Hydroxychloroquine, sulfasalazine and leflunomide

01Purpose and principlesWhat the treatment does and how it fits into care.

These conventional DMARDs are not interchangeable weaker versions of methotrexate. Hydroxychloroquine changes lysosomal and toll-like-receptor signalling and is especially valuable in systemic lupus erythematosus. Sulfasalazine is cleaved in the colon into sulfapyridine and 5-aminosalicylic acid and has systemic immunomodulatory effects in inflammatory arthritis. Leflunomide inhibits dihydro-orotate dehydrogenase, limiting pyrimidine synthesis in activated lymphocytes and providing a more potent alternative for rheumatoid or psoriatic arthritis.

The ophthalmic pathway uses spectral-domain optical coherence tomography and fundus autofluorescence, with visual-field testing directed by structural abnormalities. One abnormal test produces possible toxicity and should be repeated or investigated, while concordant abnormalities support definite toxicity and usually prompt rheumatology and ophthalmology discussion about stopping. Patients should continue treatment until the prescriber and eye team review uncertain findings because abrupt withdrawal can destabilise lupus.

Hydroxychloroquine has other rare but important toxicities. It can prolong QT, cause conduction disease or cardiomyopathy, lower glucose and produce myopathy or neuromyopathy. Review interacting QT-prolonging medicines, structural heart disease, syncope and renal impairment; obtain ECG or cardiac testing when clinical risk or symptoms justify it rather than screening every low-risk patient indiscriminately.

Sulfasalazine can cause leukopenia, agranulocytosis, thrombocytopenia, hepatitis, severe cutaneous reactions and haemolysis. Check sulfonamide or salicylate allergy, FBC, liver and renal function and G6PD status when ethnicity, history or local policy suggests risk. Warn that urine, sweat or soft contact lenses can become orange-yellow. Male oligospermia is usually reversible two to three months after withdrawal and should be discussed when conception is delayed.

Sulfasalazine is compatible with pregnancy and breastfeeding in most circumstances. Because it inhibits folate absorption and metabolism, BSR recommends folic acid 5 mg daily during periconception and the first trimester. Avoid breastfeeding a premature, jaundiced, unwell or G6PD-deficient infant without paediatric advice because sulfonamide exposure and bilirubin displacement are more relevant.

Before leflunomide, check FBC, liver profile, renal function, blood pressure, pregnancy and infection risk. Monitor counts, transaminases and pressure frequently during initiation and dose change, then at least every twelve weeks when stable, following shared care. Important harms are diarrhoea, hypertension, cytopenia, hepatotoxicity, serious infection, severe rash, interstitial lung disease and peripheral neuropathy. Alcohol and other hepatotoxic drugs require explicit review.

Leflunomide must be removed actively when pregnancy, severe toxicity or rapid switch to another hepatotoxic or myelotoxic drug makes persistence unsafe. Give cholestyramine 8 g three times daily or activated charcoal 50 g four times daily for 11 days. For pregnancy planning, verify plasma teriflunomide below 0.02 mg/L on two tests at least 14 days apart; if no washout is performed, the product information requires waiting two years after stopping.

Key points

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.
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.

02Indications, selection and cautionsWho may benefit, who needs urgent treatment and important alternatives.

Hydroxychloroquine retinal risk

Risk rises with daily dose above 5 mg/kg actual body weight, exposure beyond five years, eGFR below 60, tamoxifen and cumulative duration; symptoms occur late.

Hydroxychloroquine cardiac patternRed flag

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

Sulfasalazine hypersensitivityRed flag

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

Sulfasalazine marrow suppressionRed flag

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

Leflunomide liver and blood toxicity

Persistent diarrhoea, jaundice, fever, bruising, falling cell counts or rising transaminases requires interruption and consideration of accelerated elimination.

Leflunomide neuropathy

New symmetrical distal paraesthesia, sensory loss or weakness may be medicine-related, particularly with diabetes or older age, and should prompt early specialist review.

Red flags requiring action

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 leflunomide may represent peripheral neuropathy; early withdrawal improves the chance of recovery.

