Melanoma and rituximab: an incidental association?

Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed.

[Characteristics of hypersensitivity syndrome to lamotrigine: review of one case reported in the Regional Center of Pharmacovigilance of Nantes]. / Caractéristiques du syndrome d'hypersensibilité à la lamotrigine: revue à partir d'un cas observé au CRPV de Nantes.

Drug-induced hypersensitivity syndrome is an uncommon but potentially life-threatening idiosyncratic drug reaction. In the literature, about five cases have been reported concerning hypersensitivity syndrome with lamotrigine. Most cases concern aromatic anticonvulsants but we report a case induced by lamotrigine which is a non aromatic anticonvulsant. A 73-year-old man was treated with lamotrigine for epilepsy due to a cerebrovascular stroke for 5 weeks. After 2 weeks with a single oral dose of 50 mg lamotrigine, the patient received 100 mg. Quickly thereafter fever, erythema and edema involving the periorbital area appeared. He was then admitted to hospital and lamotrigine was immediately discontinued. He developed acute hepatic and renal failure. During his hospital stay, he was treated with systemic and topical corticosteroids. After slow improvement, he was discharged 4 weeks later. Concerning this typical case, we review the characteristics of hypersensitivity syndrome and the different etiopathogenesis. The hypersensitivity syndrome typically develops two to six weeks after a drug is first administered, later than most other serious skin reactions. This syndrome manifests as rash, fever, tender lymphadenopathy, hepatitis and eosinophilia. The mechanism of hypersensitivity syndrome is unknown. Several theories have been proposed. The reaction is secondary to circulating antibodies or concerns toxic metabolities. On the other hand, association of human herpes virus 6 infection may play a role in the development of hypersensitivity syndrome. Hypersensitivity reactions to the aromatic antiepileptic drugs appear to have an immune etiology much like lamotrigine: bioactivation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. Another theory involves toxic metabolites; the aromatic antiepileptic agents are metabolised by cytochrome P-450 to an arene oxide metabolite. This is normally detoxified by epoxide hydrolase. This enzyme may be lacking or mutated in persons that develop the syndrome, and this is genetically determined. Lamotrigine is mainly metabolised by hepatic glucuronidation, but hypersensitivity may involve similar processes such aromatic antiepileptic drugs, except that the toxic metabolite has not yet been found. Because of slow evolution and clinical similarity to many infectious illnesses, the diagnosis of hypersensitivity syndrome may be delayed. Prompt recognition and withdrawal of the suspected drug is essential. The goal of research is to describe a "susceptibility profile" identifying individuals at risk for these forms of drug toxicity.

Warning! One buflomedil may hide another one!

A 75-year-old woman experienced fever and convulsions. She was treated for diabetes mellitus, angina pectoris and also for arteritis with Buflomedil Merck (3 tab/d). Further investigations failed to find any aetiology. Buflomedil dosage was elevated to 6.3 mg/l (N = 4-4.5 mg/l). The drug was discontinued and there was no recurrence of symptoms. There was no evidence of error in dosage or interaction. A failure of the generic product was suspected. Only a pharmacist solved the problem. Fonzylane (buflomedil) had recently been switched to Buflomedil Merck. The patient misunderstood the change and took both drugs! Our purpose is not to report a known effect but to emphasize the importance of extending the information given to the patient and the risk of misuse of the generic product.

[Treatment with low dose methotrexate in rheumatoid arthritis: risk factors for severe complications]. / Traitements à faibles doses par le méthotrexate dans la polyarthrite rhumatoïde: facteurs de risque des complications graves.

Treatment with low dose methotrexate in rheumatoid arthritis is associated with serious side effects in about 5 per cent of cases (respiratory, haematological or infectious). The goal of a null risk seems unrealistic because of the idiosyncrasy of some of the risks and our poor understanding of others (enzymatic polymorphisms might be operational, and infectious agents could act as co-factors). However, risk can be greatly reduced by a careful selection of patients. Some contraindications are strict: poor compliance and the possibility of mistake in the timing of the administration; pregnancy or desire for pregnancy; treatment with trimetoprim; haemodialysis; renal insufficiency (clearance < or = 50 ml/min) (and therefore old age), alcoholism. Others remain relative although well established; hypoalbuminaemia, diabetes mellitus, obesity, past infection with hepatitis virus. Others are dubious: starvation, macrocytosis, surgical stress, NSAIDs. An extensive large study of side effects is warranted.

A 2-year evaluation of questions concerning "Drugs--Pregnancy" at the CRPV in Nantes March 1992--March 1994. / Bilan de 2 années du suivi des questions "Médicaments--Grossesse" au CRPV de Nantes entre Mars 1992 et Mars 1994.

Since 1990, the 'Centre Regional de Pharmacovigilance' of Nantes has systematically monitored pregnant women exposed to drugs. To increase physicians' participation in this study (34 per cent), the protocol was modified in 1992. Phoned answers are confirmed by mail. At the supposed time of the delivery, the physician receives a questionnaire about the outcome of pregnancy. A second letter and phone call are planned. With this method, 89 per cent of the pregnancies were fully documented between March 92 and March 94. Answers are classified according to the type of the practice. Pregnancy outcome is studied according to the drugs and the moment of exposure during pregnancy. Quality of the information, motivation of the physicians, and the benefits and difficulties of this method are discussed.

Pancytopenia and severe cytopenia induced by low-dose methotrexate. Eight case-reports and a review of one hundred cases from the literature (with twenty-four deaths)

Severe adverse effects of low-dose methotrexate (less than 20 mg per week) are believed to be rare. We report eight cases of severe tricytopenia or pancytopenia seen in two medical departments of the same hospital in patients receiving low-dose methotrexate. Three patients had been under methotrexate for less than one month. Of the six patients with joint disease, five had rheumatoid arthritis and one psoriatic arthritis. A review of the literature found 92 previously reported cases of severe tricytopenia or pancytopenia induced by low-dose methotrexate. Of the total of 100 cases, 24 were fatal and 25 occurred within one month of treatment initiation. Potential risk factors were identifiable retrospectively in at least 50% of cases but were not all predictable or present at treatment initiation. In 30% of cases, no explanation for the hematologic complication was found, and in an additional 20% missing data precluded definite conclusions. The role of the risk factors incriminated in the literature is discussed. Although infrequent, cytopenia is a severe complication of methotrexate therapy that warrants a number of precautions, including periodic creatinine clearance and serum albumin determinations. Furthermore, the weekly dosing schedule should be printed on methotrexate boxes.

[Neutropenia caused by acenocoumarol associated with hairy cell leukemia]. / Neutropénie à l'acénocoumarol associée à une leucémie à tricholeucocytes.

We report the case of a woman splenectomized to treat her hairy cell leukemia (at the moment in remission) 11 years before the detection of neutropenia. The neutropenia began just after the treatment of pulmonary embolism by acenocoumarol. The neutropenia disappeared quickly after substitution of acenocoumarol by fluindione. We discuss the attribution of the neutropenia to acenocoumarol and the part played by hairy cell leukemia.