Biologics and small molecules in dermatology

Meet the patient

A 34-year-old with severe plaque psoriasis has failed topical therapy and phototherapy. His PASI is 18, his nails and scalp are involved, and he has early morning back stiffness. He asks whether a "biologic" will fix it and whether it is safe to start while he and his partner try for a baby. [1]

Three decisions sit inside that one question: which axis drives his disease, which class fits the comorbidity profile, and what screening must clear before the first dose. Hold those three and the rest of the topic is detail. [1]

The cytokine-target framework — classify by axis, not by disease

Biologics are large recombinant proteins (monoclonal antibodies, fusion proteins, PEGylated fragments) that bind a circulating cytokine, its receptor, or a cell-surface antigen, given parenterally with half-lives of weeks to months. Small molecules (JAK, PDE4, TYK2, S1P inhibitors) are oral, low-molecular-weight compounds that act intracellularly, with short half-lives and baseline organ-function testing. [1]

The cleanest way to learn the field is by cytokine pathway, not by disease. Three T-helper axes cover almost the whole syllabus. [1]

• Th1/Th17 axis — psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis; driven by IL-12, IL-23, IL-17, IL-22, TNF-alpha.
• Th2 axis — atopic dermatitis, prurigo nodularis, chronic spontaneous urticaria; driven by IL-4, IL-13, IL-31, IgE.
• B-cell/neutrophil axis — pemphigus, hidradenitis, pyoderma gangrenosum; driven by CD20, C5a, IL-1. [1][6]

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TNF inhibitors — the workhorse, with the TB trap

TNF inhibitors were first and remain the workhorses of plaque psoriasis, psoriatic arthritis, axial spondyloarthritis, hidradenitis, IBD, Behçet and uveitis. The same biology that clears skin and joints also reactivates latent granulomatous disease — which is why TB screening is non-negotiable. [1][6][7]

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The TNF adverse-event profile falls straight out of the biology: reactivation of latent TB and endemic mycoses (histoplasmosis, coccidioidomycosis), demyelination, worsening of NYHA III/IV heart failure (TNF is paradoxically protective in advanced HF), drug-induced lupus, and rare hepatosplenic T-cell lymphoma in young males on combination immunosuppression. HBV reactivation is highest with the TNF class — screen everyone. [1]

IL-23 inhibitors — first line for plaque psoriasis

IL-23 is the master regulator of the psoriatic plaque, and selective IL-23 p19 blockade is the current first-line biologic for moderate-to-severe plaque psoriasis. Dendritic-cell IL-23 drives Th17 cells to release IL-17, which drives keratinocyte hyperproliferation. [1]

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Selective p19 inhibitors spare IL-12, so Th1-mediated anti-TB immunity is preserved — TB screening is still required, but the reactivation risk is lower than with anti-TNF. This sparing is the theoretical advantage candidates must name. [1] A note on guttate psoriasis. This acute, eruptive, teardrop form classically follows streptococcal pharyngitis in young adults and children, and it is managed first with phototherapy, emollients and strep eradication rather than a biologic — biologics (anti-TNF, anti-IL-17, anti-IL-23) and apremilast are reserved for refractory or chronic guttate disease. [5]

IL-17 inhibitors — fast and powerful, barred in IBD

IL-17 blockade gives the fastest and most powerful skin clearance in dermatology, with PASI 90 and even PASI 100 within 12 to 16 weeks. It is the first choice in psoriasis with severe nail, scalp or genital involvement, and is approved for psoriatic arthritis and axial spondyloarthritis. [1][7]

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IL-4 and IL-13 inhibitors — the Th2 axis

Dupilumab is the first-line systemic biologic for moderate-to-severe atopic dermatitis and also treats asthma, eosinophilic oesophagitis, prurigo nodularis and chronic rhinosinusitis with nasal polyps. It blocks the IL-4 receptor alpha chain, shutting down both IL-4 and IL-13 signalling. [2]

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Anti-IgE, anti-CD20, anti-IL-1, anti-C5a — the niche biologics

Omalizumab (anti-IgE) is the first-line biologic for chronic spontaneous urticaria refractory to four-fold-dose H1 antihistamines; dose by IgE level and weight, and observe for anaphylaxis (around 0.1%) after the first doses. [2]

