Clinical Immunology: Biologics, immunotherapy, checkpoint toxicity and transplant immunology

• Biologics: Monoclonal Antibodies - the Basics | Anti-TNF Therapy | Other Cytokine-targeted Biologics | B-cell, T-cell and Adhesion-targeted Therapies | JAK Inhibitors and Other Small Molecules | Practical Prescribing - Infusion Reactions, Pregnancy and Surgery
• Cancer immunotherapy: Immune Checkpoint Inhibitors | Immune-related Adverse Events - Recognition | Managing Immune-related Adverse Events | CAR-T Cells, Cytokine Release Syndrome and ICANS
• Transplant immunology: HLA Matching and Crossmatching | Transplant Rejection | Transplant Immunosuppressive Drugs | Infection and Cancer After Transplant | Stem Cell Transplant and Graft-versus-host Disease | Irradiated Blood and Transfusion-associated GVHD
• Revision: Immunotherapies at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🛡️ Biologics, immunotherapy, checkpoint toxicity and transplant immunology - page 6 of the Clinical Immunology chapter. Patients on biologics, JAK inhibitors, checkpoint inhibitors, CAR-T cells and transplant drugs now present to every ward and GP surgery. Each class has predictable infections and toxicities, and many interact with common drugs. Immune-related adverse events from checkpoint inhibitors can mimic almost any disease and can kill if missed - every acute physician needs to recognise them.
Your four questions for every patient on immune-modifying treatment: Which drug, which target, and when was the last dose? What infections and toxicities does this drug cause? Could this new problem be the drug (rejection, irAE, interaction)? Who is the specialist team - and have they been told?

Monoclonal Antibodies - the Basics

• Biologics - large protein drugs (monoclonal antibodies, fusion proteins) made in living cells; given by injection or infusion; target specific molecules (cytokines, receptors, cell-surface markers).
• Naming (traditional stems - newer drugs use a revised scheme):
  • -mab - monoclonal antibody; -ximab - chimeric (e.g. infliximab, rituximab); -zumab - humanised (tocilizumab, natalizumab); -umab - fully human (adalimumab, ustekinumab).
  • -cept - receptor–Fc fusion protein (etanercept, abatacept, aflibercept).
  • Small-molecule kinase inhibitors end in -nib (tofacitinib, ibrutinib).
• Immunogenicity - anti-drug antibodies can reduce effect or cause reactions (more with chimeric antibodies - e.g. infliximab; reduced by co-prescribing methotrexate); therapeutic drug monitoring (drug levels and antibodies) for infliximab and adalimumab in IBD.
• Half-life - long (days to weeks); effects (e.g. B-cell depletion after rituximab) can last 6–12 months.
• Biosimilars - highly similar versions of off-patent biologics (e.g. adalimumab, infliximab, rituximab biosimilars) - much cheaper; prescribe by brand name for traceability; report reactions by brand and batch.
• Monitoring - specialist-initiated, often under shared care; homecare delivery; black triangle (▼) drugs need enhanced Yellow Card reporting.

Anti-TNF Therapy

• Drugs - infliximab (IV - chimeric), adalimumab, etanercept (receptor fusion - not effective in IBD), certolizumab pegol (minimal placental transfer), golimumab.
• Uses - rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, Crohn's disease and ulcerative colitis (infliximab, adalimumab, golimumab), psoriasis, hidradenitis suppurativa, uveitis, sarcoidosis (refractory), Behçet's.
• Risks:
  • TB reactivation - often extrapulmonary or disseminated - screen and treat latent TB first.
  • Serious bacterial infections, Listeria, Legionella, fungal (histoplasmosis), HBV reactivation, VZV.
  • Demyelination (optic neuritis, MS-like) - avoid in multiple sclerosis.
  • Worsening heart failure - avoid in moderate to severe (NYHA III–IV) heart failure.
  • Drug-induced lupus (with anti-dsDNA), paradoxical psoriasis (palmoplantar pustular), vasculitis.
  • Skin cancer (non-melanoma) and possible lymphoma risk (hepatosplenic T-cell lymphoma with thiopurine combination in young men with IBD).
  • Infusion reactions (infliximab); injection site reactions.
• Hold during serious infection; restart when treated.

