GC090 Treatments For Skin Diseases
Treatments for skin diseases encompass a range of therapeutic modalities including topical agents (corticosteroids, retinoids, antifungals, antibiotics), systemic medications (immunosuppressants, biologics, antihistamines), phototherapy, and procedural interventions used to manage dermatological conditions.
Treatments for Skin Diseases
This lecture, delivered by Professor Henry H. Chan (HKU Division of Dermatology), is a comprehensive treatment-focused session covering three major dermatological conditions—eczema (atopic dermatitis), psoriasis, and chronic urticaria—plus the autoimmune blistering diseases pemphigus and bullous pemphigoid. [1]
The overarching philosophy is a stepladder approach: start with simple, safe, topical measures and escalate only when lower tiers fail. For each disease, the lecture walks through first-line → second-line → third-line → biologic therapy, with strong emphasis on the landmark clinical trials that have changed practice (Ritux 3 for pemphigus, dupilumab for AD). The lecture also weaves in pathophysiology (cytokine pathways in psoriasis, Th2 dominance in AD) to justify why specific biologics work.
How it fits into exams: Dermatology treatment SAQs and MCQs commonly ask you to list the treatment ladder, name specific drugs and their targets, describe adverse effects of topical steroids, and compare biologics. Past papers have tested TNF inhibitors, rituximab targets, and the indications for systemic therapy in psoriasis ("Rule of Tens"). [2] [3]
I. Autoimmune Blistering Diseases
A. Pemphigus — Treatment
High Yield: Previous first-line treatment for pemphigus was high-dose systemic steroid, with mycophenolate, azathioprine, cyclophosphamide, cyclosporin, plasmapheresis, and IVIG as adjuncts. More recently, biologic therapy (rituximab) has become the standard. [1]
Pemphigus is caused by IgG autoantibodies against desmogleins (Dsg1 and Dsg3) on keratinocytes, produced by autoreactive B cells. By depleting the B-cell pool, you eliminate the source of pathogenic antibodies.
Rituximab (MabThera®) is a mouse/human chimeric monoclonal antibody. The murine variable regions bind specifically to the CD20 antigen on B lymphocytes. The human IgG1 Fc domain works in synergy with human effector mechanisms. [1]
CD20 antigen is expressed on > 90% of non-Hodgkin's lymphoma B cells but NOT on stem cells or normal tissues other than B cells. This allows effective eradication of CD20+ cells without excessive toxicity because: (1) stem cells continue to differentiate into normal B cells, and (2) unaffected plasma cells continue to maintain serum immunoglobulin levels. [1]
This is critical: rituximab kills mature B cells but spares stem cells (which can replenish normal B cells) and long-lived plasma cells (which maintain existing immunoglobulin levels), so you don't leave the patient immunoglobulin-deficient immediately.
| Mechanism | Detail |
|---|---|
| Complement-Dependent Cytotoxicity (CDC) | Initiates lysis of circulating B cells via complement cascade |
| Antibody-Dependent Cellular Cytotoxicity (ADCC) | Human antibody component interacts with immune effector cells (NK cells, macrophages), leading to cytolysis of CD20+ target cells |
| Direct Apoptosis | Binding to CD20 directly triggers apoptotic pathways in B cells |
Peripheral B-lymphocyte count is reduced by ~90% within 3 days of a single MabThera infusion. [1]
This is the trial that changed practice. The lecture goes through it in detail, suggesting it is examinable:
| Feature | Detail |
|---|---|
| Design | Prospective, multicentre, parallel-group, open-label RCT across 25 French dermatology departments |
| Population | Newly diagnosed pemphigus patients aged 18-80, treated for the first time (not relapse) |
| Arms | 1:1 randomisation: (1) Prednisone alone 1.0-1.5 mg/kg/day tapered over 12-18 months vs. (2) Rituximab 1000 mg IV on days 0 and 14, 500 mg at months 12 and 18, combined with short-term prednisone 0.5-1.0 mg/kg/day tapered over 3-6 months |
| Stratification | Disease severity (severe vs moderate, Harman's criteria) |
| Primary endpoint | Complete remission off-therapy at month 24 (ITT analysis) |
| Key result | 89% of rituximab+prednisone group vs. 34% of prednisone-alone group achieved complete remission off-therapy at month 24 (p < 0.0001) |
| NNT | 1.82 (only ~2 patients need to be treated with rituximab+prednisone rather than prednisone alone for one additional complete remission) |
| Safety | No deaths. MORE severe AEs (grade 3-4) in prednisone-alone group (53 events in 29 patients) vs rituximab+prednisone (27 events in 16 patients, p = 0.0021) |
| Common AEs | Diabetes/endocrine disorder, myopathy, bone disorders |
Interpretation: First-line use of rituximab plus short-term prednisone for pemphigus is more effective than prednisone alone, with fewer adverse events. [1]
Exam Tip
If asked "What is the current first-line treatment for pemphigus?" the answer per this lecture is rituximab combined with short-term prednisone, not high-dose steroid monotherapy. This is a paradigm shift. The old answer of "high-dose systemic steroid" is now outdated but may still appear as a distractor.
