Biomedical subjects
J M Bonnetblanc
Publications and source records attributed to J M Bonnetblanc.
[Ulceration or erosion of oral and/or genital mucosa].
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[Bacterial skin infections: impetigo, furuncle, erysipelas. Etiology, diagnosis, evolution, treatment].
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[Pharmacological properties of hyaluronic acid].
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[Radiation induced skin reaction].
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[Drug hypersensitive syndrome caused by fluindione].
BACKGROUND: Fluindione (Previscan) is an oral anticoagulant prescribed in relay to heparin therapy for deep venous thrombosis, pulmonary embolism... The main complications with oral anticoagulants are bleeding. However, severe immuno-allergic complications, especially acute hepatitis, acute renal failure and acute bone marrow failure, have been described with phenindione therapy. OBSERVATIONS: The authors report herein the first five cases of drug-induced hypersensitivity syndrome due to fluindione. Clinical signs included erythroderma and severe systemic manifestations which occurred within 3 to 8 weeks after introducing the molecule. Sex ratio was four males for one female; their ages ranged from 53 to 84 years. Clinical signs included erythroderma (with photosensitivity in two patients), lymphadenopathy and fever evoking severe sepsis. In our observations, marked eosinophilia (5 cases), lymphocytosis, atypical lymphocytes (4 cases), hepatic cytolysis (4 cases), associated in 2 cases with hepatic cholestasis, and pulmonary signs were noted. Cutaneous eruption healed in about 3 to 6 weeks after withdrawal of the drug. In two cases, systemic steroids were required for the severity of systemic manifestations. Long after the acute episode and when steroids were stopped, patch testing with fluindione was still positive. DISCUSSION: To date, acute and/or severe skin diseases due to fluindione, associated or not with multisystemic involvement, have never been reported. This molecule is the most commonly used for the treatment of thromboembolic diseases. Patch testing is easy to perform and can help physicians find the responsible molecule. Moreover, skin manifestations are present only in 87 p. 100 of drug-induced hypersensitivity syndromes. Acute hepatitis and acute renal failure might be drug-induced hypersensitivity syndromes without cutaneous manifestations.
[Aphthae or painful ulcers induced by nicorandil].
A RECOGNIZED CAUSE OF BUCCAL APHTHOSIS: Nicorandil is the leading drug in a new pharmacology class of well tolerated anti-angina products with vasodilating action. The first cases of buccal aphthosis or ulcerations induced by nicorandil were reported in 1996. Among drugs inducing buccal aphthosis or ulcerations, the largest body of information available on reported cases concern nicorandil. CHARACTERISTIC LESIONS: Forty cases of painful buccal lesions induced by nicorandil have been recorded. Among the 8 publications in the literature, 7 were reported by French groups. The prevalence of this adverse effect is an estimated 5%. Patient age varies from 60 to 90 years with an even gender distribution. A history of aphthosis is noted in 23% of the cases. The lesions vary in size from 0.5 cm to 3 cm and in number from 1 to 10, generally localized on the inner aspect of the cheeks or on the tongue. The lesions develop for about 3 to 36 before diagnosis and the delay to onset of signs after initiating nicorandil treatment is 15 days to 24 months (generally 2 months). Lesions basically develop after high-dose treatments and, for a few cases, after increasing the dosage. Cure is obtained in all cases after 1 to 12 weeks. OPEN QUESTIONS: The probability that nicorandil is the cause of these ulcerations or aphthae is very high. Certain terms do however need to be defined with precision. Are we talking about aphthae or ulcerations? The term painful ulceration would appear to be preferable because it includes both ulcerations and aphthae in cases lacking further information. The wide variability in the geographical distribution could likely be linked to underreporting. The notion of a dose effect suggests a toxic mechanism that could develop in predisposed populations (ethnic origin...) and would be directed against buccal targets (salivary glands...) via the active drug or its metabolites or via drug interactions. This new adverse effect of nicorandil is quite spectacular and very painful. However, no life-threatening event has been observed.
[Cutaneous drug reactions: diagnosis and etiology].
Drug eruptions are frequently encountered in clinical practice. Their great variety raise many problems and their complete knowledge is actually impossible. A logical approach is to describe the dermatological signs and the associated signs and symptoms. All the drugs taken by the patient and the dates of doses must be referred. Secondly, more informations may be obtained thanks to the dermatologist or a Drug Alert Registry (Regional Center of Pharmacovigilance in France). Bibliographical data varied in quality; the Vidal dictionary is often used, but Internet may be questioned. Imputability methods are well developped in France. In vivo and in vitro methods do not offer sufficient sensibility and specificity.
[Pruritus (other than anal and vulvar pruritus). Diagnostic orientation].
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Adverse effects associated with EMLA cream used as topical anesthetic for the mechanical debridement of leg ulcers.
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[Cutaneous reactions or necrosis from interferon alpha: can interferon be reintroduced after healing? Six case reports].
