Dermatology SC027: Treatments For Skin Diseases (Eczema, Psoriasis And Urticaria) Flashcards
Pemphigus: Treatment
Previous 1st line:
- High dose systemic steroid / Mycophenolate / Azathioprine / Cyclophosphamide / Cyclosporin / Plasmapheresis / IVIG —> induce disease remission + control (but not cure)
Recently:
- Biologic (e.g. Rituximab: Anti-CD20 that bind to CD20 present on B cells surface —> destruction of B cells) —> potential cure
(Rituximab takes time to work —> still need Steroid for coverage)
CD-20:
- present on some B cells
- not on Stem B-cell / Plasma cell / normal tissues
—> Anti-CD20 allow effective eradication of CD20 +ve cells without excessive toxicity (∵ stem cells with continue to differentiate into B cells, plasma cells unaffected and will continue to maintain serum Ig levels)
- expressed on >90% of non-Hodgkin’s lymphoma B cells
- Pemphigus: ***abnormal clonal expansion of B cells
Rituximab:
- 3 MOA
1. Direct apoptosis
2. Complement-dependent cytotoxicity (CDC)
3. ADCC
Evidence:
- Rituximab + Steroid > Steroid alone + Less side effect
- suggest 1st line: Rituximab + Steroid
Bullous pemphigoid: Treatment
- Older age group + Milder disease
Treatment:
- Oral minocycline + ***Topical steroid
- Resistant cases: Systemic immunosuppressive e.g. Systemic steroid, Mycophenolate, Azathioprine, Cyclophosphamide, Cyclosporin, Plasmapheresis, IVIG
- Rituximab: Less evidence to support + greater risk of immunosuppression in older age group
Dermatitis: Management
Principles: Induce disease remission —> Consolidate disease control —> Gradual withdrawal of drug
1st line:
1. Avoid irritant / allergen
- soap / detergent
- washing powder (use non-biological ones)
- spicy, salty, sour food / fruit
- alcohol
- sweating
- smoking
- **wear gloves
2. **Emollient
3. **Topical steroid
4. **Antihistamine
5. Potassium permanganate
6. Treat secondary infection
Other measures:
1. Antiseptic / Dilute bleach bath
- reduce bacterial load on skin surface (e.g. staphylococcus) —> but avoid in severe eczema ∵ irritant
2. Probiotic
- immunomodulation to prevent eczema / atopy development (hypothesis only)
3. Aeroallergen
- worthwhile to avoid
4. Food allergy
- more controversial —> skin prick, IgE not reliable as a predictor for delayed reaction (allergic contact dermatitis)
- skin food patch test only done in research setting
- food diary, if relevant for severe cases for allergy test then elimination and open food re-challenge
- avoid 戒口 between 4-11 months —> need to develop immunological tolerance —> less chance of developing food allergy
2nd line:
1. **Topical calcineurin inhibitors
- Tacrolimus (moderate-severe AD), Pimecrolimus (mild-moderate)
2. **Wet wrap
3rd line (rotating regimen):
1. ***Phototherapy
2. MMF
3. Cyclosporin
4. Azathioprine
5. Systemic steroid
1st line: 2. Emollients
- ***important to treat dryness in eczema
- safe but allergic reaction can occur
- act by prevent water loss by evaporation / addition of water binding substances
- cream (contain more chemicals) vs ointment (less preservative, less chance of allergic contact dermatitis, more greasy but better for skin)
- greasier —> more effective but less acceptable
Use:
1. Use bath oil / emollient wash in bath
2. Soak for 15 mins (don’t use soap)
3. Pat dry
4. Apply other therapy (e.g. steroid)
5. Apply moderate / greasy emollient on top
***Medications first before moisturiser
1st line: 3. Topical steroids
- interact with cell nucleus —> affect mRNA expression
- anti-inflammatory + immunosupressive + anti-proliferative + vasoconstriction
- 4 types of potency (UK classification): group 1-4 (group 1: weakest)
- range of adverse effects
- use steroids with short systemic t1/2: Mometasone furoate (Elomet), Fluticasone (Cutivate), Methylprednisolone aceponate (Advantan)
- ***use till rash gone, persistent lesions: use few more days (to allow skin to repair) / use proactively (2 times / week)
- monitor SE
Adverse effects of topical steroid
Local (usually reversible):
1. **Hypopigmentation
2. **Increase hair growth
3. **Skin atrophy