Rituximab (anti-CD20, B-cell depleting) is first-line for pemphigus vulgaris (superior to corticosteroids alone) and is used off-label in bullous pemphigoid and mucous membrane pemphigoid. Hepatitis B reactivation screening is mandatory — reactivation can be fulminant. [4]

Anakinra (IL-1 receptor antagonist) and canakinumab (anti-IL-1-beta) serve the autoinflammatory syndromes (CAPS, TRAPS, FMF) and, off-label, hidradenitis and pyoderma. Vilobelimab (anti-C5a) became the first drug with a label for pyoderma gangrenosum in 2024. [1]

JAK inhibitors — the boxed warning

Janus kinases transmit cytokine signals to the nucleus, and oral JAK inhibitors carry an FDA boxed warning for serious infections (especially herpes zoster), malignancy (lymphoma, lung cancer), MACE, VTE and mortality. The signal came from the ORAL-Surveillance trial of tofacitinib in rheumatoid arthritis. [2][3]

TYK2, PDE4 and S1P — the small molecules without the JAK warning

Deucravacitinib is the first allosteric TYK2 inhibitor — it binds the pseudokinase domain, not the ATP site, so it is functionally TYK2-selective and does not carry the JAK boxed warning. POETRY-PSO showed PASI 75 in about 53% and PASI 90 in about 30% at week 16. [1]

Apremilast (oral PDE4 inhibitor, 30 mg twice daily after titration) raises intracellular cAMP and is used in psoriasis and Behçet oral ulcers; it causes self-limiting nausea and diarrhoea, weight loss (monitor), and a rare depression signal — no TB screening or routine bloods required. [1] Dimethyl fumarate causes flushing and lymphopenia; the S1P modulators (etrasimod, ponesimod) cause first-dose bradycardia and need titration with an ECG. [1]

The dosing reference — loading and maintenance

The loading and maintenance patterns below are the doses that recur in board exams and prescribing protocols. Memorise the loading (where one exists), the maintenance interval, and the route. [1][2]

For hidradenitis, adalimumab loads 160 mg then 80 mg at week 2, then 40 mg weekly; secukinumab and bimekizumab carry the IL-17 load. For alopecia areata, baricitinib 2 mg daily, ritlecitinib 50 mg daily, and deuruxolitinib 8 mg twice daily are the FDA-approved JAK options. [1][3]

Pre-treatment screening — the universal bundle

Every patient starting a biologic, JAK or TYK2 inhibitor gets the same universal screening bundle, with class-specific add-ons layered on top. [1][2]

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The indications grid — match the drug to the axis

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Special clinical scenarios

COVID-19 and vaccination. Biologic and JAK therapy attenuates vaccine antibody titres but does not abolish protection against severe disease. Continue therapy through vaccination; give recombinant zoster (Shingrix) and pneumococcal vaccines before starting. [2]

Surgery. For most biologics, withhold one dose around major surgery. For rituximab, defer elective surgery 4 weeks. For JAK inhibitors, withhold 1 week pre- and post-operatively if VTE risk is elevated. [1]

Pregnancy and breastfeeding. Certolizumab is the biologic of choice (no Fc); infliximab and adalimumab may be continued to around week 26 to 28 then withheld. Methotrexate, acitretin and JAK inhibitors are contraindicated — methotrexate needs a 3-month washout. Avoid live vaccines in the neonate until 6 months if the mother was on a biologic. [1][2]

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Exam pearls

Exam application bank (NEET-PG and INICET)

One-line answer

Biologics (large molecules, parenteral) and small molecules (oral, intracellular) target cytokines and kinases. TNF inhibitors need TB screening and avoid NYHA III/IV heart failure; IL-17 inhibitors are contraindicated in IBD; dupilumab (IL-4R-alpha) is first-line for atopic dermatitis with conjunctivitis as the class effect; JAK inhibitors carry an FDA boxed warning (VTE, zoster, MACE, malignancy); deucravacitinib (TYK2) does not; certolizumab is the pregnancy biologic; rituximab is first-line for pemphigus. [1]