Bullous pemphigoid affects an older age group and is a milder disease. First-line: oral minocycline and topical steroid. Only if resistant, escalate to systemic immunosuppressive therapy: mycophenolate, systemic steroid, azathioprine, cyclophosphamide, cyclosporin, plasmapheresis, IVIG. [1]
Rituximab has less evidence to support its use in BP and carries greater risk due to the age of the population. [1]
Why minocycline for BP? Minocycline has anti-inflammatory properties beyond its antibiotic effect—it inhibits neutrophil chemotaxis and metalloproteinases. In elderly patients with comorbidities, it avoids the systemic toxicity of steroids. Topical potent corticosteroids (e.g., clobetasol) applied to the whole body surface have been shown in trials to be as effective as oral prednisolone for moderate BP, with fewer side effects.
Pemphigus vs BP Treatment Comparison
| Feature | Pemphigus | Bullous Pemphigoid |
|---|---|---|
| Severity | More severe, potentially fatal | Milder, older patients |
| First-line (current) | Rituximab + short-term prednisone | Oral minocycline + topical steroid |
| Rituximab role | First-line (strong evidence) | Limited (less evidence, higher risk in elderly) |
| Escalation | MMF, azathioprine, CYC, CSA, IVIG, plasmapheresis | Same agents, only if resistant |
II. Eczema (Atopic Dermatitis) — Treatment Ladder
First-Line Management
1st line management of dermatitis: (1) Avoid irritant or allergen, (2) Emollient, (3) Topical steroids, (4) Antihistamine, (5) Potassium permanganate, (6) Treat secondary infection. [1]
Irritants to avoid: soap/detergent, washing powder (use non-biological), spicy food/fruit, alcohol, sweating, smoking. [1]
Why? These strip natural lipids from the skin barrier or cause vasodilation/inflammation that worsens the impaired barrier in eczema. The filaggrin-deficient epidermis in AD is already unable to retain moisture—any further insult accelerates transepidermal water loss (TEWL).
Emollients are important to treat the dryness in eczema. They are safe but allergic reactions can occur. They act by either preventing water loss by evaporation or addition of water-binding substances. [1]
Types of emollients listed in the lecture: Aqueous cream, Ung emulsifying oint., Vaseline, Oilatum, Urederm, 10% urea cream, E45 cream, Dermacare, Alcoderm, Keri lotion, Alpha-keri, Diprobase, Lacticare, Lipobase, Aquadrate, Calmurid. [1]
The greasier the emollient, the more effective but less cosmetically acceptable. [1]
Suggested routine from the lecture:
- Use bath oil or emollient wash in bath
- Soak for 15 minutes (don't use soaps)
- Pat dry, then apply topical steroid to affected areas first
- Apply a moderate or greasy emollient over everything
Why this order? Soaking hydrates the stratum corneum. Patting (not rubbing) prevents mechanical trauma. Applying steroid first ensures it contacts inflamed skin directly. The emollient over the top acts as an occlusive seal, enhancing both steroid penetration and moisture retention.
Antiseptic bath, probiotics, aeroallergen avoidance, food allergy assessment. [1]
Aeroallergen (house dust mite): worthwhile to avoid. Food allergy: more controversial—skin prick test and IgE are not reliable as a predictor for delayed reactions. Skin food patch test only done in research settings. For severe cases: food diary → elimination → open food re-challenge. [1]
Common Exam Trap
Students often state that positive skin prick tests or elevated specific IgE "diagnose" food allergy in eczema. Per the lecture, these tests are not reliable predictors for delayed food reactions in AD. The gold standard is an elimination diet followed by open food re-challenge. Only a positive re-challenge confirms clinical relevance.
Topical steroids interact with cell nucleus affecting mRNA expression. They are anti-inflammatory, cause vasoconstriction, have immunosuppressive action, and are anti-proliferative. [1]
UK Classification (4 potency groups):
| Group | Relative Potency | Examples (HK steroid ladder) |
|---|---|---|
| Group 1 (weakest) | 1× | Hydrocortisone 0.5%, 1% |
| Group 2 | 2.5× stronger than Group 1 | Clobetasone butyrate (Eumovate), Synalar low-strength |
| Group 3 | 10× stronger than Group 1 | Betnovate, Elomet, Cutivate, Advantan, Synalar 0.025% |
| Group 4 | 50× stronger than Group 1 | Dermovate, Diprocel, Nerisone |
Adverse Effects of Topical Steroids (comprehensive list from lecture):
Hypopigmentation, increased hair growth, skin atrophy, telangiectasia, easy bruising, stretch marks, acne, perioral dermatitis, infection, rebound, tachyphylaxis, contact dermatitis, Cushing syndrome, pituitary-adrenal suppression. [1]
Why tachyphylaxis occurs: Prolonged exposure leads to downregulation of glucocorticoid receptors in the skin. The same dose becomes less effective over time, tempting clinicians to escalate potency. This is why intermittent/pulsed regimens are preferred over continuous daily application.