4. **Telangiectasia
5. **Easy bruising
6. **Stretch mark
7. Acne
8. Peri-oral dermatitis
9. Contact dermatitis
Systemic:
1. Infection (if appropriately used can actually decrease infection, ∵ decrease break in skin)
2. Tachyphylaxis
3. Rebound
4. Cushing
5. Pituitary adrenal suppression
Steroids with short systemic t1/2:
1. Mometasone furoate (Elomet)
- low systemic absorption
- rapid breakdown in liver
- potency equivalent to Betnovate
- 6 week therapy local effect ~ to 1% HC
- Fluticasone (Cutivate)
- rapid breakdown in liver
- potent steroid equivalent to class 3
- local safety with short term use - Methylprednisolone aceponate (Advantan)
- once daily
- fast inactivation within the circulation
- low risk of systemic + cutaneous SE
- 4 months - 14 years
Topical calcineurin inhibitors
- Use in combination with Topical steroid
- can be use proactively
Tacrolimus:
- immunosuppressant with MOA ~ Cyclosporin
- lower molecular weight (able to penetrate skin) with potency in inhibiting T cells 10-100x of cyclosporin
- topical ointment available
- topical form: mild burning sensation, undetectable plasma level
- advantage:
—> **Steroid sparing (can be used at site of skin atrophy after steroid use)
—> Less skin atrophy than steroid
- disadvantage:
—> **Less effective
Pimecrolimus:
- anti-inflammatory macrolactams
- block synthesis of both Th1, Th2 type cytokines in targets cells
- effective in AD and Allergic contact dermatitis
- potency less than mid-potency steroid
- not cause skin atrophy
- weaker than Tacrolimus
2nd line: 2. Wet wrap
- ***Rehydrate skin
- ***Enhance absorption of topical ointment
- ***Reduce dose of topical steroid
- Prevent scratching
- Cooling effect to reduce itchiness
Use:
1. Bath
2. Topical steroid (Elomet / Vaseline 1:10) apply to affected area
3. Vaseline to unaffected area
4. Wet layer of tubrifast covered by a dry layer of tubrifast
5. Sedative antihistamine
Can do short period (~30 mins), not necessarily overnight
3rd line (rotating regimen)
Rotating regimen (to reduce SE of each medication)
Steroid + Azathioprine
—> Cyclosporin
—> Phototherapy
3rd line: 1. Phototherapy
- ***Suppress cutaneous immunological system selectively (UV suppress Langerhans cells, allow expression of non-Langerhans cells which preferentially activate CD8 rather than CD4)
- Lower risk of skin cancer in Chinese —> suitable for phototherapy
- Mainly for adult (>15)
- Need systemic steroid to cover initial period
Narrow band UVB:
- like other form of phototherapy: induce immunosuppression by altering cutaneous APC
- increase non-Langerhans cell APC which stimulate suppressor CD8
- 331nm
- 3 times a week therapy
Narrow band UVB vs Broad spectrum:
- 5-10 times less potent than broad spectrum UVB for erthema induction (less sunburn)
- more immunosuppressive
- 2-3 times more carcinogenic
- more effective for psoriasis, AD
Narrow band UVB vs PUVA (psoralen + UVA):
- less carcinogenic
- can be used in pregnant women + children
- PUVA more superior for chronic plaque psoriasis but not statistically significant
- not need to wear eye protection afterward
3rd line: 2. MMF
- ***Inhibit de novo purine synthesis —> block proliferative responses of T + B lymphocyte
- SE: Zoster, Herpes simplex reactivation reported
- Less effective than Cyclosporin
3rd line: 3. Cyclosporin
- Potent immunosuppressive —> down-regulate cytokine production by inhibit **calcineurin —> reduced transcription of genes for **IL2 + other lymphokines
- Rapid acting + Effective treatment for AD
- SE: ***Nephrotoxicity, HT, Hypertrichosis —> limit use <12 months
3rd line: 4. Azathioprine
- Used many years for severe AD
- Slow onset + Risk of ***neutropenic fever
- used with caution at a dose of 2-3.5 mg/kg/day
New direction: Dupilumab
Immunopathogenesis of AD:
- Microbial toxins + Allergens + Mechanical trauma (e.g. scratching)
—> T cell infiltrate
—> Cytokines (e.g. IL5, IL13, IL4)
Acute skin lesions in AD:
- Th2 predominant —> **IL4, **13, 16, 17
Chronic skin lesions in AD:
- Th1 predominant —> IL5, 11, GM-CSF
Dupilumab:
