18.2 DMARDs, Biologics & Their Toxicities
Key Takeaways
- Methotrexate is given weekly with folic acid; co-prescription with trimethoprim or co-trimoxazole can cause fatal pancytopenia.
- All patients must be screened for latent tuberculosis and hepatitis B before starting a TNF inhibitor, which can reactivate both.
- Hydroxychloroquine requires baseline and annual retinopathy screening; sulfasalazine causes reversible oligospermia and orange discolouration of body fluids.
5. RA Pharmacotherapy: csDMARDs, Biologics & Crucial Toxicities
Modern UK (NICE NG100) guidelines mandate a "treat-to-target" strategy, initiating conventional synthetic DMARD (csDMARD) monotherapy or step-up combination therapy immediately upon diagnosis to arrest joint erosion.
Stepwise Pharmacotherapy in Rheumatoid Arthritis
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1. First-Line csDMARD 2. Biologic / tsDMARD
- Methotrexate (once weekly) - Criteria: DAS28 > 5.1
+ Folic Acid (5 mg weekly) despite >= 2 csDMARDs
- Alternatives: Sulfasalazine, - First-Line: Anti-TNF
Leflunomide, Hydroxychloroquine (Adalimumab, Infliximab)
- Screening: Latent TB (IGRA)
and Hepatitis B/C
- Alternatives: Rituximab,
Tocilizumab, JAK inhibitors
Conventional Synthetic DMARDs (csDMARDs)
- Methotrexate (MTX): The gold-standard anchor csDMARD. Inhibits dihydrofolate reductase (DHFR) and aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, promoting intracellular accumulation of adenosine, a potent endogenous anti-inflammatory mediator.
- Dosing Safety: Must be prescribed ONCE WEEKLY (never daily; accidental daily dosing causes fatal bone marrow aplasia and mucositis).
- Co-Prescription: Prescribe with folic acid (e.g. 5 mg once weekly), taken on a day other than the methotrexate dose, to minimize gastrointestinal upset, stomatitis, and transaminitis.
- Toxicities: Myelosuppression (leukopenia, thrombocytopenia), hepatotoxicity (transaminitis, hepatic fibrosis; monitored with LFTs), acute hypersensitivity pneumonitis (dry cough, dyspnoea, fever, bilateral diffuse ground-glass infiltrates; requires immediate permanent discontinuation), stomatitis, and teratogenicity (must be discontinued >= 3 months prior to planned conception in women and men).
- Critical Drug Interactions:
- Co-trimoxazole / Trimethoprim: Concomitant use precipitates fatal bone marrow aplasia and pancytopenia through dual mechanisms—synergistic inhibition of the folate biosynthetic pathway and competitive displacement/inhibition of renal tubular excretion of methotrexate.
- NSAIDs & Aspirin: High-dose NSAIDs inhibit renal prostaglandin-mediated perfusion and compete for renal organic anion transporters, reducing methotrexate excretion and raising serum levels.
- Leflunomide: Inhibits dihydroorotate dehydrogenase (DHODH), blocking de novo pyrimidine synthesis in proliferating activated lymphocytes. Adverse effects include hepatotoxicity, hypertension, diarrhoea, peripheral neuropathy, and teratogenicity. Has an exceptionally long enterohepatic circulation half-life (~2 weeks); in acute toxicity or pregnancy planning, accelerated drug elimination via cholestyramine washout (8 g three times daily for 11 days) is required.
- Sulfasalazine: Cleaved by colonic bacterial azoreductases into 5-aminosalicylic acid (5-ASA) and sulfapyridine (the active moiety in RA). Adverse effects include reversible male oligospermia, agranulocytosis, haemolysis in G6PD deficiency, and bright yellow/orange discoloration of urine and contact lenses. It is considered safe during pregnancy.
- Hydroxychloroquine: Antimalarial that inhibits lysosomal acidification and toll-like receptor signaling in antigen-presenting cells. Does not cause myelosuppression or hepatotoxicity, making it an excellent combination agent. Toxicity: Retinal toxicity with irreversible macular depigmentation ("bull's-eye" maculopathy). UK guidelines mandate a baseline ophthalmological examination (optical coherence tomography [OCT] and fundus autofluorescence) within 12 months of initiation and annual screening after 5 years of continuous therapy. Safe in pregnancy.
Biologic DMARDs (bDMARDs) & Targeted Synthetic DMARDs (tsDMARDs)
Indicated under NICE criteria for patients with severe active disease (DAS28 > 5.1) despite an adequate trial of at least two csDMARDs (including methotrexate at optimal dose):
- TNF-α Inhibitors: Infliximab (chimeric IgG1 mAb), adalimumab (recombinant human mAb), certolizumab pegol (pegylated Fab fragment; does not cross placenta, safe throughout pregnancy), golimumab, and etanercept (soluble recombinant TNF receptor-Fc fusion protein).
- Mandatory Pre-Treatment Screening: TNF-α is crucial for phagosomal maturation and granuloma maintenance within macrophages. Anti-TNF agents cause rapid dissolution of tuberculous granulomas; therefore, screening for latent tuberculosis with an Interferon-Gamma Release Assay (IGRA / QuantiFERON) and a plain chest radiograph is mandatory before therapy. Positive latent TB mandates chemoprophylaxis (e.g. 3 months of rifampicin/isoniazid) before biologic initiation. Screening for Hepatitis B and C is also required.