Why rebound occurs: Chronic steroid use suppresses natural inflammatory regulators. When steroids are suddenly withdrawn, inflammation "rebounds" worse than baseline because the skin's own anti-inflammatory mechanisms have been suppressed. This is particularly dangerous in psoriasis (can trigger erythroderma or pustular flare).
| Drug | Key Features |
|---|---|
| Mometasone furoate (Elomet) | Low systemic resorption, rapid breakdown in liver, 6 weeks therapy local effect similar to 1% HC, potency equivalent to Betnovate |
| Fluticasone (Cutivate) | Rapidly broken down in liver, potent steroid equivalent to class III, local safety with short-term use |
| Methylprednisolone aceponate (Advantan) | Once daily, fast inactivation within the circulation, low risk of systemic and cutaneous adverse effects, approved for age 4 months to 14 years |
Why these are preferred: They are designed with a "soft steroid" concept—potent at the site of application but rapidly inactivated systemically, reducing HPA axis suppression and systemic Cushingoid effects. This is especially important in children (Advantan is approved from 4 months old) and when treating large body surface areas.
Topical Calcineurin Inhibitors: In the US, second-line treatment. Tacrolimus (Protopic) and Pimecrolimus (Elidel). [1]
| Feature | Tacrolimus (Protopic) | Pimecrolimus (Elidel) |
|---|---|---|
| Indicated population | Moderate-severe AD | Mild-moderate AD |
| Mechanism | Immunosuppressant similar to cyclosporin; inhibits calcineurin → blocks T-cell activation. 10-100× more potent than cyclosporin in inhibiting T cells. | Anti-inflammatory macrolactam; blocks synthesis of both Th1 and Th2 type cytokines in target cells |
| Potency | 0.1% as effective as mid-potency topical steroid; 0.03% less than mid-potency but more than low-potency steroid | Less than mid-potency steroid |
| Key advantage over steroids | Does not cause skin atrophy | Does not cause skin atrophy |
| Side effects | Mild burning sensation (topical); in most cases undetectable plasma levels | Burning/stinging (transient) |
| Long-term concern | Theoretical increased risk of skin cancer/lymphoma (FDA black box warning) | Same theoretical concern |
Why TCIs are important for the face/eyelids: The face, especially the eyelids (which absorb 42% of applied drug), is extremely susceptible to steroid atrophy. TCIs provide anti-inflammatory control without the atrophy, telangiectasia, or perioral dermatitis risk of steroids. They are the treatment of choice as steroid-sparing agents for facial eczema.
Wet wraps: rehydrate the skin, enhance absorption of topical ointment, reduce the dose of topical steroid, prevent scratching. [1]
Method (from the lecture):
- Bath
- Apply topical steroid (Elomet/Vaseline 1:10 dilution) to affected areas
- Apply Vaseline to unaffected areas
- Apply wet layer of Tubifast covered by a dry layer of Tubifast
- Sedative antihistamine
Pilot study (Tang & Chan, 1999): 12 patients with refractory AD received wet wrap therapy using mometasone (1/10) ointment for 2 weeks. Well-tolerated; plasma cortisol was not depressed. 60-85% reduction in objective and subjective scores. [1]
Pei & Chan (Pediatr Dermatol 2001): 40 children randomized to wet wraps with 1/10 Elomet vs. Cutivate ointment. Significant improvement from baseline during first 2 weeks of open application (p=0.043). Wet wraps further improved severity and extent after week 2 (p < 0.05). Both mometasone furoate and fluticasone propionate ointments effective for wet wrap dressing. [1]
Why 1:10 dilution? Diluting the potent steroid with Vaseline reduces the risk of systemic absorption through occlusion while still delivering enough anti-inflammatory effect. The wet layer increases hydration and acts as a vehicle for enhanced penetration, while the dry outer layer maintains the dressing in place and provides a physical barrier against scratching.