03Assessment before treatmentTests and checks that guide safe selection.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line shared baselineFirst stepFirst line
Why
Establish blood, liver, renal, infection and reproductive safety before selecting among the three DMARDs.
Interpretation and limitations
Obtain FBC, ALT or AST, albumin, creatinine and eGFR; add blood pressure for leflunomide, weight for hydroxychloroquine dosing, pregnancy testing and disease-directed infection screening.
02
Actual-weight hydroxychloroquine calculation
Why
Keep chronic retinal exposure at or below the recommended daily threshold.
Interpretation and limitations
Divide the prescribed milligrams by actual kilograms; if the result exceeds 5 mg/kg/day, reduce the average daily dose rather than relying on a normal eye examination.
03
RCOphth retinal monitoring
Why
Detect presymptomatic hydroxychloroquine toxicity before central vision is lost.
Interpretation and limitations
Begin annual OCT and fundus-autofluorescence monitoring after five years, or after one year with renal impairment, high daily dose or tamoxifen; confirm suspected toxicity with the programme's multimodal algorithm.
04
Sulfasalazine serial FBC and organ profile
Why
Detect leukopenia, thrombocytopenia, hepatitis and renal intolerance during early treatment.
Interpretation and limitations
Monitor frequently during initiation, then reduce frequency only under the current shared-care plan; symptoms such as sore throat, ulcers or bruising require immediate testing between scheduled checks.
05
Leflunomide FBC, liver profile and pressure
Why
Identify cytopenia, hepatotoxicity and hypertension before irreversible harm.
Interpretation and limitations
Use close initiation and dose-change monitoring, then at least twelve-weekly tests when stable and low risk; increasing ALT or falling cell lines may require dose reduction, cessation and washout.
06
Teriflunomide plasma concentration
Why
Confirm adequate leflunomide elimination before planned pregnancy or after a protocol-defined severe exposure.
Interpretation and limitations
A concentration below 0.02 mg/L must be demonstrated twice at least 14 days apart; repeat washout if either measurement remains above target.
07
Symptom-directed cardiac, neurological or haemolysis tests
Why
Investigate uncommon but serious toxicities rather than relying on routine DMARD panels.
Interpretation and limitations
Use ECG, echocardiography and troponin for cardiac features; neurological examination and neurophysiology for neuropathy; and blood film, bilirubin, LDH, haptoglobin and G6PD review for haemolysis.

04Treatment approachPreparation, options, escalation and aftercare.

01Selection stepMatch medicine to disease and life planFirst stepPreferredA conventional DMARD is required and methotrexate is insufficient, unsuitable or not preferred.

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

02Hydroxychloroquine safetyDose first, then monitor retinaHydroxychloroquine is selected for expected long-term treatment.

1Calculate no more than 5 mg/kg/day from actual weight, check renal function, tamoxifen, cardiac risk and interacting medicines and explain delayed benefit.
2Refer for annual retinal monitoring after five years, or after one year if high dose, eGFR below 60 or tamoxifen increases risk.
3If retinal change is suspected, obtain multimodal confirmation and coordinate any withdrawal with rheumatology so disease control is not abandoned.

03Sulfasalazine titrationIncrease slowly with blood surveillanceSulfasalazine is selected and baseline counts and organ function permit treatment.

1Start 500 mg daily and increase by 500 mg weekly to 2 g daily in divided doses, slowing titration if gastrointestinal or neurological adverse effects emerge.
2Use serial FBC, liver and renal tests and instruct the patient to stop and seek testing for fever, sore throat, ulcers, bruising, jaundice or severe rash.
3EscalationAssess benefit after an adequate trial and consider specialist escalation up to 3 g daily only when partial response and tolerance justify it.

04Leflunomide monitoringControl exposure and blood pressureLeflunomide is chosen and pregnancy, major liver disease and uncontrolled infection have been excluded.

1Start 10–20 mg once daily, commonly without the three-day loading regimen, and check FBC, liver profile and blood pressure closely during initiation.
2Withhold for significant cytopenia, liver injury, infection, severe rash or neuropathy and decide promptly whether accelerated elimination is required.
3Use cholestyramine or activated charcoal washout for pregnancy or severe toxicity and verify plasma levels when reproductive safety depends on elimination.

05Reproductive planningPreserve control with compatible treatmentPregnancy or breastfeeding is planned or occurs during conventional-DMARD treatment.

1Continue hydroxychloroquine when clinically indicated and use sulfasalazine with folic acid 5 mg daily because disease flare can be more harmful than compatible treatment.
2Stop leflunomide and perform accelerated elimination, then confirm two teriflunomide concentrations below 0.02 mg/L before conception.
3During breastfeeding, use compatible medicines only after infant-specific review, particularly for prematurity, jaundice or G6PD risk with sulfasalazine.

