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Educational draft · awaiting clinical reviewUse Rapid for revision, not patient-care decisions. Check current national and local guidance and the BNF or BNFC before acting.

Hydroxychloroquine, sulfasalazine and leflunomide

Rheumatology · UK scope · Sources checked 27 Aug 2026 · Clinical review pending

RapidFull
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Severe conventional-DMARD toxicity

Visual change, syncope or arrhythmia on hydroxychloroquine; fever, mucosal ulceration, bruising or haemolysis on sulfasalazine; or jaundice, cytopenia, severe infection, pregnancy or progressive neuropathy on leflunomide requires urgent interruption and assessment.

Action: Withhold the suspected drug, arrange syndrome-directed same-day testing and specialist advice, treat infection or cardiac instability immediately, and start accelerated leflunomide elimination when severe toxicity or pregnancy makes rapid drug removal necessary.

Synopsis

Choose and monitor hydroxychloroquine, sulfasalazine or leflunomide according to disease, time to effect and comorbidity, while preventing retinal, cardiac, marrow, hepatic, infection and reproductive harm.

  • Hydroxychloroquine is slower and less powerfully immunosuppressive than methotrexate, but is valuable in lupus and milder inflammatory arthritis and is compatible with pregnancy and breastfeeding.
  • Dose hydroxychloroquine by actual body weight and keep long-term exposure at no more than 5 mg/kg/day, usually 200–400 mg daily, to reduce retinal risk.
  • RCOphth no longer recommends routine baseline retinal testing for every new user; annual monitoring starts after five years, or after one year when risk factors such as eGFR below 60, tamoxifen or dose above 5 mg/kg/day are present.
  • Sulfasalazine commonly starts at 500 mg daily and increases by 500 mg each week to 2 g daily in divided doses; a specialist may use up to 3 g daily when response and tolerance justify it.
  • Sulfasalazine is compatible with pregnancy and breastfeeding in a healthy full-term infant; prescribe folic acid 5 mg daily during periconception and the first trimester.
  • Leflunomide is a once-daily DMARD, usually 10–20 mg, with a very long-lived active metabolite; an optional loading course often causes more adverse effects and is commonly omitted.

Key red flags

New paracentral visual disturbance, reading difficulty or colour change on hydroxychloroquine needs prompt ophthalmic assessment, although early retinal toxicity may be asymptomatic.

Syncope, palpitations, conduction change, unexplained heart failure, severe hypoglycaemia or proximal weakness may reflect hydroxychloroquine cardiac or neuromuscular toxicity.

Fever, sore throat, oral ulcers, bruising, bleeding, jaundice or severe rash during sulfasalazine or leflunomide treatment requires immediate withholding and FBC or liver assessment.

Dark urine, pallor or jaundice after sulfasalazine can indicate haemolysis, particularly with glucose-6-phosphate dehydrogenase deficiency.

Pregnancy on leflunomide requires immediate cessation, urgent specialist counselling and an accelerated-elimination procedure with verified plasma concentrations.

Progressive distal sensory loss or weakness on

Investigation priorities

01
First-line shared baselineFirst stepFirst line

Establish blood, liver, renal, infection and reproductive safety before selecting among the three DMARDs.

Management branches

Selection stepMatch medicine to disease and life plan

A conventional DMARD is required and methotrexate is insufficient, unsuitable or not preferred.

  1. Choose hydroxychloroquine for lupus or milder disease when retinal dose can be safe; choose sulfasalazine for appropriate peripheral arthritis and reproductive compatibility.
  2. Choose leflunomide for active rheumatoid or psoriatic arthritis when once-daily potent therapy fits liver, blood pressure, infection and pregnancy constraints.
  3. Record time to effect, monitoring owner, dose-escalation plan and what response or toxicity will trigger switching.

Key medicines

HydroxychloroquineGive 200–400 mg orally daily with food, keeping the long-term average at no more than 5 mg/kg actual body weight each day; use an alternating 200 mg and 400 mg schedule when needed to achieve a safe average.Monitor retinal risk and renal function; review QT-prolonging combinations, hypoglycaemia, cardiomyopathy, neuromyopathy and severe skin reactions. It is compatible with pregnancy and breastfeeding.
SulfasalazineStart 500 mg orally once daily and increase by 500 mg each week to 2 g daily in divided doses; a specialist may increase to 3 g daily when response and blood monitoring permit.Avoid severe sulfonamide or salicylate allergy; monitor cytopenia, liver injury, rash and haemolysis. Give folic acid 5 mg daily during periconception and the first trimester.
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Sources and review status8 sources · checked 27 Aug 2026 · clinical review pending+
Sources

Sources and review status

National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.

  • BSR 2025 conventional DMARD guidelineSelection, dosing, blood monitoring and adverse-effect management.
  • RCOphth hydroxychloroquine monitoring 2020 revisionDose threshold, risk factors, annual timing and multimodal retinal monitoring.
  • Hydroxychloroquine 200 mg UK product informationDose, retinal, cardiac, glucose, neuromuscular and reproductive safety.
  • Sulfasalazine 500 mg UK product informationTitration, blood dyscrasia, hypersensitivity, fertility and pregnancy information.
  • Leflunomide 20 mg UK product informationMaintenance and loading doses, contraindications and accelerated elimination.
  • BSR immunomodulatory medicines in pregnancy and breastfeedingCompatibility of hydroxychloroquine and sulfasalazine, folate and leflunomide washout.
  • SPS leflunomide monitoringInitiation, stable monitoring and action thresholds.
  • SPS sulfasalazine monitoringBlood, liver and renal schedules and toxicity actions.

Editorial contact: Doctor’s Passport editorial team. Source-check date is separate from clinical approval. Report a content problem ·

Leflunomide is incompatible with pregnancy and breastfeeding. Use cholestyramine 8 g three times daily for 11 days or activated charcoal 50 g four times daily for 11 days when accelerated elimination is required.
  • After leflunomide washout, verify plasma teriflunomide below 0.02 mg/L twice at least 14 days apart before conception or when the product protocol requires proof of elimination.
  • All three medicines need a baseline FBC, liver and renal review, but ongoing surveillance differs: hydroxychloroquine centres on retinal and dose-risk review, while sulfasalazine and leflunomide require serial blood monitoring.
  • Choose between these drugs through the disease pathway, speed and strength required, pregnancy plan, liver and renal state, eye risk, infection burden and what the patient can reliably monitor.
    • leflunomide
    may represent peripheral neuropathy; early withdrawal improves the chance of recovery.
    Hydroxychloroquine cardiac pattern

    Syncope, conduction block, QT prolongation, ventricular thickening or unexplained biventricular failure after prolonged exposure needs cardiology and drug review.

    Sulfasalazine hypersensitivity

    Fever, rash, facial swelling, lymphadenopathy, eosinophilia or organ injury can indicate a severe drug reaction and demands immediate cessation and urgent assessment.

    Sulfasalazine marrow suppression

    Sore throat, oral ulcers, bruising or infection can precede laboratory detection of leukopenia or agranulocytosis and must override the routine blood-test date.

    Content changes
    Authoring stateRapid draftClinical stateAwaiting reviewJurisdictionUnited Kingdom