Leflunomide-induced ILD: A rare and potentially fatal complication

Case report A 48-year-old male, a chronic smoker and a known case of hypertension, presented to the clinic with a one-year history of inflammatory polyarthritis. Clinical and lab investigations revealed: rheumatoid factor positive, anti-CCP >200 IU/ ml, ANA by immunofluorescence negative, c-reactive protein (CRP) 62 mg/l, and ESR 80 mm/hr. Baseline chest X-ray was normal with no interstitial lung disease (ILD). The disease was diagnosed as RA with disease activity score (DAS28) of 7.57. Intra-articular injection was administered to both the knee joints and was initiated with methotrexate 10 mg/week, which was increased to 15 mg/week on subsequent visit after 1 month. However, the disease activity was still high (DAS28: 5.13) even after 2 months and he had gastrointestinal intolerance to oral methotrexate. Hence methotrexate was made parenteral and leflunomide 10 mg/day was added.

After one month, the patient presented with low-grade fever, non-productive cough and breathlessness at rest of 5 days duration. He was admitted in intensive care unit and provided the support of non-invasive positivepressure ventilation. On examination, his respiratory rate was 30/minute, pulse 140/min, temp: 98.6°F, BP: 130/90 mm/Hg, oxygen saturation (SpO2) on room air was 89% and 94% with fraction of inspired oxygen (FiO2) of 70%. Chest examination revealed bilateral extensive coarse crepitations. Other system examinations were normal. Investigations revealed: hemoglobin 11.6 g%, WBC count 10270 /mm 3 and platelet count 2.3 lac/mm 3 . Renal and liver function tests were within normal limits. Arterial blood gas showed a pH of 7.36, pO2 of 52.1 mm Hg, pCO2 of 42 mm Hg and bicarbonate of 23 mmol/L. ECG was indicative of sinus tachycardia, while ECHO was normal with ejection fraction of 60%. Serum procalcitonin was normal.
Chest X-ray showed bilateral diffuse fluffy lung infiltrates. High-resolution computed tomography (HRCT) of thorax revealed bilateral ground glass opacities in all the lung fields with patchy consolidation (Fig. 1). Possibilities considered were: lower respiratory tract infection, rheumatoid arthritis associated-interstitial lung disease (RA-ILD) and drug-induced ILD. The patient was started on IV antibiotics and cholestyramine washout with 8 g three times a day for 11 days. Methotrexate and leflunomide were stopped. Infection work-up was negative (including blood and urine cultures, and H1N1). Bronchoalveolar lavage was not performed. The patient was subsequently administered with methylprednisolone injection 1 g for 3 days followed by prednisolone 0.5 mg/kg. The patient gradually improved over next 4 days and the respiratory support was removed.
He was prescribed with sulfasalazine for treating arthritis after 1 month of follow-up, as he could not afford rituximab. Repeated HRCT thorax showed near complete resolution of lung infiltrates (Fig. 2).

Discussion
Leflunomide is a pro-drug of teriflunomide (A77-1726) that acts by hindering the de novo pyrimidine synthesis by reversible inhibition of dihydroorotate dehydrogenase and tyrosine kinase. 2,3 It is a disease modifying anti-rheumatic drug used for treating RA in those who have inadequate response or contraindication to methotrexate. 4 The usual dose is 10-20 mg/d in adults. Common adverse effects include gastrointestinal (diarrhea, nausea, vomiting, oral ulcers), transaminitis, infections and hypertension. 5 Prevalence of leflunomide-induced ILD worldwide is around 0.02% and varies among different populations ranging from 0.3-0.5% in Australia to 0.4-1.1% in Japan. Genetic polymorphisms and differences in average body weight between Asians and Caucasians are possible explanations for the variation in prevalence. Leflunomide-induced ILD generally occurs after a mean duration of 13 (2-133) weeks of treatment and it is associated with a mortality rate of 20-40%. 2 Mice model studies have shown that leflunomide induces epithelial-mesenchymal transition of pulmonary epithelial cells in the presence of other fibrosis-inducing stimuli such as bleomycin. 6 Bilateral diffuse, patchy ground glass opacities or consolidation usually in upper, anterior and central fields are the most common radiologic findings. Honeycombing is seen in 14% patients. No residual changes are usually noted after recovery. 7 Diffuse alveolar damage was the most common finding on histopathology. 2,3 Factors that increase risk of ILD include: ethnicity (Japanese> Western), history of methotrexate use, pre-existing ILD (OR -8.2, 95%CI 4.6-14.4), use of a loading dose (OR-4.0, 95% CI 1.2-12.9), low body weight (<40 kg) (OR-2.9, 95% CI 1.1-7.3) and cigarette smoking (OR-3.1, 95% CI 1.7-6.0). 2, 3 Our patient was a smoker and was already on methotrexate. However, he had no pre-existing ILD and loading dose of leflunomide was not used.
Predictors of mortality are pre-existing ILD, severe hypoxemia, need for mechanical ventilation, elevated c-reactive protein, low serum albumin and persistent lymphopenia. 8 Management of leflunomide-induced ILD include drug discontinuation, cholestyramine washout and use of high-dose corticosteroids. Further use of leflunomide in the patient is contraindicated. The present case illustrates a rare and potentially fatal complication of leflunomide therapy that can be managed well, if suspected early.