Ticlopidine induces lupus in a haemodialysis patient

Sir,

It is widely believed that patients on dialysis are immunocompromised and less commonly afflicted by autoimmune diseases. However, in our dialysis units we often encounter patients with allergies to particular drugs. Ticlopidine hydrochloride is a platelet aggregation inhibitor, which has been shown to reduce the risk of thrombotic strokes and also is used in the treatment of claudication and in patients with cardiac stents [1]. Its uncommon but serious adverse effects are neutropenia, aplastic anaemia, thrombotic thrombocytopenic purpura and cholestatic hepatitis – the latter two being thought to be due to autoimmune mechanisms [2]. Recently, cases of lupus induced by ticlopidine were reported [3]. In this letter we, too, describe a haemodialysis (HD) patient who suffered from ticlopidine-induced lupus.

Case. A 55-year-old male visited our hospital in November 2002, because of mild fever (~37.5°C) and chronic arthralgias of hands, shoulders and knees bilaterally, without signs of arthritis. He had started HD in a local HD unit in 1995 due to an advanced chronic glomerulonephritis of unknown type (which was unlikely lupus nephritis, because of a lack of anti-nuclear antibodies). His medications were allopurinol 100 mg, ranitidine hydrochloride 150 mg, CaCO3 3.0 g and ticlopidine 200 mg. His nutritional state was good and his uraemia was well controlled by HD. In the middle of October 2002, he had started to have pain in multiple joints and fever up to 37.5°C in the evenings. Oral antibiotics (clarithromycin and ciprofloxacin) were not effective and, therefore, the intermittent use of a non-steroidal anti-inflammatory drug, loxoprofen, became necessary. His pre-dialysis laboratory tests at our outpatient clinic showed 9000/µl white cells with 80% neutrophils, haemoglobin 10.5 g/dl, haematocrit 35%, platelets 290 000/µl, blood urea 80 mg/dl, serum creatinine 10.91 mg/dl, albumin 4.0 g/dl, total cholesterol 210 mg/dl, GOT 8 IU/l, GPT 10 IU/l, total bilirubin 0.9 mg/dl, calcium 9.0 mg/dl, inorganic phosphate 5.6 mg/dl and C-reactive protein 11.7 mg/dl. His physical examination revealed no specific findings, except for bilateral joint tenderness in the hands, shoulders and knees. Chest X-ray and echocardiography were normal. Joint X-rays suggested early dialysis-related osteodystrophy, but neither showed abnormal calcification nor destructive arthritis. Blood cultures and galium scintigraphy were negative. Serum intact parathyroid hormone was 202 pg/ml, suggesting slight hyperparathyroidism. His serology tests showed 1615 mg/dl immunoglobulin G (IgG), 46 mg/dl IgM, 286 mg/dl IgA, 101 mg/dl C3, 25 mg/dl C4, 33.6 anti-nuclear antibody by enzyme immunoassay (ANA-EIA; normal <20), 26.3 IU/ml IgG class anti-double-stranded DNA antibody (anti-dsDNA; normal <10 IU/ml) and ++ positivity for anti-histone antibody (normal being negative). All of these findings suggested drug-induced lupus.

Comment. Allopurinol, ranitidine, loxoprofen, clarithromycin and ciprofloxacin each sometimes induce allergic dermatitis and bone marrow suppression, but except for ticlopidine none of the medications prescribed to this patient have been implicated in lupus [3–5]. Therefore, although a lymphocyte drug stimulation test was negative, ticlopidine was suspected to be the causative drug and it was stopped immediately. During the following weeks, along with decreases in the serum levels of C-reactive protein, ANA-EIA and anti-dsDNA antibody, fever and arthralgia gradually subsided.

The release of free circulating DNA has been shown during HD and it has been claimed that antibodies are formed against native DNA and other nuclear antigens in HD patients [6], which might lead to de novo lupus-like syndromes in HD patients. Alternatively, a number of drugs are able to induce a lupus-like syndrome [4]. The real frequency of drug-induced lupus in HD patients remains unknown. Ticlopidine clearance is decreased in patients with renal dysfunction [7], which may have been the pathogenesis of lupus in this patient. In addition, there is a genetic predisposition determined by drug acetylation rates [4]. Individuals with a mutation of the N-acetyltransferase-2 gene have an impaired enzyme function and, thus, are slow acetylators. They have been reported to have a higher incidence of drug-induced lupus. Unfortunately, so far it is uncertain whether drug acetylation in HD patients is slow or normal [8].

It is of interest that our patient took 7 months to manifest symptoms after first exposure to ticlopidine (March 2002). In addition, in contrast to rapid decreases in the serum levels of C-reactive protein, ANA-EIA and anti-dsDNA, his anti-histone antibodies remained high for nearly 1 year after ticlopidine withdrawal (Table 1). Spiera et al. [3] reported four cases with ticlopidine-induced lupus. The intervals between exposure to the drug and the development of symptoms and clinical signs were >1 year in these patients. All four patients were positive for anti-histone antibodies and in two of them anti-histone antibodies remained detectable for >9 months after drug withdrawal. The experience with the present patient and the information in the literature lead us to the notion that when we meet HD patients with de novo lupus-like syndromes, we should suspect ticlopidine and other drugs, even those that patients have been using for years. In such circumstances, the detection of anti-histone antibodies seems useful for diagnosing drug-induced lupus, but their titres are unlikely to parallel clinical improvement.


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Table 1. Changes in C-reactive protein and autoantibodies

 
Conflict of interest statement. None declared.

Hirokazu Okada, Tomohiro Kikuta, Yusuke Watanabe, Yoshihiko Kanno, Souichi Sugahara and Hiromichi Suzuki

Department of Nephrology Saitama Medical College Saitama Japan Email: iromichi{at}saitama-med.ac.jp

References

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  3. Spiera RF, Berman RS, Werner AJ, Spiera H. Ticlopidine-induced lupus. Arch Intern Med 2002; 162: 2240–2243[Abstract/Free Full Text]
  4. Vergne P, Bertin P, Bonnet C, Scotto C, Treves R. Drug-induced rheumatic disorders: incidence, prevention and management. Drug Safety 2000; 23: 279–293[ISI][Medline]
  5. Knowles SR, Shapiro LE, Shear NH. Reactive metabolites and adverse drug reactions: clinical considerations. Clin Rev Allergy Immunol 2003; 24: 229–238[CrossRef][ISI][Medline]
  6. Nolph KD, Husted FC, Sharp GC, Siemensen A. Antibodies to nuclear antigens in patients undergoing long-term haemodialysis. Am J Med 1976; 60: 673–676[CrossRef][ISI][Medline]
  7. Buur T, Larsson R, Berglund U, Donat F, Tronquet C. Pharmacokinetics and effect of ticlopidine on platelet aggregation in subjects with normal and impaired renal function. J Clin Pharmacol 1997; 37: 108–115[Abstract/Free Full Text]
  8. Drayer DE, Lowenthall DT, Woosley RL et al. Cumulation of N-acetyl procainamide, an active metabolite of procainamide in patients with impaired renal function. Clin Pharmacol Ther 1977; 22: 63–69[ISI][Medline]




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