(O-Med) Lecture 1: Immunosuppressives

glucocorticosteroids

• 1. glucocorticoids
• 2. cytotoxic drugs
• 3. immunophilin ligands
• 4. immune modulators
• 5. DMARDS

cytotoxic drugs

disease modifying anti-rheumatic drugs

• immunophlin ligands
• immune modulators

anti-inflammatory effect 

- interferes w/ protein, fat and carb metabolism

• - Antagonize histamine release
• - Inhibit prostaglandin synthesis
• - Reduce leukocyte migration & adhesion
• - Reduce macrophage exudation
• - Decrease fibroblast proliferation (i.e., fluorinated compounds)

- used for autoimmune dz

- similar to natural, endogenous steroids

- modifications: methylation, fluroination (makes the compound stronger)

1. Prednisone

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

3. Dexamethasone (Decadron)

- 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)

• 1. Azathioprine
• 2. Mycophenolate motefil
• 3. Methotrexate

- type of cytotoxic drug

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

- Imuran (oral tablets)

- Cytotoxic drug,  purine antagonist

- brand name: CellCept (tab or suspension)

- cytotoxic drug. folic acid antagonist

- brand name (Rheumatrex)

- 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

• 1. Cyclosporine
• 2. Tacrolimus
• 3. Sirolimus

- 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)

- ex of immunophilin ligands

• 1. Protopic ointment
• 2.  Prograf caps

- ex of immunophilin ligands

1. Rapamune (tabs and oral solution)

• 1. Thalidomide
• 2. Biological agents

- immune modulator

- anti-tumor necrosis factor (TNF) action

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

- off label use: rheumatic dz

• - immune modulators
• - cytokine regulatory function used in rheumatic and CT dz
• - risk of TB reactivation, lymphoma, and other malignancies

• 1. Anti-TNF agents
• - Etanercept (Enbrel) SubQ
• - Adalimumab (Humira) SubQ
• - Infliximab (Remicade) I.V.

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

- RA and other autoimmune conditions

- limited in tx of oral mucosal conditions

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

• - ex of DMARDS
• - brand name: Auranofin
• - interferes w/ macrophage fxn

• - ex of DMARDS
• - brand name: Cuprimine

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

• - ex of DMARDS
• - brand name: Azulfidine
• - anti-prostaglandin synthesis
• - tx of ulcerative colitis

• - ex of DMARDS
• - (Dapsone)
• - antibiotic
• - tx of: leprosy, malaria, dermatitis herpetiformis
• - prophylaxis against PCP and Toxoplasmosis in AIDS

• - ex of DMARDS
• - abx
• - used against malaria 
• - inhibits lyphocyte proliferation

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

• - minor aphthae
• - major aphthae
• - herpetiform ulcers

• - 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

- 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

NO

• - emotional stress
• - mechanical trauma
• - dietary deficiencies
• - food allergies
• - habits
• - local factors (pathogens, chemicals & foods)

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

strep. sanguis

• - Adenovirus
• - HSV-1

• 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

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

- toothpaste w/out sodium lauryl sulfate:

• Biotene dry mouth toothpaste
• Rembrandt whitening toothpaste for canker sore sufferers
• Squigle enamel saver
• TheraBreath toothpaste
• CloSYSII toothpaste

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

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

• - skin lesions
• - vulvovaginal lesions
• - penile and anal lesions
• - scalp lesions
• - nail involvement

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

- 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

• Stress
• Trauma
• Environmental exposures
• - Diet
• - Medications

Treatment reserved for atrophic & ulcerated lesions

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?

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

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

- 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

Although flare ups may be unpredictable, some factors may increase frequency:

• - Stress
• - Trauma (Dry mouth??)
• - Environmental factors (Diet, Medications, Oral hygiene)

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

Autoantibodies against epithilial adhesion components:

- Desmoglein 3 in the mucosal dominant type

- Desmoglein 1 mostly in mucocutanoeus variant

- 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)

Flare ups are persistent and unpredictable, some factors may increase frequency:

• - Stress
• - Trauma (Dry mouth??)
• - Environmental factors (Diet, Medications, Oral hygiene)

skin conditions

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)

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

• 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

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

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

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

Dexamethasone    (Decadron 4 mg/ml)n1 ml submucosal   administration

Triamcinolone    (Kenalog 10 mg/ml)n1 ml submucosal administration

- 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

Cyclosporine (Sandimmune®) oral solution

Tacrolimus (Protopic®) ointment

Both are immunophilin ligands and interfere with T-cell activation

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®)

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)

- short course burst for localized but multiple sites


- higher dose and longer course used for widespread or mucocutaneous involvement

• 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

calculated based on the patient’s weight, usually up to 1 mg/Kg

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

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

Systemic management is always required – topical agents are useful for adjunctive therapy

• 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®)

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

• 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

• 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

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

- toxic in thiopurine methyltransferase         (TPMT) deficiency

- inhibition of coumadin

- hepatotoxicity

- BM suppression

- increased rate of malignancy

- caution w/ alcohol

• - BM suppression
• - hepatic & renal toxicity
• - CNS effects (seizures)
• - GI and BM toxicity enhanced with NSAIDs

• CV
• CNS
• endocrine
• hematologic side effects