Third-Line: Systemic & Phototherapy
Third-line options: Phototherapy, MMF, cyclosporin, azathioprine, systemic steroid. [1]
Phototherapy in HK—Chinese have lower risk of skin cancer (~400 cases of non-melanoma skin cancer in HK per year). Phototherapy is suitable for Chinese patients. Mainly for adults (age ≥ 15). Need systemic steroid to cover the initial period. [1]
Narrow-band UVB (311 nm): like other forms of phototherapy, induces immunosuppression by altering cutaneous antigen-presenting cells. Increases non-Langerhans cell APCs which stimulate suppressor T8 cells. Three times a week therapy. [1]
NB-UVB vs. Broadband UVB:
| Feature | NB-UVB | BB-UVB |
|---|---|---|
| Erythema induction | 5-10× less potent for erythema | More potent |
| Immunosuppression | More immunosuppressive | Less |
| Carcinogenicity | 2-3× more carcinogenic than BB-UVB | Less carcinogenic |
| Clinical efficacy | More effective for psoriasis and eczema | Less effective |
NB-UVB vs. PUVA:
| Feature | NB-UVB | PUVA |
|---|---|---|
| Carcinogenicity | Less carcinogenic | More carcinogenic |
| Use in pregnancy/children | Can be used | Cannot |
| Efficacy in chronic plaque psoriasis | Slightly inferior (not statistically significant) | Slightly superior |
| Eye protection after treatment | Not needed | Needed (psoralen causes photosensitivity) |
| Drug | Mechanism | Key Points from Lecture | Major Side Effects |
|---|---|---|---|
| MMF | Inhibits de novo purine synthesis; blocks T and B lymphocyte proliferative responses | 1g BD for 4 weeks then 500mg BD; all patients showed significant reduction; one discontinued due to herpes retinitis | Herpes simplex/zoster reactivation, herpes retinitis |
| Azathioprine | Purine antimetabolite | Used for many years; TPMT-based dosing; 39% decrease in disease activity vs 24% with placebo; slow onset; prolonged improvement 3-6 months after treatment; dose 2-3.5 mg/kg/day | Neutropenic fever (slow onset), bone marrow suppression; check TPMT and NUDT15 before starting |
| Cyclosporin | Calcineurin inhibitor; down-regulates cytokine production; reduces IL-2 and lymphokine transcription | Rapid-acting; 5 mg/kg/day → 55% reduction in 8 weeks; can be used in children (2-16 years); initial dose 2.5-5 mg/kg/day; limit use to 12 months; most patients relapse within weeks of stopping → taper gradually | Nephrotoxicity, hypertension (limiting long-term use beyond 12 months) |
| Systemic steroid | Broad immunosuppression | Last resort; avoid if possible due to rebound on withdrawal | Cushingoid features, osteoporosis, DM, adrenal suppression |
TPMT and NUDT15 Before Azathioprine
Always check TPMT enzyme activity AND NUDT15 (especially important in HK/Asian populations) before starting azathioprine. Deficiency leads to excessive accumulation of toxic 6-TGTP metabolite → severe myelosuppression/neutropenic fever. Also check if patient is on xanthine oxidase inhibitors (allopurinol, febuxostat) as these block alternative metabolism of azathioprine. [6]
Biologic Therapy for AD: Dupilumab
The lecture presents three immunological stages:
- Uninvolved skin in AD: Langerhans cells, mast cells with surface IgE, CD4+ T cells present but quiescent
- Acute AD skin: Allergen exposure → Th0 cells differentiate into Th2 cells under IL-4 drive → Th2 cells produce IL-4, IL-5, IL-13 → IgE production → mast cell degranulation → histamine release
- Chronic AD skin: Epidermal hyperplasia from scratching → scratching damages epidermis, releasing cytoplasmic autoallergens → superantigens (from Staph. aureus colonization) → IL-12 drives a shift to Th1 response alongside ongoing Th2
Dupilumab is a fully human monoclonal antibody that blocks IL-4 and IL-13. These are the key drivers of Th2-mediated inflammation. [1]
Why block both IL-4 AND IL-13? Dupilumab targets the IL-4 receptor alpha subunit, which is shared by both the IL-4 receptor and the IL-13 receptor. IL-4 drives Th2 differentiation and IgE class switching. IL-13 promotes mucus production, fibrosis, and barrier dysfunction. Blocking both simultaneously addresses multiple pathogenic pathways.
