PharmacologyTier 1Medical Sciences concept

Biologic/targeted therapy mechanisms in rheumatoid arthritis (TNF, IL-6, JAK, B-cell, T-cell costimulation)

Core concept

1. TNF-alpha

Blocking TNF -> dec synoviocyte survival signalling, dec chemokines, dec IL-1/IL-6, dec osteoclastogenesis
Structural difference matters
- Whole mAbs (infliximab chimeric, adalimumab and golimumab human) - bind membrane TNF -> ADCC and complement-mediated lysis of TNF-expressing macrophages
- Certolizumab - PEGylated Fab' fragment, no Fc -> no ADCC, minimal placental transfer -> preferred in pregnancy
- Etanercept - soluble p75 TNF receptor-Fc fusion, a decoy; binds TNF-alpha and lymphotoxin-alpha
- Etanercept does not work in granulomatous disease (Crohn's, uveitis, sarcoid) - the mAbs do

2. IL-6

Tocilizumab (anti-IL-6R), sarilumab - block classical and trans-signalling

3. JAK-STAT (targeted synthetic, oral)

Tofacitinib (JAK1/3), baricitinib (JAK1/2), upadacitinib (JAK1)
Block cytokine receptor signal transduction for IL-6, IFN, GM-CSF, common gamma-chain cytokines

4. B cells

Rituximab - anti-CD20, depletes pre-B to memory B cells; spares plasma cells (CD20-negative)

5. T-cell costimulation

Abatacept - CTLA-4-Ig fusion; binds CD80/86 -> blocks signal 2 (CD28) -> anergy

Agent	Target	Signature risk
TNF inhibitors	TNF-alpha	TB reactivation, HBV reactivation, demyelination, drug-induced lupus, worsens heart failure
Tocilizumab	IL-6R	CRP suppressed - infection masked; GI perforation, dec neutrophils, inc lipids, inc ALT
JAK inhibitors	JAK1/2/3	Herpes zoster, VTE/PE, dec neutrophils/lymphocytes, inc lipids, inc NMSC
Rituximab	CD20	Hypogammaglobulinaemia, HBV reactivation, PML, blunted vaccine response
Abatacept	CD80/86	Mildest infection profile; avoid in COPD

Screen before any biologic: TB (IGRA/Quantiferon + CXR), HBsAg and anti-HBc, HCV, HIV, varicella serology
- Live vaccines are contraindicated on therapy - give zoster and other live vaccines 4 weeks before
2025 EULAR update - JAK inhibitors carry a clear excess of herpes zoster and VTE/pulmonary embolism vs biologics, but no consistent excess of MI/stroke overall
- Caution over age 65, smokers, prior malignancy or VTE
Tocilizumab normalises CRP and ESR regardless of infection - use clinical assessment and procalcitonin
Rituximab -> check immunoglobulins before each cycle; vaccinate before, response is lost for 6+ months
MTX co-prescription reduces anti-drug antibodies, especially with infliximab

Sequence: MTX (+/- steroid bridge) -> add a bDMARD or tsDMARD after failure of csDMARD with poor prognostic factors
Choose by comorbidity, not by potency
- Interstitial lung disease -> abatacept or rituximab preferred over TNFi
- Prior lymphoma -> rituximab
- Heart failure -> avoid TNF inhibitors
- Demyelinating disease -> avoid TNF inhibitors
- Pregnancy -> certolizumab (no Fc transfer); avoid JAK inhibitors, MTX, leflunomide
- Recurrent zoster or VTE -> avoid JAK inhibitors
Anti-TNF drug-induced lupus: ANA and anti-dsDNA positivity is common, clinical lupus is rare - do not stop for serology alone
Perioperative: withhold biologics for one dosing interval, resume at wound healing

Immunosuppressant mechanisms of action; corticosteroid potency
Monoclonal antibody nomenclature and target identification
Infection patterns by immunodeficiency type - TB, PJP, HBV reactivation
Anti-IgE and anti-cytokine biologics in asthma
Immune checkpoint inhibitors - abatacept is CTLA-4 agonism, ipilimumab its blockade

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