- Contraindications: Active serious infection, moderate-to-severe congestive heart failure (NYHA Class III/IV), demyelinating disease (multiple sclerosis, optic neuritis).
- Anti-CD20 Monoclonal Antibody (Rituximab): B-cell depleting antibody indicated for severe active seropositive RA refractory to anti-TNF agents. Administered as two 1,000 mg intravenous infusions two weeks apart. Hepatitis B serology must be checked prior to initiation due to risk of fatal fulminant hepatic reactivation.
- Anti-IL-6 Receptor Antagonists (Tocilizumab, Sarilumab): Directly block IL-6 signaling. Key clinical pearl: Tocilizumab directly suppresses hepatic CRP synthesis; CRP levels remain falsely normal or near-zero even during life-threatening bacterial infections or acute gastrointestinal perforation (increased risk of lower bowel perforation in patients with diverticular disease).
- Janus Kinase (JAK) Inhibitors (tsDMARDs): Oral small molecules (tofacitinib, baricitinib, upadacitinib, filgotinib) targeting JAK1/JAK2/JAK3/TYK2 signaling. Carries increased risk of herpes zoster reactivation (shingles prophylaxis recommended). MHRA and EMA safety alerts highlight an increased risk of venous thromboembolism (DVT/PE), major adverse cardiovascular events (MACE), and malignancy in patients >= 65 years, active smokers, or those with cardiovascular risk factors.
Biologic and Targeted Synthetic Classes
| Class | Examples | Distinguishing point |
|---|---|---|
| TNF inhibitors | Infliximab, adalimumab, etanercept, golimumab, certolizumab | Reactivate latent tuberculosis and hepatitis B; etanercept is a receptor fusion protein and is the least effective in granulomatous disease |
| Anti-CD20 | Rituximab | Depletes B cells; causes hypogammaglobulinaemia and late-onset neutropenia; screen for hepatitis B |
| IL-6 receptor blockade | Tocilizumab, sarilumab | Suppresses CRP, so CRP becomes useless as an infection marker; risk of lower gastrointestinal perforation, especially with diverticular disease |
| T-cell co-stimulation blockade | Abatacept | Lower infection risk profile |
| JAK inhibitors (targeted synthetic) | Baricitinib, tofacitinib, upadacitinib | Venous thromboembolism, herpes zoster, and increased major cardiovascular events and malignancy in older smokers |
| IL-17 / IL-23 | Secukinumab, ustekinumab, guselkumab | Used in psoriatic disease; IL-17 agents can worsen inflammatory bowel disease |
The single most examinable safety point across the group is screening before initiation: latent tuberculosis (interferon-gamma release assay or tuberculin test plus chest radiograph), hepatitis B and C, HIV, and varicella immunity.
Vaccination and Pregnancy
Live vaccines are contraindicated in patients on biologics or on significant immunosuppression — this includes yellow fever, live shingles vaccine, MMR and BCG. Inactivated influenza, pneumococcal and COVID-19 vaccines are recommended, ideally two weeks before starting therapy.
In pregnancy the rules are specific and frequently tested:
- Methotrexate and leflunomide are teratogenic and absolutely contraindicated. Methotrexate should be stopped at least three months before conception in both women and men; leflunomide requires a cholestyramine washout because of its very long half-life.
- Hydroxychloroquine, sulfasalazine (with folic acid) and azathioprine are the DMARDs generally continued in pregnancy.
- Mycophenolate mofetil is teratogenic and must be switched, usually to azathioprine, before conception.
- Cyclophosphamide causes premature ovarian failure and infertility; fertility preservation should be discussed before use in young patients.
Corticosteroid Stewardship
Corticosteroids remain a bridging therapy, not a maintenance strategy. Any patient expected to receive prednisolone 7.5 mg daily or more for three months or longer needs bone protection assessment, and prolonged therapy requires gastroprotection where NSAIDs are co-prescribed, glycaemic monitoring, and clear sick-day rules against adrenal crisis.
A 54-year-old woman with a 6-year history of erosive rheumatoid arthritis attends the acute medical take with severe malaise, painful oral ulceration, and a low-grade fever. Her current medications include oral methotrexate 20 mg once weekly, folic acid 5 mg once weekly, and paracetamol as required. Three days ago, her general practitioner prescribed an oral antibiotic for an uncomplicated urinary tract infection. On examination, she appears pale and toxic with extensive necrotic mucosal ulceration over her tongue and buccal mucosa. Vital signs show blood pressure 104/62 mmHg, heart rate 108 beats/min, and temperature 38.3 °C. Urgent blood investigations demonstrate: Haemoglobin 78 g/L, White cell count 0.9 x 10^9/L (neutrophils 0.2 x 10^9/L), Platelets 28 x 10^9/L, Serum creatinine 148 umol/L (baseline was 68 umol/L 2 months ago), ALT 112 U/L. Which antimicrobial co-prescription is the most likely cause of this patient's acute presentation?