12-week monotherapy study: 85% of dupilumab group vs. 35% of placebo had ≥50% reduction in EASI score (p < 0.001). 40% of dupilumab group vs. 7% of placebo had IGA 0-1 (clear/near-clear) (p < 0.001). Pruritus scores decreased 55.7% vs. 15.1% (p < 0.001). [1]
Phase 3 study design (R668-AD-1416):
- Eligibility: IGA 3 (moderate) or 4 (severe), or inadequate response/intolerance to topical AD medications
- Randomisation: 1:1:1 — dupilumab 600mg loading then 300mg weekly : 600mg loading then 300mg biweekly : placebo
- Treatment period: 16 weeks
- Primary endpoint: IGA 0 or 1, OR EASI 75 at week 16, not on rescue therapy
Dupilumab was designated by USFDA as a breakthrough therapy. FDA approval: 28 March 2017. Cost: ~US$37,000/year. [1]
On March 11, 2019, FDA approved dupilumab for adolescents aged 12-17 with moderate-to-severe AD for whom other treatments have not worked. [1]
AD Treatment Summary from the Lecture
"Newer topical steroids have a low adverse effect profile. Tacrolimus and pimecrolimus are second-line agents that can be used. MMF, azathioprine and phototherapy can be used as third-line treatment. Biologics are promising new therapeutic options." [1]
The 2026 Derm General Clerkship slides confirm the same three-tier structure and add JAK inhibitors and tralokinumab (anti-IL-13) as additional systemic options. [7]
III. Psoriasis — Treatment
Psoriasis is a chronic, inflammatory, immune-mediated skin disease affecting ~2% of the European population. It occurs in individuals with genetic susceptibility (PSORS1 on chromosome 6, within MHC region, accounts for up to 50% of genetic susceptibility) in conjunction with environmental stimuli. [1]
The "Vicious Cycle" of psoriatic plaque development:
- Genetic predisposition + trigger → dendritic cell activation
- Dendritic cells produce IL-12 → Th1 differentiation; IL-23 → Th17 differentiation
- Th1 cells produce IFN-γ, IL-2; Th17 cells produce IL-17
- These cytokines → keratinocyte activation and proliferation, chemokine release, leucocyte recruitment, angiogenesis
- Sustained inflammation → plaque formation
Histological hallmarks: (1) Epidermal hyperplasia, (2) Dilated prominent dermal blood vessels, (3) Leucocyte infiltrate (mainly dermal, also epidermal), (4) Neutrophil accumulation [1]
Important Cytokines in Psoriasis
| Cytokine | Proposed Role |
|---|---|
| IFN-γ | ↑ keratinocyte proliferation |
| IL-2 | ↑ T-cell growth |
| TNF-α | ↑ vascular adhesion molecules, ↑ macrophage cytokines/chemokines |
| TGF-α, Amphiregulin | EGF-R ligand → keratinocyte proliferation |
| IL-6 | ↑ angiogenesis |
| IL-8 | Neutrophil attractant |
| IL-1 | ↑ vascular permeability |
| IL-12 | ↑ Th1 differentiation |
| IL-23 | ↑ Th17 differentiation |
Psoriasis patients are at increased risk for: obesity (~2-fold), smoking (~2-fold), diabetes (~1.5-fold), hypertension (~2-fold), heart failure (~2-fold), MI (mild psoriasis ~1.5-fold; severe psoriasis ~7-fold), increased inpatient cardiovascular mortality (~1.5-fold), depression (5.5% have suicidal ideation), mortality (severe psoriasis ~1.5-fold). [1]
Increased arterial stiffness in patients with psoriasis is associated with active systemic inflammation (Yiu, Yeung, Chan et al., Br J Dermatol 2011) [1]
Why do psoriasis patients get cardiovascular disease? Psoriasis is a systemic inflammatory condition. Chronic systemic inflammation (elevated TNF-α, IL-6, CRP) promotes endothelial dysfunction, accelerated atherosclerosis, insulin resistance, and dyslipidaemia. This is analogous to RA. Severe psoriasis confers CV risk comparable to diabetes.
Topical agents: Tar, steroid, keratolytic, Vitamin D analogue, dithranol, emollient. [1]
| Agent | Mechanism/Use | Drawbacks |
|---|---|---|
| Tar | Mechanism not known; used as shampoo, bath, in combination with other agents | Messy, irritation, phototoxic |
| Dithranol | Antiproliferative and anti-inflammatory; applied as short-contact therapy | Messy, irritation, stains skin |
| Calcipotriol (Daivonex) | Vitamin D analogue; inhibits keratinocyte proliferation; flattens psoriatic plaques; once daily; does NOT cause skin atrophy | Irritation (main side effect) |
| Topical steroids | Anti-inflammatory | Risk of rebound/pustular psoriasis on withdrawal |
| Keratolytics (e.g., salicylic acid) | Remove thick scale to allow penetration of other agents | Irritation |
| Emollients | Maintain hydration, reduce scaling | — |
2nd line for psoriasis: Phototherapy. 308 nm UVB excimer laser can be used for localized lesions. [1]
NB-UVB (311 nm) is the workhorse. PUVA is reserved for resistant chronic plaque psoriasis.
3rd line: Retinoid, methotrexate, cyclosporin, hydroxyurea. [1]
Indications for Systemic Therapy — The "Rule of Tens"
Indications for systemic therapy in psoriasis:
- Failure of adequate trial of topical therapy
- Repeated hospital admissions for topical therapy
- Extensive chronic plaque psoriasis in the elderly or infirm
- Generalised pustular or erythrodermic psoriasis
- Severe psoriatic arthropathy
- "Rule of Tens": BSA > 10%, OR PASI > 10, OR DLQI > 10 [1]
Rule of Tens — High Yield
Any ONE of BSA > 10%, PASI > 10, or DLQI > 10 qualifies a patient for systemic therapy consideration. This is a favourite exam question.
