Rheumatoid arthritis treatment options - common disease-modifying antirheumatic drugs (DMARDs)

What csDMARDs are

csDMARDs - conventional synthetic disease-modifying antirheumatic drugs
Defined by slowing radiographic progression, not by symptom relief
Onset is slow (6-12 weeks) - hence bridging glucocorticoid whenever one is started or changed

Drug	Mechanism
Methotrexate	Folate antagonist; anti-inflammatory effect is via adenosine release, not antifolate cytotoxicity
Leflunomide	Inhibits dihydroorotate dehydrogenase (DHODH) -> blocks de novo pyrimidine synthesis -> arrests activated T cells (which need an 8-16x increase in pyrimidine supply)
Sulfasalazine	Sulfapyridine + 5-ASA; mechanism uncertain
Hydroxychloroquine	Raises lysosomal pH, blocks antigen processing and TLR7/9 signalling
Gold, penicillamine, azathioprine, ciclosporin	Largely historical in RA

Use and response rates

Methotrexate is the anchor drug of every RA treatment strategy and the comparator in every trial
~60% of RA patients respond to leflunomide, with efficacy similar to methotrexate and sulfasalazine
~30-40% of patients remain in sustained control on a csDMARD alone and never need a biologic

Methotrexate - what it actually does in RA

Polyglutamated intracellularly -> inhibits AICAR transformylase -> accumulation of adenosine
Adenosine is the anti-inflammatory mediator - suppresses neutrophil and macrophage function
Dihydrofolate reductase inhibition explains the toxicity (mucositis, cytopenias, hepatotoxicity) but not the efficacy - which is why folic acid rescues the toxicity without abolishing the benefit**

Leflunomide - mechanism

Leflunomide

Prodrug -> active metabolite teriflunomide
DHODH inhibition -> pyrimidine depletion -> cell-cycle arrest in activated lymphocytes
Enterohepatic recirculation -> half-life ~2 weeks and detectable levels for up to 2 years

Baseline before starting

FBE, UEC, LFT
Hepatitis B and C serology, HIV
Chest X-ray (baseline for methotrexate pneumonitis and to exclude TB)
Pregnancy test and contraception discussion
Alcohol history

Monitoring

	Interval
Methotrexate, leflunomide	FBE, UEC, LFT 2-4 weekly for 3 months, then 3-monthly
Sulfasalazine	FBE, LFT monthly x3, then 3-monthly
Hydroxychloroquine	No blood monitoring required. Baseline then annual OCT + visual fields after 5 years

Withhold and investigate if: ALT >2-3x ULN, WCC <3.5, neutrophils <1.5, platelets <100
Add an interim check after any dose increase

Methotrexate

Axis: by drug, with the decision points that change prescribing.

10-25 mg ONCE WEEKLY, oral or subcutaneous
- Switch to SC if inadequate response or GI intolerance - higher and more reliable bioavailability above 15 mg
Folic acid 5 mg weekly, on a different day from the methotrexate
*Fatal errors are from daily rather than weekly dosing* - state the day of the week on every prescription
Renally cleared - avoid if eGFR <30; reduce dose in moderate impairment; dehydration or AKI precipitates pancytopenia
Relatively avoid in: mild seronegative disease, renal impairment, liver disease, high alcohol intake, significant lung disease, pregnancy planning
Interactions: trimethoprim/co-trimoxazole (additive antifolate -> pancytopenia), NSAIDs and probenecid (reduce clearance), PPIs

### Methotrexate toxicity

Common: nausea, mucositis, alopecia, fatigue ("methotrexate fog"), transaminitis, cytopenias
Hepatotoxicity
- Strong risk factors: alcohol, pre-existing liver disease, renal insufficiency
- Probable: duration >2 years, cumulative dose >1500 mg, obesity, diabetes
- *Routine liver biopsy is not required* - monitor LFTs; consider fibrosis assessment (elastography) in high-risk patients
Methotrexate pneumonitis
- Fever, dyspnoea, non-productive cough, sometimes pleuritic pain; crepitations, hypoxia, reduced DLCO
- CXR: bibasal acute interstitial/alveolar infiltrates; BAL lymphocytosis with low CD4:CD8
- Usually within the first 2 years; not dose-related
- *The key differential is opportunistic infection* - exclude it before attributing
- Management: stop methotrexate permanently, supportive care, prednisolone 60 mg for 2-4 weeks
  - Folinic acid has no proven benefit here
  - Most recover fully; death is usually from superinfection
Overdose or acute toxicity: folinic acid (leucovorin) rescue, hydration, urinary alkalinisation
Teratogenic and abortifacient - stop >=3 months before conception in women AND men; effective contraception
Lymphoproliferative disease: methotrexate-associated, often EBV-driven B-cell lymphoma that can regress on stopping the drug; RA itself carries a ~3x background lymphoma risk, so attribution is uncertain