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose and route if drug therapy is standard. [1] Stem 2 — Unstable or complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote or reperfusion — and what you do in the first 15 minutes. [1] Stem 3 — Atypical group. Elderly, pregnancy, child or immunocompromised: how presentation and thresholds change. [1] Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. [1] Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU, ICU or theatre, and what follow-up is mandatory. [1]

Rapid viva checklist

1. Definition and classification
2. Pathophysiology chain
3. Bedside signs and criteria
4. Score with exact components
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline or trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Biologics and small molecules in dermatology. [1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the psoriasis patient trying for a baby (answer)

The 34-year-old with severe plaque psoriasis, nail and scalp disease, and morning back stiffness, who wants to start a family. Which class, which drug, and what must clear first? Model: His phenotype (psoriasis plus psoriatic arthritis) sits on the Th17 axis. First-line biologic for moderate-to-severe plaque psoriasis is a selective IL-23 p19 inhibitor (guselkumab or risankizumab); nail, scalp and genital involvement tilt toward an IL-17 inhibitor (secukinumab or ixekizumab). For conception, certolizumab (no Fc, minimal placental transfer) is the pregnancy biologic. Before any dose: latent TB screening (IGRA plus chest X-ray), HBV, HCV and HIV serology, FBC and LFTs, and bring vaccines up to date (live vaccines at least 4 weeks before starting). Screen for axial spondyloarthritis given the back stiffness. [1]

Stem 2 — the atopic dermatitis patient with a red eye (answer)

A 28-year-old started dupilumab for severe atopic dermatitis eight weeks ago. Her skin is dramatically better, but both eyes are gritty and red. What is it, and what do you do? Model: This is dupilumab-associated conjunctivitis — the class-specific adverse effect, peaking in the first 8 to 16 weeks, in 10 to 20% of patients. It is usually mild and managed with lubricants and topical calcineurin inhibitors; rarely needs ophthalmology referral or drug cessation. Check for blepharitis and keratoconjunctivitis at baseline. It is not an allergy and it is not a reason to stop a drug that is working. [2]

Stem 3 — the patient with Crohn disease offered secukinumab (answer)

A 45-year-old with Crohn disease and severe psoriasis is started on secukinumab. Three weeks later his bowel symptoms flare and he has bloody diarrhoea. What went wrong? Model: IL-17 blockade is contraindicated in inflammatory bowel disease — IL-17 is unexpectedly protective in the gut mucosa, and blockade can trigger or worsen Crohn disease or ulcerative colitis. The error was prescribing an IL-17 inhibitor without screening for bowel symptoms. Stop the drug, manage the IBD flare (gastroenterology, steroids, biologic for IBD such as anti-TNF or anti-IL-12/23), and re-choose the psoriasis therapy along an axis that does not threaten the gut — an anti-IL-23 p19 inhibitor or an anti-TNF (not etanercept). [1]

The mantra: match the drug to the axis, screen TB and hepatitis before the first dose, and never give an IL-17 inhibitor to a patient with inflammatory bowel disease. [1][2]

References

1. [1]Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review JAMA, 2020.PMID 32427307
2. [2]Chu DK, Schneider L, Asiniwasis RN, et al. Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations Ann Allergy Asthma Immunol, 2024.PMID 38108679
3. [3]Mateos-Haro M, Novoa-Candia M, Sánchez Vanegas G, et al. Treatments for alopecia areata: a network meta-analysis Cochrane Database Syst Rev, 2023.PMID 37870096
4. [4]Powers CM, Thakker S, Gulati N, et al. Bullous pemphigoid: A practical approach to diagnosis and management in the modern era J Am Acad Dermatol, 2025.PMID 39914667
5. [5]Zhou T, Koussiouris J, Kim L, et al. Management of Guttate Psoriasis: A Systematic Review J Cutan Med Surg, 2024.PMID 39080843
6. [6]Azuaga AB, Ramírez J, Cañete JD. Psoriatic Arthritis: Pathogenesis and Targeted Therapies Int J Mol Sci, 2023.PMID 36902329
7. [7]Bittar M, Deodhar A. Axial Spondyloarthritis: A Review JAMA, 2025.PMID 39630439