names:   Dermasone (Canada); Dermatovate (Mexico); Dermovate® (Canada); Gen-Clobetasol (Canada); Novo-Clobetasol (Canada) 

    • Rx: 
    • Temovate 0.05% cream 
    • Disp: 15 gr (15, 30, 45 & 60 gr tubes) 
    • Sig: apply to oral lesions bid
  66. Other Options – Intralesional Corticosteroid Injections
    Dexamethasone    (Decadron 4 mg/ml)n1 ml submucosal   administration

    Triamcinolone    (Kenalog 10 mg/ml)n1 ml submucosal administration
  67. Remember these facts about topical corticosteroids…

    - absorption?
    - suppression of what?
    - effectiveness?
    - continual use leads to?
    - All preparations are absorbed through ulcerated and inflamed surfaces, some more than others

    - Once absorbed systemically, they can cause adrenal suppression esp if used for more than 2 weeks

    - Continuous use reduces their effectiveness; withdrawal for 2 to 4 days restores their action

    - Continuous use may lead to opportunistic Candida infection
  68. Topical Cytotoxic Agents
    Cyclosporine (Sandimmune®) oral solution

    Tacrolimus (Protopic®) ointment

    Both are immunophilin ligands and interfere with T-cell activation
  69. Systemic Immunosuppressive Therapies in RAS
    Reserved for cases of RAS major or those associated with systemic diseases

    Glucocorticoids (Prednisone®)

    • Thalidomide (Thalomid®)
    • - Clinical trials involved RAS associated w/ HIV (50-100 mg/day)

    • Etanercept (Enbrel®) SUBQ
    • - Used in management of Behçet’s syndrome

    Dapsone (Dapsone®)
  70. Systemic Oral LP Management
    Management is always focused on suppressing the immune responses

    Disease characteristics, severity and the extent of involvement determine the type of treatmentn (Single agent or combination treatment)
  71. Systemic Glucocorticoid for OLP

    - short course bursts used for?
    - higher dose and longer course?
    - short course burst for localized but multiple sites


    - higher dose and longer course used for widespread or mucocutaneous involvement
  72. Systemic Glucocorticoid for OLP

    - name 3
    • Prednisone
    • - Prednisone tablets (20-30 mg/day for 1 week)

    • Methylprednisolone
    • - Medrol dose pack (6 day course, 24 mg titrated down to 4 mg)

    • Dexamethasone
    • - Decadron elixir (0.5 mg/5 ml) – 1.5 mg/day x 1 week, repeat as needed
  73. Systemic Glucocorticoid for OLP

    what is the max daily dose?
    calculated based on the patient’s weight, usually up to 1 mg/Kg
  74. Other systemic immunosuppressive agents for severe/ refractory OLP cases

    - name 3
    Azathioprine: antimetabolite, usually used in combination with corticosteroids. Must watch for thiopurine methyltransferase (TPMT) deficiency

    Levamisole: antihelmetic, usually used in combination w/ corticosteroidsn. Causes neutropenia

    Dapsone: antibiotic with immune suppressive effectnWatch for G6PDH
  75. Management of Pemphigoid
    Dz requires a moderately long course of systemic Tx

    - Systemic corticosteroids + combine with topical agents for better results

    - Prednisone for several weeks commonly used at 1mg/Kg. Once controlled, taper medication to minimize side effects

    - Even w/ remission, a maintenance dose is required. Low dose steroid and/or cycline drugs (tetracycline, minocycline, or doxycycline)

    Other Immune Modulating or Anti-inflammatory AgentsMethotrexate (Rheumatrex®) – good data for effectiveness
  76. Management of Pemphigus

    - systemic management vs topical agents?
    Systemic management is always required – topical agents are useful for adjunctive therapy
  77. Management of Pemphigus

    - name 3
    • Corticosteroids
    • - 1 mg/kg of Prednisone
    • - Once controlled, taper steroid and continue w/ maintenance dose

    • Other immunosuppressants commonly used
    • - Azathioprine (Imuran®) often in combination with corticosteroids
    • - Mycophenolate mofetil (CellCept®) has good data for effectiveness esp for cutaneous lesions
    • - IVIG injections (Gamimune®) used for very severe cases

    • Other agents
    • - Cyclophosphamide (Cytoxan®), cyclosporine (Sandimmune ®), dapsone (Dapsone®), methotrexate (Rheumatraex®), gold (Aurolate®)
  78. Management of Pemphigus
    Before drug treatment, PV was 99% fatal, but today, with the current therapies, the mortality rate is only 5 to 15%. Treatment involves mono or combination therapy

    To date, no studies have shown that alternative, homeopathic, or any other non-traditional method has been successful in treating PV

    Medications can have serious side effects

    Because of drug side effects patients must have blood and urine monitored on a regular basis
  79. Immunosuppressive Agents… Corticosteroid Side Effects (1)
    • Fluid and electrolyte disturbances
    • - Sodium and water retention, CHF, HTN, K loss

    • Musculoskeletal
    • - Muscle weakness, myopathy, osteoporosis, pathologic fractures, tendon rupture

    • Gastrointestinal
    • - Peptic ulcer and possible perforatio

    • Dermatologic
    • - Impaired wound healing, echymoses, allergy
  80. Immunosuppressive Agents… Corticosteroid Side Effects (2)
    • Neurologic
    • - Increased intracranial pressure, convulsions, papilledema, vertigo, headaches

    • Endocrine
    • - Decrease in adrenocortical & pituitary functions, reduced growth, insulin tolerance & hyperglycemia

    • Ophthalmic
    • - Increased intraocular pressure, glaucoma

    • Cardiovascular
    • - Myocardial rupture following recent MI

    • Other
    • - Weight gain, malaise, nausea
  81. Corticosteroids Drug Interactions
    The risk of GI ulceration is increased w/ concomitant use of NSAIDs

    Potassium reducing effect enhanced w/ other K depleting drugs (Thiazides, furosemide)

    They alter the effectiveness of oral anticoagulants
  82. Azathioprine Risks:
    - toxic in thiopurine methyltransferase         (TPMT) deficiency

    - inhibition of coumadin

    - hepatotoxicity

    - BM suppression

    - increased rate of malignancy

    - caution w/ alcohol
  83. Methotrexate Risks:
    • - BM suppression
    • - hepatic & renal toxicity
    • - CNS effects (seizures)
    • - GI and BM toxicity enhanced with NSAIDs
  84. Mycophenolate mofetil (CellCept®) Risks:
    • CV
    • CNS
    • endocrine
    • hematologic side effects
Author
jlyip
ID
318045
Card Set
(O-Med) Lecture 1: Immunosuppressives
Description
O-Med, D3 Spring.
Updated