Leflunomide

Loading dose usually omitted (diarrhoea); maintenance 10-20 mg daily
Response is relatively rapid - functional improvement and reduced joint destruction by ~3 months
Common: diarrhoea, hair loss, hypertension, weight loss, transaminitis
Rare but serious: pancytopenia, severe skin reactions (SJS/TEN), pneumonitis, peripheral neuropathy
- *Stop immediately if burning pain develops in the hands or feet*
Contraindicated: pregnancy, breastfeeding, liver disease, haematological abnormality, childbearing potential without reliable contraception
Half-life ~2 weeks with enterohepatic recirculation -> cholestyramine 8 g three times daily for 11 days as a washout
- Required before pregnancy, and for serious toxicity
- Confirm with two teriflunomide levels

Sulfasalazine

Titrate to 2-3 g daily in divided doses
The DMARD of choice in pregnancy and breastfeeding (with folic acid 5 mg daily)
Effective for peripheral arthritis in spondyloarthritis; not axial disease
Side effects: nausea, headache, rash, reversible oligospermia, orange discoloration of urine and contact lenses
Rare: agranulocytosis (first 3-6 months), hepatitis, DRESS, haemolysis in G6PD deficiency
Avoid with sulfonamide allergy

Hydroxychloroquine

200-400 mg daily; target <=5 mg/kg actual body weight/day
The safest DMARD - no marrow, renal or hepatic toxicity; safe in pregnancy and breastfeeding
Useful in mild RA, palindromic rheumatism, and as part of combination ("triple") therapy
Retinopathy is the limiting toxicity
- Risk factors: >5 mg/kg, duration >5 years, renal impairment, pre-existing maculopathy, concurrent tamoxifen
- Baseline screening, then annually from 5 years (OCT + automated visual fields)
Other: GI upset, rash, skin and hair hypopigmentation, rare cardiomyopathy and neuromyopathy
Long half-life (~40 days) - benefit takes 3-6 months

Combination

"Triple therapy" (MTX + sulfasalazine + hydroxychloroquine) is non-inferior to MTX + a TNF inhibitor in several trials and remains a reasonable, cheap option
Do not combine methotrexate with leflunomide routinely (additive hepatotoxicity)

Pregnancy summary

Compatible	Contraindicated
Hydroxychloroquine, sulfasalazine, azathioprine, ciclosporin, tacrolimus, prednisolone	Methotrexate, leflunomide, mycophenolate, cyclophosphamide, JAK inhibitors

Hydroxychloroquine should be continued through pregnancy - stopping precipitates flare

Interactions and cautions

Alcohol + methotrexate - the dominant modifiable hepatotoxicity risk
Trimethoprim + methotrexate - a recurring cause of avoidable pancytopenia
CKD + methotrexate - accumulation and marrow suppression
G6PD deficiency + sulfasalazine - haemolysis
Tamoxifen + hydroxychloroquine - retinopathy risk
Live vaccines - contraindicated on any csDMARD except hydroxychloroquine
Infection risk is modest with csDMARDs alone; concurrent glucocorticoid is the dominant driver

Response and drug survival

Response takes 6-12 weeks; assess at 3 months and change if there is no improvement, or by 6 months if the target is not met
Only a minority achieve sustained remission on a csDMARD alone - most require escalation within 6-12 months
Drug survival: methotrexate has the longest of any csDMARD; discontinuation is more often for toxicity than inefficacy
Sustained remission allows dose reduction, but complete withdrawal usually flares - keep the csDMARD when tapering a biologic
Cumulative glucocorticoid exposure, not csDMARD toxicity, remains the main long-term harm in RA

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