Other Cytokine-targeted Biologics

B-cell, T-cell and Adhesion-targeted Therapies

• Anti-CD20 - rituximab (IV), ocrelizumab, ofatumumab, obinutuzumab:
  • Uses - B-cell lymphoma and CLL, RA, ANCA vasculitis, SLE (off-label), membranous nephropathy, MS (ocrelizumab, ofatumumab), myasthenia (MuSK), ITP, autoimmune haemolysis, pemphigus, cryoglobulinaemia, IgG4-RD.
  • Risks - infusion reactions (first dose - premedicate), HBV reactivation (screen; prophylaxis if anti-HBc positive), hypogammaglobulinaemia (repeated courses), PCP, PML, late-onset neutropenia, poor vaccine responses for 6–12 months (vaccinate before), severe COVID-19.
• Anti-CD38 (daratumumab - myeloma) - interferes with blood bank crossmatch (pan-reactive antibody screen - tell the lab).
• Abatacept (CTLA-4–Ig) - blocks T-cell co-stimulation - RA, juvenile idiopathic arthritis; CTLA4 haploinsufficiency.
• Natalizumab (anti-α4 integrin) - highly effective in MS - risk of PML (stratified by JC virus antibody index, duration over 2 years and prior immunosuppression) - MRI surveillance; extended-interval dosing.
• Vedolizumab (anti-α4β7 integrin) - gut-selective - IBD - low systemic infection risk and no PML signal.
• Alemtuzumab (anti-CD52) - profound lymphocyte depletion - MS (restricted use), transplant induction - infections (listeria, CMV), secondary autoimmunity (thyroid disease in about 40%, ITP, anti-GBM disease) - monthly blood and urine monitoring for 4 years; stroke and cardiovascular events soon after infusion.
• S1P receptor modulators (fingolimod, siponimod, ozanimod) - trap lymphocytes in lymph nodes - MS, UC - bradycardia on first dose, macular oedema, VZV, PML (rare), rebound MS on stopping.
• Anti-CD3 (teplizumab) - delays type 1 diabetes onset in at-risk people (not routinely available in the UK).

JAK Inhibitors and Other Small Molecules

• JAK inhibitors - tofacitinib, baricitinib, upadacitinib, filgotinib, abrocitinib, ritlecitinib, ruxolitinib (myelofibrosis, GVHD).
  • Uses - RA, psoriatic arthritis, axial SpA, UC and Crohn's, atopic dermatitis, alopecia areata, GVHD.
  • Oral, rapid onset, no immunogenicity.
  • Risks - herpes zoster (vaccinate with Shingrix first), serious infections and TB, venous thromboembolism, major cardiovascular events and cancer (ORAL Surveillance trial), lymphopenia, neutropenia, raised lipids and CK.
  • MHRA (2023) - in people aged 65 or over, current or long-term past smokers, or with cardiovascular or cancer risk factors, use only if there is no suitable alternative; caution with VTE risk factors.
• Apremilast (PDE4 inhibitor) - psoriasis, psoriatic arthritis, Behçet's oral ulcers - diarrhoea, nausea, weight loss, depression.
• Deucravacitinib (TYK2 inhibitor) - psoriasis.
• BTK inhibitors - ibrutinib, acalabrutinib, zanubrutinib (CLL, lymphoma) - bleeding, AF, hypertension, infections; remibrutinib (chronic urticaria - emerging).
• Calcineurin inhibitors and mTOR inhibitors - see transplant drugs below; voclosporin for lupus nephritis.
• Interactions - many small molecules are CYP3A4 substrates (tofacitinib, BTK inhibitors) - check with strong inhibitors and inducers.