- Human monoclonal Ab targetting IL4R —> modulate effect of IL4, IL13 in Th2 pathway
- can worsen parasitic infestation (∵ depend on IL4 pathway —> humoral immunity)
- ***not affect other infections (e.g. TB, Hep B) (∵ cell-mediated immunity)
- 2 weekly injection —> 8-10 week for effect —> effect maximise in 4-6 months —> consolidate control —> gradual withdrawal
- SE: localised reaction at injection site, eye problem
Summary in Management of Dermatitis
- Newer topical steroids have low SE profile
- Tacrolimus, Pimecrolimus: 2nd line agents
- Phototherapy, MMF, Azathioprine: 3rd line agents
- Biologic: promising new therapeutic option
Psoriasis: Management
1st line
Topical:
1. **Emollient
2. **Steroid
3. **Tar
4. **Keratolytic (cause thickened plaque to peel off)
5. **Vit D analogue (Calcipotriol (Daivonex))
6. **Dithranol (aka Anthralin)
2nd line:
1. ***Phototherapy
3rd line:
1. **Retinoid (affect inflammatory reaction, reduce thickening of skin, only for Pustular, Erythrodermic type, NOT effective for Chronic plaque type)
2. **Methotrexate (Liver toxicity, Liver fibrosis, Lung fibrosis)
3. ***Cyclosporin (Nephrotoxicity, HT, Hypertrichosis)
4. Hydroxyurea
4th line:
1. ***Biologics
Indications for Systemic therapy:
- Failure of adequate trial of topical therapy
- Repeated hospital admissions for topical therapy
- Extensive chronic plaque psoriasis in the elderly / infirm
- Generalised pustular / erythrodermic psoriasis
- Severe psoriatic arthropathy
- Rule of 10: BSA >10% (now 5%) / PASI score >10 / DLQI >10
Conventional treatment (Methotrexate, Cyclosporin):
- Non-selective + suppress immunological system
- Systemic SE
- Tar
- MOA not known
- Use as shampoo, bath
- Use in combination with others
- Topical application is ***messy
- Irritation, phototoxic
- Vit D analogue
Calcipotriol (Daivonex)
- MOA: binding nuclear vitamin D3 receptors (involved in cellular proliferation, differentiation and inflammation)
—> ***Inhibit keratinocyte proliferation / turnover + Pro-differentiating effects
—> Flatten psoriasis plaque
- OD
- Not cause skin artophy
- Irritation
- Use in combination with steroid
- Dithranol (aka Anthralin)
- **Anti-proliferative + **Anti-inflammatory (X used as local cytotoxic agent)
- Apply topically as short contact
- Use in combination with others
- Irritation, messy
Biologics
Indications for Biologics:
- **Moderate-Severe psoriasis + **Failed 2 out of 3 systemic treatment
Past:
**TNF inhibitors (Adalimumab, Infliximab, Etanercept)
- activated T cells stimulate **macrophages + fibroblasts to secrete TNFα
- MOA: inhibit TNFα-induced joint damage
- However, TNFα really impair immunological defence (esp. against TB infection —> may cause reactivation of TB)
Now:
- target Th1 + Th17 cells —> more selective (rather than just inhibit all macrophages)
- Th1 develop in presence of IL12 secreted by DC
- Th17 develop in presence of IL1β + IL23 secreted by DC
- **Anti-IL12: Ustekunumab
- **Anti-IL17: Secukinumab, Ixekizumab, Brodalumab (Anti-IL17R)
- ***Anti-IL23: Tildrakizumab, Guselkumab, Risankizumab
Advantages:
- Much better tolerance
- Much better SE profile (e.g. more selective —> less immunological compromise)
- Potential long term clearance
(SE of Biologics)
All biologics:
- Infections
- **Hepatitis B / C / TB reactivation
- Immunogenicity
- **Malignancy
TNF inhibitors:
- Infusion reactions
- **Drug-induced lupus erythematosus
- **Hepatotoxicity
- ***Cytopenia
- Exacerbation / new onset of congestive heart failure
- Multiple sclerosis (rare)
IL12 / IL23 inhibitor:
- ***Hypersensitivity reactions (anaphylaxis, angioedema)
IL17 inhibitor:
- Candidiasis
- IBD
- Hepatotoxicity
- Neutropenia (rare)
IL17RA inhibitor:
- Depression + risk of suicide
- Increased liver transaminases (rare)
Chronic urticaria: Management
1st line:
1. ***2nd generation Antihistamine (less sedative, longer t1/2 (OD dose))
- Fexofenadine
- Cetirizine
- Loratadine
- Desloratadine
- Levocetirizine
2nd line:
1. Increase dose up to 4 fold
3rd line:
1. H2 blocker
2. Leukotriene antagonist
3. Cyclosporin
4. Short course systemic steroid