PASI 75 comparison (from lecture): In an RCT comparing MTX vs. cyclosporin:
- MTX 15 mg/week: 60% achieved PASI 75 at week 16
- Ciclosporin 3 mg/kg/day: 71% achieved PASI 75 at week 16
QMH cohort (80 patients): 57% mild (PASI < 10), 30% moderate (PASI 10-20), 13% severe (PASI > 20). Treatment breakdown: 45% topical only, 25% methotrexate, 12.5% acitretin, 5% biologics, 10% TCM, 2.5% cyclosporin, 1.3% phototherapy. [1]
Local survey: 35.9% of the community considered TCM effective for psoriasis. A randomized trial at QMH compared MTX vs. TCM vs. placebo to determine efficacy, safety and quality of life. [1]
Biologic Therapy for Psoriasis
Biologic therapies are indicated for moderate-to-severe plaque psoriasis in adult patients who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapy including ciclosporin, methotrexate or PUVA. [1]
| Name (Brand) | Target | Route | Dosing | Year Approved |
|---|---|---|---|---|
| Adalimumab (Humira) | TNF | SC | 80mg wk0 → 40mg q2w from wk1 | 2007 |
| Etanercept (Enbrel) + biosimilars | TNF | SC | 25mg×2/wk or 50mg/wk (can uptitrate to 50mg×2/wk for 12wk) | 2004 |
| Infliximab (Remicade) + biosimilars | TNF | IV | 5mg/kg at wk0, 2, 6 then q8w | 2006 |
| Ustekinumab (Stelara) | IL-12/23 (p40 subunit) | SC | 45mg at wk0, wk4, then q12w (90mg if > 100kg) | 2009 |
| Secukinumab (Cosentyx) | IL-17 | SC | 300mg at wk0,1,2,3 then monthly from wk4 (2×150mg) | 2015 |
| Ixekizumab (Taltz) | IL-17 | SC | 160mg wk0 (2×80mg), then 80mg q2w to wk12, then 80mg q4w | 2017 |
| Brodalumab (Kyntheum/Siliq) | IL-17 receptor (IL-17RA) | SC | 210mg | 2017 |
| Tildrakizumab (Ilumya) | IL-23 (p19) | SC | 100mg at wk0, 4, then q12w (200mg in heavier patients) | 2018 |
| Guselkumab (Tremfya) | IL-23 (p19) | SC | 100mg at wk0, 4, then q8w | 2018 |
| Risankizumab (Skyrizi) | IL-23 (p19) | SC | 150mg at wk0, 4, then q12w | 2019 |
Evolution of therapeutic targets: MTX → anti-TNF → anti-IL-12/23 → anti-IL-17 → anti-IL-23p19. Each generation achieves higher PASI responses:
PASI 75/90/100 response rates improve progressively: MTX < anti-TNF < anti-IL-12/23 < anti-IL-17 ≈ anti-IL-23p19, with anti-IL-23p19 agents achieving the highest PASI 90 and 100 rates. [1]
Activated T cells stimulate macrophages and fibroblasts to secrete TNF-α. Adalimumab, infliximab and etanercept inhibit TNF-α-induced joint damage. [1]
| Drug | Type |
|---|---|
| Adalimumab | Fully human anti-TNF monoclonal antibody |
| Infliximab | Chimeric (mouse/human) anti-TNF monoclonal antibody |
| Etanercept | Soluble TNF receptor fusion protein (decoy receptor) |
Why distinguish these? Infliximab can trigger anti-drug antibodies (immunogenicity) more readily due to its chimeric nature. Etanercept, being a fusion protein rather than an antibody, binds TNF differently and is less effective for Crohn's disease (a common exam trap). All three are effective for psoriasis and psoriatic arthritis.
| Drug | Rheumatology | Dermatology | GI |
|---|---|---|---|
| Adalimumab | RA, PsA, AS, JIA | Ps, ped Ps, HS | CD, UC, ped CD |
| Etanercept | RA, PsA, AS, JIA | Ps, ped Ps | — |
| Infliximab | RA, PsA, AS | Ps | CD, UC, ped CD, ped UC |
| Ustekinumab | PsA | Ps, ped Ps | CD |
| Secukinumab | PsA, AS | Ps | — |
| Guselkumab | PsA | Ps, ped Ps, HS | — |
| Risankizumab | PsA | Ps, ped Ps, HS | CD (MC) |
| Category | Adverse Events |
|---|---|
| All biologics | Infections, Hepatitis B/C or TB reactivation, immunogenicity, malignancy |
| TNF inhibitors | Infusion reactions, drug-induced lupus, hepatotoxicity, cytopenia, exacerbation/new onset CHF, MS (rare), hypersensitivity reactions |
| IL-12/23 inhibitors | (Relatively benign profile; see "all biologics") |
| IL-17 inhibitors | Candidiasis, inflammatory bowel disease, hepatotoxicity, neutropenia (rare) |
| IL-17RA inhibitors (brodalumab) | Depression and risk of suicide, increased liver transaminases (rare) |
Anti-IL-17 and IBD — Exam Trap
IL-17 inhibitors (secukinumab, ixekizumab) can WORSEN or trigger inflammatory bowel disease. This is because IL-17 has a protective role in gut mucosal immunity. If a patient has psoriasis AND IBD, do NOT use an anti-IL-17 agent. Use ustekinumab (anti-IL-12/23) or an anti-TNF agent instead—both are approved for IBD.