Practical Prescribing - Infusion Reactions, Pregnancy and Surgery

• Infusion reactions - fever, rigors, flushing, rash, hypotension, bronchospasm - usually cytokine release on the first infusion (rituximab, alemtuzumab, obinutuzumab) rather than IgE allergy:
  • Prevention - premedication (paracetamol, antihistamine, IV methylprednisolone), slower initial rates.
  • Treatment - stop or slow the infusion, treat symptoms; anaphylaxis treatment if severe; restart at a slower rate when settled if appropriate.
• Before starting - screening and vaccination (see page 3); document baseline; plan for monitoring.
• Infection while on treatment - hold biologics and JAK inhibitors during serious infection; restart after recovery (specialist advice); remember blunted fever and CRP.
• Surgery - usually hold biologics before elective surgery for about one dosing interval (BSR guidance) and restart once the wound is healing and there's no infection; continue most conventional DMARDs; don't stop steroids abruptly (peri-operative steroid cover).
• Pregnancy and breastfeeding (BSR 2022–23 guidance):
  • Most anti-TNF drugs can be continued through pregnancy when needed to control disease; certolizumab has minimal placental transfer.
  • IgG antibodies cross the placenta in the third trimester - infants exposed after about 28 weeks should not receive live vaccines (e.g. BCG, rotavirus - seek advice) until at least 6 months (12 months for some drugs).
  • Data for newer biologics are limited - individual decisions.
  • Teratogenic - methotrexate, mycophenolate, leflunomide (washout), cyclophosphamide, JAK inhibitors (avoid).
  • Most biologics are compatible with breastfeeding.
• Travel - inactivated travel vaccines only; avoid yellow fever and oral typhoid; carry letters for injectables.

Immune Checkpoint Inhibitors

• Checkpoints (CTLA-4, PD-1, PD-L1, LAG-3) normally switch off T cells to prevent autoimmunity; tumours exploit them to escape immune attack.
• Checkpoint inhibitors "take the brakes off" anti-tumour T cells:
  • Anti-PD-1 - pembrolizumab, nivolumab, cemiplimab, dostarlimab.
  • Anti-PD-L1 - atezolizumab, durvalumab, avelumab.
  • Anti-CTLA-4 - ipilimumab, tremelimumab.
  • Anti-LAG-3 - relatlimab (with nivolumab).
• Uses - melanoma, lung, kidney, bladder, head and neck, Hodgkin lymphoma, MMR-deficient (MSI-high) cancers, oesophageal, liver, cervical, triple-negative breast cancer - increasingly in early-stage (adjuvant and neoadjuvant) disease, so more patients are well and working.
• Response - durable responses in some; pseudoprogression can occur.
• Immune-related adverse events (irAEs) - immune attack on normal tissues:
  • Common - any-grade irAEs in most patients on combination ipilimumab + nivolumab; severe (grade 3–4) in about 10–20% on monotherapy and over half on combination therapy.
  • Timing - typically within the first 3–6 months, but can occur at any time, including months after stopping.
  • Risk factors - combination therapy (CTLA-4 + PD-1), pre-existing autoimmune disease.
• Patients carry an alert card - always ask about cancer immunotherapy in an unwell patient with cancer, and contact the acute oncology team.

Immune-related Adverse Events - Recognition

⚠️ Safety Pearl: In any unwell patient on (or recently on) a checkpoint inhibitor, check glucose and ketones, cortisol, TFTs, troponin, LFTs and U&E. New diarrhoea, breathlessness, fatigue with low sodium, or chest pain may be an irAE - and hypophysitis, adrenal crisis, DKA and myocarditis can be fatal within hours.

Managing Immune-related Adverse Events

• Exclude other causes - infection, disease progression, other drugs.
• Grade severity (CTCAE 1–4) and follow ESMO, ASCO or UK Acute Oncology guidance; involve acute oncology and organ specialists early.
• General approach:

  Grade	Usual management
  1 (mild)	Continue checkpoint inhibitor with close monitoring; symptomatic treatment
  2 (moderate)	Withhold; oral prednisolone 0.5–1 mg/kg/day; restart when grade 1 or better and steroid dose low
  3 (severe)	Withhold; admit; IV methylprednisolone 1–2 mg/kg/day; second-line immunosuppression if no response in 48–72 hours
  4 (life-threatening)	Permanently discontinue (usually); IV methylprednisolone (higher doses for myocarditis); critical care

