Service of Rheumatology, 1 Cardiology and 2 Clinical Pharmacology, Hospital Universitario Marqués de Valdecilla, Facultad de Medicina, Universidad de Cantabria, Santander, Spain
Correspondence to: V. Rodríguez-Valverde, Rheumatology Service, Hospital Universitario "Marqués de Valdecilla", Avda. Valdecilla s/n, 39008 Santander, Spain. E-mail: rodriguv{at}unican.es
SIR, Leflunomide (LFN) is a disease-modifying anti-rheumatic drug that reduces the signs and symptoms of rheumatoid arthritis (RA) and delays the radiological progression of the disease [1, 2]. The most common adverse reactions leading to LFN withdrawal are gastrointestinal symptoms, skin reactions, alopecia, systemic arterial hypertension and elevated liver enzymes. Although a small percentage of patients with RA develop systemic arterial hypertension while taking LFN, no other serious cardiovascular adverse reactions have been reported [3].
Here we report one patient with severe refractory RA treated with LFN who developed pulmonary hypertension (PH) while on therapy with this drug. To the best of our knowledge this side-effect has not been previously reported. The study was approved by the Local Ethical Committee, and the patient gave written informed consent.
A 70-yr-old woman with a 13-yr history of seropositive erosive RA [4], had been previously treated with seven different DMARDs that were discontinued because of inefficacy or side-effects. In November 2000 the patient developed a deep venous thrombosis of the left leg and a pulmonary thromboembolism. Despite appropriate anticoagulation, in December 2000 she suffered another episode of pulmonary thromboembolism and a vena cava filter (Greenfield) was placed together with continuous dicumarin therapy.
In November 2000, LFN was begun at 20 mg/day with marked improvement in the joint symptoms. In May 2002, the patient was admitted because of a 4-month history of severe and persistent dyspnoea at rest. The physical examination showed a dyspnoeic patient with mild peripheral cyanosis, an accentuated second heart sound and distal pitting oedema in the lower extremities. At the time of admission she had an INR of 2.6. A ventilation/perfusion scan and a helicoidal CT showed no evidence of pulmonary thromboembolism. A cardiac MRI eliminated the possibility of constrictive pericarditis. The echocardiogram showed a mild left ventricular hypertrophy with normal systolic function and delayed relaxation. The right ventricle was hypertrophied with preserved size and systolic function. A mild tricuspid regurgitation allowed a calculating systolic right ventricularatrial pressure gradient of 45 mmHg.
LFN was withdrawn, and to hasten the elimination of LFN she was discharged on treatment with cholestyramine 8 g three times a day for 11 days. One month later, when she was seen at the out-patient clinic, the dyspnoea at rest, peripheral cyanosis and oedema of the lower extremities had resolved. In October 2002 a new echocardiogram showed similar left and right cavities. There was no tricuspid regurgitation. Right ventricular outflow tract flow was of type I, indicating a pulmonary vascular resistance within the normal range.
We have described a patient with RA who developed severe PH while on treatment with LFN, with rapid and lasting improvement after withdrawal of LFN and specific treatment of possible LFN toxicity, with cholestyramine. In order to assess the likelihood of a causal connection between an environmental exposure and an adverse event we followed the criteria proposed by Miller et al. [5]. Three of the primary elements support a true association between LFN and PH in this patient. Regarding the temporal relationship, the interval between the onset of LFN therapy and the onset of the PH was approximately 13 months. During this time, no other modifications were made to her previous treatment. In this regard, other cases of PH following the use of drugs such as appetite-suppressant agents occurred with exposure times ranging between 3 and 61 months [6]. When we searched for likely alternative explanations, we thoroughly excluded other causes of dyspnoea and we did not find reports of PH associated with her other concomitant medications. Dechallenge, or discontinuation of LFN in this patient, resulted in complete and lasting resolution of her symptoms, accompanied by a normalization of the echocardiographic abnormalities. Furthermore, she has remained clinically stable for over 17 months after discontinuation of LFN therapy. Due to the severity of the symptoms and the poor prognosis of PH [7] a rechallenge with the drug was not considered. Biological plausibility in the case of LFN is somehow difficult to assess. In fact, we should notice that there is no reasonable explanation for systemic arterial hypertension, which is a relatively frequent cardiovascular adverse effect of LFN therapy.
Chronic PH has been reported in association with several drugs [6]. It has been reported that use of appetite-suppressant drugs was associated with the development of PH [8]. It is interesting to notice that a small percentage of patients on treatment with LFN develop unexplained, and usually severe, weight loss [9]. The mechanism for this side-effect is unknown. Whether or not there could be a common underlying mechanism between the PH developed in our patient while on LFN therapy and the PH produced by anorexic drugs remains to be clarified.
Due to her previous history, the initial clinical suspicion was a new thromboembolic event. However, all the studies done ruled out this possibility and excluded other causes of dyspnoea as well. The complete clinical and echocardiographic resolution of the PH after LFN withdrawal strongly supports the possibility of a drug-induced adverse reaction. It is important to note that she had recurrent pulmonary thromboembolisms. Although her clinical condition was stable for the last year, it is tempting to speculate that a previous pulmonary arterial involvement, although by a different cause, could predispose this patient to the development of severe PH after institution of LFN therapy.
The authors have declared no conflicts of interest.
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