Rheumatology Advance Access originally published online on May 22, 2006
Rheumatology 2006 45(7):918-920; doi:10.1093/rheumatology/kel130
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LETTER TO THE EDITOR |
Severe infections following leflunomide therapy for Rheumatoid Arthritis
All India Institute of Medical Sciences, Clinical Immunology and Rheumatology Service, Medicine, New Delhi, India
Correspondence to: Rahul Grover, Room No. 4076, Teaching Block, Department of Medicine, New Delhi – 110029, India. E-mail: dr_rahulgrover{at}yahoo.com
SIR, We read with great interest the report by Hocevar et al. [1] about the association of pulmonary tuberculosis with leflunomide therapy in rheumatoid arthritis (RA). We face a similar problem in our rheumatology practice. The average prevalence of all forms of tuberculosis in India is estimated to be 5.05 per thousand [2], so it is not surprising that the commonest infectious complication of disease-modifying anti-rheuumatic drug (DMARD) therapy that we see is tuberculosis (TB). We find most cases of TB in patients receiving methotrexate, a possible reflection of its use as a first-line drug in our practice. Leflunomide has fast risen in popularity as a preferred drug for combination therapy in patients with poor response to methotrexate alone. Although most of our patients tolerate it well, and respond favorably to its addition, there have been infectious complications including TB in some. What concerns us more is the severity of infections that occasionally occur while patients are receiving these therapies. We report here two patients with RA who had atypical and severe infectious complications while they were receiving leflunomide.
The first patient was a 48-yr old lady who first came to the rheumatology clinic of our institute 6 months back. She had symmetric polyarthritis for last 5 yrs and had a RF positive and erosive disease. She had not received any DMARDs previously. At presentation her Disease Activity Score 28 (DAS28) score was 6.4. She was managed with a short course of steroids (depomedrol 80 mg i.m. weekly for 4 weeks) along with oral methotrexate 10 mg weekly (titrated upwards to 20 mg weekly over 3 months for poor response). Leflunomide (20 mg daily) was added in the fourth month in view of persistent active disease. By the fifth month she had achieved a good clinical response (DAS28 = 2.6). One month later she started to have upper-abdomen pain, weakness and weight loss. Two weeks later, she developed recurrent vomiting, not associated with other gastrointestinal symptoms or fever, and severe low backache. On examination, she had only mild synovitis; however, there was marked tenderness in the region of the thoracic spine. Chest examination revealed stony dullness to percussion and decreased air entry in the left infrascapular region. The abdomen was soft without any guarding.
A chest radiograph (Fig. 1A) revealed what appeared, at first glance, to be a double left heart border. Careful reviewing suggested a large hemispherical radio-opaque shadow with its outer contour extending beyond the cardiac shadow and cutting across the left hemidiaphragm (a routine chest radiograph obtained at the start of therapy was totally normal). MRI was obtained, whose images (Fig. 1B) showed a large left-sided paravertebral abscess extending along almost the entire thoracic spine, with erosions and partial collapse of D8–D12 vertebrae. The radiological features were consistent with a diagnosis of ‘Potts spine’ with a large paraspinal abscess [3]. A pigtail catheter was inserted into the paraspinal abscess, and 500 ml of pus was drained. Smear examination did not demonstrate bacteria, mycobacterium and fungi, and cultures were sterile. The patient was started on anti-TB therapy, and at 2 months follow-up, there was significant clinical improvement.
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The second patient, a 36-yrs-old lady had seropositive and erosive RA for the past 12 yrs. Previously, she had received multiple DMARDs (methotrexate, sulfasalazine, hydroxychloroquine and myocrisin) with poor response. She was switched to monotherapy with leflunomide 20 mg once daily, to which she responded partially. Five months after starting leflunomide she presented with pain and swelling in left forearm (4 x 3 cm) and right calf (10 x 5 cm) with overlying bullous lesions. There was no fever or any other constitutional symptoms. A clinical diagnosis of pyomyositis was suspected and confirmed by ultrasound examination. Around 500 ml of pus was drained from calf muscles and 50 ml was drained from lesion in the forearm. Streptococcus pneumoniae was cultured from the pus. Leflunomide was discontinued, and pyomyositis responded to a prolonged course of antibiotics.
Infectious complications come as a part and parcel of immunosuppressive therapy. Reactivation of tuberculosis including spinal TB in patients receiving DMARDs is well described [4–6]. In the first patient, the size of paravertebral abscess and the rapidity with which it developed were unusual. Immunosuppression is a known risk factor for pyomyositis [7]. The severe and multi-focal presentation of pyomyositis in the second patient was also striking. Aggressive DMARD therapy aimed at achieving remission is fast becoming the norm in management of RA, and increased rates of infectious complications are expected. It is difficult to ascertain the relative contribution of immunomodulatory effects of leflunomide in the first case, but in the second one, evidence was more direct. This report underscores the importance of carefully assessing patients on any immunosuppressive (and not just anti-tumour necrosis factor-
drugs) for infectious complications, especially for TB, in areas of high prevalence. Clinical presentations may be unusual, and extensive lesions may appear in a short time.
References
- Hocevar A, Rozman B, Praprotnik S et al. Leflunomide-associated tuberculosis?. Rheumatology 2006;45:228–9.
[Free Full Text] - Chakraborty AK. Epidemiology of tuberculosis: current status in India. Indian J Med Res 2004;120:248–76.[Medline]
- Ledermann HP, Schweitzer ME, Morrison WB, Carrino JA. MR imaging findings in spinal infections: rules or myths?. Radiology 2003;228:506–14.
[Abstract/Free Full Text] - Binymin K, Cooper RG. Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis. Rheumatology 2001;40:341–2.
[Free Full Text] - Boerbooms AM, Kerstens PJ, van Loenhout JW, Mulder J, van de Putte LB. Infections during low-dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995;24:411–21.[CrossRef][Web of Science][Medline]
- Hernandez-Cruz B, Sifuentes-Osornio J, Ponce-de-Leon Rosales S, Ponce-de-Leon Garduno A, Diaz-Jouanen E. Mycobacterium tuberculosis infection in patients with systemic rheumatic diseases. A case-series. Clin Exp Rheumatol 1999;17:289–96.[Web of Science][Medline]
- Chauhan S, Jain S, Varma S, Chauhan SS. Tropical pyomyositis (myositis tropicans): current perspective. Postgrad Med J 2004;80:267–70.
[Abstract/Free Full Text]
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