• Steroid tapering - slowly over at least 4–6 weeks (faster tapers cause relapse); PCP prophylaxis, gastric and bone protection, glucose monitoring with prolonged high doses.
• Steroid-refractory disease:
  • Colitis - infliximab or vedolizumab.
  • Hepatitis - mycophenolate (avoid infliximab - hepatotoxic).
  • Myocarditis - high-dose methylprednisolone; abatacept, mycophenolate, ATG; cardiology input.
  • Pneumonitis - infliximab, mycophenolate, IVIG.
  • Neurological - IVIG or plasma exchange.
• Endocrine irAEs - usually replace hormones and continue immunotherapy:
  • Hypothyroidism - levothyroxine; thyrotoxic phase - beta-blocker.
  • Hypophysitis or adrenal insufficiency - hydrocortisone (start before levothyroxine if both are deficient, to avoid adrenal crisis); steroid sick day rules and emergency card; usually lifelong.
  • Type 1 diabetes - insulin (steroids don't help); treat DKA.
• Rechallenge - sometimes possible after resolution (multidisciplinary decision); not after severe myocarditis or neurological irAEs.

CAR-T Cells, Cytokine Release Syndrome and ICANS

• CAR-T cell therapy - the patient's T cells are genetically engineered to express a chimeric antigen receptor (e.g. against CD19 - B-cell lymphoma and ALL; BCMA - myeloma) and reinfused after lymphodepleting chemotherapy; given in specialist centres.
• Bispecific T-cell engagers (blinatumomab, teclistamab, glofitamab, epcoritamab) cause similar toxicities.
• Cytokine release syndrome (CRS):
  • Usually within the first 1–2 weeks - fever (often the first sign), hypotension, hypoxia, tachycardia, organ dysfunction; graded by ASTCT criteria.
  • Treatment - supportive care, exclude neutropenic sepsis (treat with antibiotics too), tocilizumab (IL-6 receptor blocker), steroids for higher grades or refractory CRS, vasopressors and critical care.
• Immune effector cell-associated neurotoxicity syndrome (ICANS):
  • Usually after or with CRS - confusion, expressive aphasia and dysgraphia (handwriting test), tremor, reduced consciousness, seizures, cerebral oedema.
  • Monitored with the ICE score (orientation, naming, following commands, writing, attention).
  • Treatment - dexamethasone or methylprednisolone (tocilizumab doesn't treat ICANS); seizure prophylaxis (levetiracetam); critical care.
• Other complications - prolonged cytopenias, B-cell aplasia and hypogammaglobulinaemia (immunoglobulin replacement), infections (bacterial, viral, fungal, PCP), HLH-like syndrome, tumour lysis, rare secondary T-cell malignancies.
• Practical - patients must stay near the treating centre for about 4 weeks and avoid driving for 8 weeks (neurotoxicity risk); carry an alert card.

HLA Matching and Crossmatching

• ABO compatibility is required for solid organ transplant (ABO-incompatible kidney transplant is possible with antibody removal).
• HLA typing - donor and recipient HLA-A, B, C, DR, DQ, DP.
  • Kidney - matching (especially HLA-DR) improves graft survival; national allocation scheme (NHS Blood and Transplant) balances matching, waiting time and age.
  • Liver - HLA matching less important.
  • Stem cell transplant - a close match is essential (usually 10/10 or 8/8 at HLA-A, B, C, DRB1, DQB1) to reduce GVHD and graft failure - siblings have a 1 in 4 chance of being a full match; alternatives - matched unrelated donors (Anthony Nolan, NHS registries), haploidentical family donors (with post-transplant cyclophosphamide), cord blood.
• HLA antibodies (sensitisation) - from pregnancy, blood transfusion or a previous transplant - make finding a compatible donor harder ("highly sensitised" patients wait longer).
• Crossmatching - tests for donor-specific antibodies (DSA) before transplant:
  • Virtual crossmatch - compares recipient antibodies (single-antigen bead assays) with donor HLA type.
  • Flow cytometry and complement-dependent cytotoxicity crossmatches - a positive crossmatch predicts hyperacute or early antibody-mediated rejection.
• Living donation - kidney (the best outcomes) and liver; paired or pooled exchange schemes for incompatible pairs.
• Organ donation law - "opt-out" (deemed consent) in England, Wales, Scotland and Northern Ireland, with family involvement.