05Regimens, contraindications and interactionsTreatment details and the circumstances that modify them.

Core therapy for systemic lupus erythematosus and a conventional option in mild or combination inflammatory arthritis.

Hydroxychloroquine

Give 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.

Conventional DMARD for rheumatoid and selected peripheral spondyloarthritis, including pregnancy-compatible disease control.

Sulfasalazine

Start 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.

Once-daily conventional DMARD for active rheumatoid arthritis and psoriatic arthritis when methotrexate is unsuitable or inadequate.

Leflunomide

Give 10–20 mg orally once daily; the licensed loading regimen is 100 mg once daily for three days, but it may be omitted to reduce early adverse effects.

Avoid pregnancy, breastfeeding, major liver disease, severe immunodeficiency and uncontrolled infection; monitor counts, liver, pressure, neuropathy and lung symptoms.

Interrupts enterohepatic recirculation to remove the long-lived active metabolite after pregnancy exposure, severe toxicity or a high-risk treatment switch.

Cholestyramine leflunomide washout

Give 8 g orally three times daily for 11 days; the days need not be consecutive unless rapid elimination is clinically essential, then verify teriflunomide concentration when required.

It can bind other oral medicines and cause constipation or gastrointestinal intolerance; a shortened or incomplete course may not reach the required concentration.

Alternative to cholestyramine when rapid teriflunomide removal is necessary and the patient can tolerate activated charcoal.

Activated charcoal leflunomide washout

Give 50 g orally four times daily for 11 days as the product-listed alternative accelerated-elimination procedure.

Aspiration, vomiting, constipation and binding of other medicines are important; use under specialist supervision and verify elimination where the protocol requires it.

06Complications, monitoring and follow-upAdverse effects, response and longer-term review.

For hydroxychloroquine, recalculate mg/kg actual body weight after meaningful weight loss or renal decline and verify enrolment in the correct annual retinal pathway.
Ask hydroxychloroquine users about visual change, syncope, palpitations, weakness and hypoglycaemia, while remembering that absence of visual symptoms does not exclude early retinopathy.
For sulfasalazine, track FBC, liver and renal trends closely during initiation and at the risk-adjusted stable interval; new ulcers, sore throat, rash or jaundice triggers an unscheduled test.
For leflunomide, measure FBC, transaminases, albumin, renal function and blood pressure at the shared-care frequency and review diarrhoea, infection, neuropathy and reproductive intention.
Measure disease-specific activity and function after the expected onset period, and change treatment when a tolerated regimen is ineffective rather than retaining it because monitoring is convenient.
At every transfer of care, state which medicine is active, the latest dose and result, the next test due, stop thresholds and who can authorise restart or accelerated elimination.

07Special situationsVariants, exceptions and circumstances that change the usual approach.

Retinal risk follows average daily exposure

Alternating tablet numbers across the week can keep a small adult below 5 mg/kg/day when available strengths make a fixed daily dose excessive.

Retinopathy can progress after stopping

Long tissue persistence means early detection matters and delayed progression can occur even after withdrawal.

Orange urine is usually benign

Sulfasalazine can colour urine, sweat and tears, but jaundice, dark haemolytic urine or systemic illness still requires assessment.

Male fertility effects are usually reversible

Sulfasalazine-associated oligospermia commonly improves within two to three months of stopping, allowing a planned temporary switch if conception is delayed.

Leflunomide persists through enterohepatic cycling

Stopping tablets alone may leave teriflunomide for up to two years, whereas binding resins greatly accelerate clearance.

A loading dose is not mandatory

Omitting the three-day 100 mg leflunomide load delays steady state but often improves early tolerability without losing the maintenance strategy.

08Common pitfallsFrequent interpretation and management errors.

01
Prescribing hydroxychloroquine 400 mg daily to every adult without calculating actual-body-weight exposure or revisiting it after weight loss.
02
Waiting for visual symptoms before enrolling a high-risk hydroxychloroquine user in annual retinal monitoring.
03
Calling sulfasalazine fever or rash a routine start-up effect without considering agranulocytosis or severe hypersensitivity.
04
Omitting folic acid 5 mg daily from the pregnancy plan for a patient continuing sulfasalazine.
05
Stopping leflunomide for pregnancy but not performing and verifying an accelerated-elimination procedure.
06
Restarting leflunomide after serious toxicity without accounting for persistent metabolite and the need for washout.