Highly efficacious treatments combined with a treat-to-target approach to achieve and maintain skin clearance is pivotal to maximizing long-term health-related QoL. Target: PGA of clear or nearly clear. Involves: appropriate treatment selection, monitoring of treatment response, treatment optimization (dose adjustment, switching). [1]
Treatment of chronic urticaria:
- 1st line: Second-generation antihistamine
- 2nd line: Up-dose antihistamine up to 4-fold
- 3rd line: H2 blocker, leukotriene antagonist, ciclosporin (CSA), and short course of systemic steroid [1]
Second-generation antihistamines listed:
Fexofenadine, cetirizine, loratadine, desloratadine, levocetirizine. [1]
Why second-generation (non-sedating) first? First-generation antihistamines (e.g., chlorpheniramine, hydroxyzine) cross the blood-brain barrier → cause sedation, impaired psychomotor performance, and anticholinergic effects. Second-generation agents are designed to be lipophobic → poor BBB penetration → minimal sedation, making them safer for chronic daily use.
Why up-dose to 4-fold? Standard dosing may not saturate H1 receptors sufficiently. Evidence shows that increasing to 4× the licensed dose of second-generation antihistamines improves control in ~60-70% of patients who don't respond to standard doses, with a good safety margin. This is now in international guidelines (EAACI/GA²LEN).
Why add H2 blockers? H2 receptors are present on dermal blood vessels and can contribute to vasodilation and wheal formation. Combining H1 and H2 blockade provides additive effect.
Leukotriene antagonists (e.g., montelukast): Leukotrienes contribute to urticarial inflammation, especially in NSAID-exacerbated or autoimmune urticaria.
Ciclosporin (CSA) in urticaria: Reserved for refractory cases. It suppresses T-cell-mediated inflammation and has been shown to be effective in autoimmune chronic urticaria (where functional IgG autoantibodies against FcεRI or IgE drive mast cell degranulation).
Omalizumab — Missing from lecture but important
Omalizumab (anti-IgE monoclonal antibody) is now used as add-on therapy for antihistamine-refractory chronic spontaneous urticaria in current guidelines. It was not explicitly listed in this lecture, but it may appear in updated exam material. The lecture's third-line list (H2 blocker, leukotriene antagonist, CSA, systemic steroid) should be your primary answer in an exam testing this lecture specifically.
In HK (1996): melanoma 26 cases, non-melanoma 355 cases. Mortality (1998): melanoma 18, non-melanoma 16. [1]
SCC age-adjusted incidence: Australia 250/100,000; USA 30-154/100,000; Japanese in Hawaii 23/100,000 (45× that of Japanese in Japan). Sun exposure and skin colour are important for the lower prevalence of non-melanoma skin cancer in Chinese populations. [1]
Why is this relevant to treatment? This data justifies phototherapy use in Chinese patients—the baseline skin cancer risk is much lower than in Caucasian populations, making the risk-benefit ratio of phototherapy more favorable.
VI. Exam Intelligence
| Likely Stem | Expected Answer Points |
|---|---|
| "List the stepwise management of moderate atopic dermatitis" | 1st line: Avoid irritants, emollients, topical steroids, antihistamines, treat secondary infection → 2nd line: TCIs (tacrolimus/pimecrolimus), wet wraps → 3rd line: phototherapy, MMF/azathioprine/cyclosporin → Biologic: dupilumab |
| "What is the current first-line treatment for pemphigus?" | Rituximab (anti-CD20) + short-term prednisone (Ritux 3 trial) |
| "Name 3 adverse effects of topical corticosteroids" | Skin atrophy, telangiectasia, striae, hypopigmentation, tachyphylaxis, rebound, HPA suppression, perioral dermatitis, acne |
| "What is the 'Rule of Tens' in psoriasis?" | BSA > 10%, PASI > 10, or DLQI > 10 → indication for systemic therapy |
| "List the targets of biologic agents used in psoriasis" | TNF-α (adalimumab, etanercept, infliximab), IL-12/23 (ustekinumab), IL-17 (secukinumab, ixekizumab), IL-17R (brodalumab), IL-23 (guselkumab, risankizumab, tildrakizumab) |
| "What is dupilumab and how does it work?" | Fully human monoclonal antibody targeting IL-4Rα subunit, blocking both IL-4 and IL-13. FDA-approved breakthrough therapy for moderate-severe AD |
| "What is the first-line treatment for chronic urticaria?" | Second-generation antihistamine (e.g., cetirizine, fexofenadine, loratadine). If inadequate: up-dose to 4-fold. Third-line: H2 blocker, leukotriene antagonist, CSA |