Transplant Rejection

• Chronic rejection by organ - kidney (transplant glomerulopathy, interstitial fibrosis), lung (bronchiolitis obliterans syndrome), heart (cardiac allograft vasculopathy - silent ischaemia), liver (vanishing bile ducts).
• Signs of rejection - often silent - rising creatinine (kidney), raised LFTs (liver), falling FEV₁ (lung), arrhythmia or heart failure (heart); fever and graft tenderness occasionally. Biopsy confirms.
• Non-adherence is a major cause of late rejection - especially adolescents and young adults.
• Drug interactions that lower tacrolimus levels (rifampicin, carbamazepine, St John's wort) can precipitate rejection.

Transplant Immunosuppressive Drugs

• Induction - basiliximab (IL-2 receptor antibody) or anti-thymocyte globulin or alemtuzumab, with high-dose steroids.
• Maintenance - usually tacrolimus + mycophenolate ± prednisolone.
• Tacrolimus (calcineurin inhibitor):
  • Narrow therapeutic index - trough level monitoring.
  • Toxicity - nephrotoxicity, tremor, headache, PRES (posterior reversible encephalopathy), new-onset diabetes after transplant, hyperkalaemia, hypomagnesaemia, hypertension, hair loss.
  • CYP3A4 interactions - inhibitors raise levels (toxicity) - clarithromycin, erythromycin, azole antifungals (fluconazole, voriconazole, posaconazole), diltiazem, verapamil, grapefruit, some HIV drugs; inducers lower levels (rejection) - rifampicin, carbamazepine, phenytoin, St John's wort.
  • Prescribe by brand (MHRA) - immediate-release (e.g. Prograf) and prolonged-release (Advagraf, Envarsus) are not interchangeable - dosing errors have caused rejection and toxicity.
• Ciclosporin - similar to tacrolimus plus gingival hyperplasia, hirsutism, hyperuricaemia and gout; same interactions.
• Mycophenolate - diarrhoea, leucopenia, anaemia; teratogenic - MHRA pregnancy prevention (two forms of contraception for women; condoms for male patients and their partners).
• Azathioprine - check TPMT (and NUDT15); myelosuppression, hepatotoxicity, pancreatitis, skin cancer; allopurinol and febuxostat interaction - severe myelosuppression (reduce azathioprine to a quarter of the dose or avoid).
• mTOR inhibitors (sirolimus, everolimus) - poor wound healing, mouth ulcers, pneumonitis, proteinuria, hyperlipidaemia, oedema; fewer skin cancers.
• Corticosteroids - usual steroid toxicities; some protocols withdraw early.
• Belatacept (co-stimulation blocker, IV monthly) - avoids calcineurin nephrotoxicity; PTLD risk in EBV-negative recipients (contraindicated).

Infection and Cancer After Transplant

• Infection timeline (solid organ transplant):
  • First month - hospital-acquired and surgical infections (wound, line, UTI, pneumonia, C. difficile), donor-derived infection.
  • 1–6 months - opportunistic infections - CMV (highest risk if donor-positive and recipient-negative), PCP, BK virus (kidney), Listeria, Toxoplasma, TB reactivation, fungal infections, HBV and HCV reactivation.
  • After 6 months - mostly community-acquired infections; late CMV, PML, cryptococcus, PTLD.
• Prophylaxis - co-trimoxazole (PCP), valganciclovir (CMV - 3–6 months) or letermovir, or pre-emptive CMV PCR monitoring; antifungals in some.
• BK polyomavirus - BK virus nephropathy in kidney transplants (rising creatinine, viraemia) - reduce immunosuppression; haemorrhagic cystitis after stem cell transplant.
• Post-transplant lymphoproliferative disorder (PTLD) - EBV-driven B-cell proliferation to lymphoma - highest in EBV-negative recipients of EBV-positive organs, children, intensive immunosuppression (ATG, belatacept); fever, lymphadenopathy, graft dysfunction, GI symptoms - EBV PCR monitoring; reduce immunosuppression, rituximab, chemotherapy, tabelecleucel (EBV-specific T cells).
• Skin cancer - squamous cell carcinoma up to 100 times more common (azathioprine, voriconazole, sun exposure) - strict sun protection and regular skin checks; switch to an mTOR inhibitor for recurrent SCC.
• Other cancers - HPV-related (cervix, anus), Kaposi sarcoma (HHV-8), renal cell carcinoma (native kidneys) - cervical screening and vigilance.
• Other long-term problems - cardiovascular disease (leading cause of death with a functioning kidney graft), diabetes, hypertension, dyslipidaemia, CKD (calcineurin inhibitors), bone disease, gout.
• Vaccines - inactivated only after transplant; complete live vaccines (MMR, varicella) at least 4 weeks before; annual influenza, pneumococcal, COVID-19, Shingrix.

