Reappraisal of the clinical use of leflunomide in rheumatoid arthritis and psoriatic arthritis

Figures & data

Figure 1 Range of American College of Rheumatology responder rates from different clinical studies of leflunomide. Data at six months and one year are taken from double-blind randomized placebo and active comparator-controlled clinical trials.^8,24,25 Patients completing 12 months were re-enrolled to a year 2 cohort and remained blinded to treatment allocation.^33–35 Those completing two years were eligible to enroll in an open-label, non-controlled extension study to complete five years of treatment.³⁷

Figure 2 Sustained DAS28 response over time for leflunomide 20 mg daily following a loading dose of 100 mg daily for three days (percentage of patients with a response maintained to 24 weeks). Data from the RELIEF study.⁵¹

Abbreviation: DAS 28, Disease Activity Score 28 joint count.

Figure 3 Quality of life changes in randomized controlled trials of LEF versus MTX over two years assessed by Medical Outcomes Survey Short Form 36 (SF-36). Vertical bars show baseline and 24-month data for each domain of the SF-36, dashed horizontal lines show US population norms.¹⁴³

Abbreviations: LEF, leflunomide, MTX, methotrexate.

Figure 4 American College of Rheumatology response rates for combination therapy of leflunomide plus methotrexate versus methotrexate plus placebo.⁴⁹

Abbreviations: MTX, methotrexate; PBO, placebo; LEF, leflunomide.

Figure 5 Change in quality of life occurring over time by treatment allocation with biologic DMARDs in combination with methotrexate or leflunomide.⁷⁶

Abbreviations: ADA, adalimumab; ETN, etanercept; INF, infliximab; LEF, leflunomide; MTX, methotrexate; MCID, minimum clinically important difference;⁷⁷ mHAQ, modified Health Assessment Questionnaire; DMARDs, disease-modifying antirheumatic drugs.

Table 1 Management strategies for side effects of leflunomide

	Diarrhea	Alopecia	Liver enzymes	Hypertension	Skin rash	Cytopenia
Occurrence	24% in trials, withdrawals 2.2%.^Citation12	14% in trials, withdrawals 1%. Usually mild and transient.	5%–10% had rises in transaminases. Most common in first 6 months. No cumulative effect or cirrhosis reported.	Occurs in up to 10% usually in known hypertensives or with NSAID use. New onset hypertension 1.6%, equal to placebo in trials. Sudden rise in BP has been reported.	12% in trials, discontinuation 1%.^Citation12 SJS and TEN occur.	These occur but are rare with monotherapy.
Prediction	Patients with loose bowel motions more likely to be affected.	No predisposing factors identified. Ask patient how acceptable hair fall would be.	Avoid in patients with pre-existing liver disease. Caution with patients who have had liver toxicity with other drugs.	Measure blood pressure at baseline. Record history of hypertension and treatment. Record all drugs that may elevate blood pressure.	Ask about allergy, in particular any past cutaneous reactions to drugs.	Baseline CBC to assess significance of any fall on treatment.
Prevention	Avoid loading dose, start at 10 mg/day or 10 mg alternate days.	Avoid loading dose.	Screen for hepatitis B and C, pretreatment liver enzymes. Monitor patients on therapy. Advise against alcohol use.	Monitor blood pressure while on treatment. Avoid use in uncontrolled hypertension.	Caution in patients with prior history of cutaneous reactions to drugs	CBC every 2–4 weeks for first 3 months, every 8–12 weeks thereafter. Caution in combination with methotrexate or if there is a history of drug induced cytopenia
Management	Mild/moderate: reduce dose or frequency. Moderate: use antidiarrheal agent short term. Severe: stop drug for 1–2 weeks	Reduce dose or frequency. Discontinue if severe.	For persistent transaminase rise <2 × ULN reduce dose. Discontinue treatment and consider washout for more significant rises.^Citation98	Mild rise (SBP > 140 < 170 mmHg or DBP > 90 mmHg <110 mmHg): reduce dose. Very high BP (SBP > 170 mmHg, DBP > 110 mmHg): discontinue	Mild: continue and use antihistamines Moderate: stop temporarily Severe: discontinue and give washout (anaphylaxis, bullous reactions, purpura, mucosal lesions, fever)	Evaluate for possible causes. Look for signs of infection. Mild changes: observe or reduce dose. Moderate falls: temporarily withhold treatment. Severe cases (neutrophil count <1.0 × 10^9/L) discontinue and use washout.
Education	Tell patients about risk of diarrhea, manage expectations.	Discuss with patient sensitively. Emphasize reversibility of condition.	Discuss alcohol use. Emphasize importance of regular blood test monitoring.	Advise patients of the need to have blood pressure checked while on treatment (eg, at GP or nurse clinic).	Tell patients about risk of rashes.

Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; SJS, Stevens Johnson Syndrome; TEN, toxic epidermal necrolysis; CBC, complete blood count; GP, general practitioner.

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