| "Why are topical calcineurin inhibitors preferred for facial eczema?" | They do not cause skin atrophy (unlike steroids), making them safer for thin-skinned areas like eyelids |
| "What checks are needed before starting azathioprine?" | TPMT enzyme activity, NUDT15 (especially in Asian populations), check for concomitant xanthine oxidase inhibitors (allopurinol) |
| "Name 2 side effects specific to IL-17 inhibitors" | Candidiasis, exacerbation/new onset of IBD |
- Confusing pemphigus with pemphigoid treatment: Pemphigus = rituximab + short-course steroid. BP = minocycline + topical steroid (conservative first)
- Stating that topical steroid is the most important treatment for eczema: While steroids control inflammation, emollients are the foundation of eczema management
- Using anti-IL-17 in a psoriasis patient with co-existing IBD: Anti-IL-17 can worsen IBD. Use anti-TNF or ustekinumab instead
- Forgetting tachyphylaxis as a steroid adverse effect: This is commonly tested as a reason for steroid treatment failure
- Mixing up UK and US steroid potency classifications: The lecture uses the UK system (Group 1 weakest → Group 4 strongest). The US system is reversed (Class I strongest → Class VII weakest)
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SAQ: A 35-year-old man presents with widespread blisters and erosions of the oral mucosa and trunk. Skin biopsy shows intraepidermal split with acantholysis. Direct immunofluorescence shows intercellular IgG. (a) What is the diagnosis? (b) What is the current first-line treatment? (c) Name the mechanism of action of the biologic used.
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MCQ: Which of the following is NOT an adverse effect of topical corticosteroids? (A) Skin atrophy (B) Telangiectasia (C) Hypertrichosis (D) Hyperpigmentation (E) Perioral dermatitis → Answer: D (steroids cause hypo-, not hyper-pigmentation)
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SAQ: List three indications for systemic therapy in psoriasis.
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EMQ: Match the biologic to its target: Ustekinumab → IL-12/23; Secukinumab → IL-17; Dupilumab → IL-4/IL-13
High Yield Summary
Eczema treatment ladder: Emollients + avoid irritants → topical steroids (UK Group 1-4) → TCIs (tacrolimus for moderate-severe, pimecrolimus for mild-moderate; no atrophy) → wet wraps → phototherapy (NB-UVB 311nm) / systemic (MMF, azathioprine with TPMT/NUDT15 check, cyclosporin limited to 12 months by nephrotoxicity) → dupilumab (anti-IL-4/13, breakthrough biologic).
Psoriasis: Topical (calcipotriol = Vit D analogue, no atrophy; tar; dithranol; steroids) → phototherapy → systemic (MTX, cyclosporin, retinoid) when "Rule of Tens" met (BSA > 10%, PASI > 10, DLQI > 10) → biologics (anti-TNF → anti-IL-12/23 → anti-IL-17 → anti-IL-23p19). Remember comorbidities: CV disease, depression, metabolic syndrome.
Pemphigus: Rituximab (anti-CD20) + short-term prednisone is now first-line (Ritux 3 trial: 89% vs 34% complete remission). Bullous pemphigoid: Minocycline + topical steroid first (older, frailer patients).
Chronic urticaria: 2nd-gen antihistamine → up-dose 4× → H2 blocker/leukotriene antagonist/CSA/short-course steroid.
Active Recall - Treatments for Skin Diseases
[1] Lecture slides: GC 090. Treatments for skin diseases.pdf (all pages referenced throughout) [2] Past papers: 2019 Fourth Summative MCQ.pdf (EMQ sections on dermatological conditions and drugs in inflammatory arthritis) [3] Past papers: 2021 Fourth Summative SAQ.pdf (Q7 on skin pathology and treatment) [4] Senior notes: Ryan Ho Fundamentals.pdf (p419-420, steroid ladder in HK, topical treatments) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf (p404, approach to management of AD) [6] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (p45, TPMT/NUDT15 and azathioprine) [7] Medicine lecture slides: Derm General Clerkship 2026 Part1.pdf (p14, treatment tiers for AD including JAK inhibitors)
GC089 Syncope And Irregular Heart Beat
Syncope is a transient loss of consciousness due to cerebral hypoperfusion, and irregular heartbeat (arrhythmia) refers to abnormal cardiac rhythm disturbances, which together represent a clinical presentation where cardiac dysrhythmias may cause hemodynamic compromise leading to fainting episodes.
GC091 Unsteady Gait Cerebellar Lesions; Movement Disorders; Parkinsonism
Unsteady gait is a disturbance in walking stability that can arise from cerebellar lesions causing ataxia, movement disorders such as dystonia or chorea, or parkinsonism characterized by shuffling steps, festination, and postural instability.