Stem Cell Transplant and Graft-versus-host Disease

• Haematopoietic stem cell transplant (HSCT):
  • Autologous (patient's own cells) - allows high-dose chemotherapy (myeloma, lymphoma); no GVHD.
  • Allogeneic (donor cells) - leukaemia, myelodysplasia, aplastic anaemia, primary immunodeficiencies, haemoglobinopathies - donor immune cells provide a graft-versus-leukaemia effect but can cause GVHD.
• Graft-versus-host disease - donor T cells attack recipient tissues:
  • Acute GVHD (usually within the first 100 days) - skin (maculopapular rash, often palms, soles and ears - can blister), liver (cholestatic jaundice), gut (profuse watery diarrhoea, abdominal pain).
  • Chronic GVHD - later; resembles autoimmune disease - lichen planus-like oral and skin changes, sclerotic skin, dry eyes and mouth (sicca), bronchiolitis obliterans, oesophageal strictures, joint contractures, cytopenias.
  • Prevention - HLA matching, methotrexate plus ciclosporin or tacrolimus, post-transplant cyclophosphamide, ATG.
  • Treatment - corticosteroids (topical for mild skin, systemic for more); steroid-refractory - ruxolitinib (JAK inhibitor), belumosudil (chronic), extracorporeal photopheresis.
• Other complications - infection (prolonged immunosuppression - CMV, adenovirus, fungal, encapsulated bacteria late - re-vaccination programme), veno-occlusive disease (sinusoidal obstruction syndrome - painful hepatomegaly, jaundice, weight gain - defibrotide), graft failure, infertility, secondary cancers, cataracts, endocrine problems.

Irradiated Blood and Transfusion-associated GVHD

• Transfusion-associated GVHD - viable donor lymphocytes in blood products engraft in a recipient who can't reject them - fever, rash, diarrhoea, hepatitis and pancytopenia (marrow failure) 1–6 weeks after transfusion - almost always fatal.
• Prevention - irradiated cellular blood products (red cells, platelets, granulocytes) for at-risk patients (BSH 2020):
  • Allogeneic and autologous stem cell transplant recipients (from conditioning; for at least 6 months - longer if GVHD or ongoing immunosuppression).
  • Purine analogue therapy (fludarabine, cladribine, bendamustine), alemtuzumab, ATG in some settings.
  • Hodgkin lymphoma (at any stage, lifelong).
  • Congenital T-cell immunodeficiency - SCID, 22q11.2 deletion (until T-cell function known), Wiskott–Aldrich.
  • CAR-T cell therapy (around collection and after infusion).
  • HLA-matched platelets and directed donations from relatives; intrauterine and neonatal exchange transfusions.
• Not needed for most patients on chemotherapy, solid organ transplants (in general), HIV or immunosuppressive drugs for autoimmune disease - check local policy.
• CMV-negative products - leucodepletion (universal in the UK) reduces CMV transmission; CMV-seronegative components are still used for intrauterine transfusions and neonates (and some protocols).
• Ensure the alert is on the record and the patient carries a card - missed irradiation is a common transfusion error (SHOT reports).

Immunotherapies at a Glance