PURPOSE: Alpha, beta or gamma interferon (INF) are cytokines produced by cells in response to antigenic stimulation. They are used to treat various hepatic, hematological, oncological and neurological diseases. Cutaneous reactions (rash, alopecia, labial herpes, erythema, or induration at the site of injection, and more rarely cutaneous necrosis) represent 5 to 12% of side-effects observed in patients receiving INF. The authors report six cases of local cutaneous reactions to alpha INF, five of which corresponded to cutaneous necrosis. This makes them question the relevance of INF reintroduction. METHODS: The study included 5 male and 1 female patients (mean age: 59.1 years; range: 42 to 74 years old). Three patients had chronic hepatitis C, while three others presented a blood disease. RESULTS: Cutaneous necrosis occurred after 1 to 10 months of treatment. The mean time to healing was 16.2 weeks. Reintroduction of the drug including injection in other sites did not lead to recurrence of necrosis in five out of the six cases. CONCLUSION: INF-induced cutaneous necrosis does not depend on the type of INF, the site of injection, the dose and may occur 2 months to 9 years after treatment implementation. The exact mechanisms involved in cutaneous necrosis remain unknown. Morbidity is due to a very long time to healing (4 to 6 months). Futhermore, healing sometimes requires prior surgery. Physicians should be aware of the potential occurrence of erythema in patients treated by INF, as it is the first sign of necrosis. The site of injection should then be modified. In case of necrosis, risk factors for thrombophilia, factors reducing microcirculation (DHE, beta-blockers, cigarette smoking) should be investigated. INF injections should be cautiously reintroduced in other sites with the help of a nurse in case of self-injections prior to the occurrence of necrosis. Regarding self-injections patients' training should be emphasized.
[Drug-induced hypersensitivity syndrome in internal medicine: diagnostic and therapeutic traps. Eight observations].
PURPOSE: Drug-induced hypersensitivity syndrome (DIHS) is an acute and severe drug reaction. Manifestations include severe skin lesions, fever, nodal enlargement, blood eosinophilia and multisystemic involvement. The severe systemic manifestations of DIHS are responsible for a 10% mortality rate. The pertinence of corticosteroid therapy is discussed. METHODS: The authors report eight retrospective cases of DIHS obtained from the PMSI (Programme de Médicalisatiopn des Systèmes d'Information) between November 1991 and November 1998. RESULTS: The series consisted of five male and three female patients (mean age: 52.6 years; range: 23-83 years). The interval between the introduction of the drug and the onset of the reaction varied from two to eight weeks. Due to severe systemic manifestations, three patients were given corticosteroid therapy. Healing of skin and systemic disorders resolved with a mean delay of 4.4 weeks (range: 1 to 56 weeks). CONCLUSION: DIHS can be a diagnostic trap, as there are no diagnostic criteria for DIHS. Only the association of multiple arguments such as the time to the occurrence of symptoms, clinical similarity to many infectious illnesses, hypereosinophilia, atypical lymphocytosis, etc. may help guide diagnosis. DIHS can also be a therapeutic trap, as prompt withdrawal of the offending drug is essential to minimize morbidity. Although still controversial in the literature, the pertinence of corticosteroid therapy may be discussed in case of severe systemic effects. Patch testing can be a valuable tool to determine the responsibility of a drug; however it proves to be useful only when positive.
Role of drug exposure in aphthous ulcers: a case-control study.
BACKGROUND: Drug-induced aphthous ulcers have been the subject of several isolated and heterogeneous case reports for the last three decades. OBJECTIVES: To perform a case-control study to evaluate the risks linked to drug exposure in aphthous ulcers. METHODS: Eighty patients with typical clinical patterns of aphthous ulcers and 152 control patients who had had consultations for skin tumours were studied. A standardized questionnaire, concerning clinical features, life-style and medications taken during the last month, was completed for each patient. RESULTS: Case patients had a much higher intake of medications than control patients, respectively, 5.1 and 2. 8 medications per patient (P < 0.0001). Multivariate paired analysis showed an association between aphthous ulcers and two classes of drugs: non-steroidal anti-inflammatory drugs (P < 0.001) and beta-blockers (P = 0.002). Smoking could have a protective effect against aphthous ulcers (P < 0.001). CONCLUSIONS: Previous case reports and the results of this study suggest a real link between beta-blockers and aphthous ulcers. Our study did not confirm a role of other drugs but a few interesting case reports with positive reintroduction have to be considered. These results could be beneficial for patients, as healing may occur when the incriminated drug is discontinued.
CTLA4 exon 1 dimorphism in bullous and cicatricial pemphigoid.
The human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene encodes proteins regulating the immune response. The polymorphism of this gene is associated with some autoimmune diseases. In this study, we analysed the distribution of the dimorphisms of exon 1 (+ 49 A/G) in bullous pemphigoid (BP) and cicatricial pemphigoid (CP), two types of autoimmune bullous skin diseases that occur in elderly people. The frequency of the exon 1 A-G genotype was marginally decreased in patients (36.4%; n = 55) compared with controls (52.8%, n = 53), but the results were not statistically significant (P = 0.09).
[Analysis of the literature about drug-induced aphthous ulcers].
OBJECTIVES: Analysis of the literature on drug-induced aphthous ulcers and mucosal ulcerations and evidence-based grading. MATERIAL AND METHODS: Four literature sources were analyzed. Three groups of key words were used: 1) oral, buccal, genital, mucosal; 2) ulcer, ulceration, aphthous, aphthosis; 3) induced, drug, adverse-effects, with cross-overs. Four grading patterns were used: presence of aphthous term or synonym, typical clinical description of aphthous ulcer, presentation suggesting diagnosis of aphthous ulcer, criteria defining likelihood of drug causality. RESULTS: We examined 66 of the 220 publications responding to our selection criteria. Typical clinical description of aphthous ulcer and/or clinical presentation suggesting the diagnosis of aphthous ulcer were noted for 8 compounds with likely or palausible patterns of causality. For 21 compounds, we found only aphthous term or synonym without a clinical description or presentation. DISCUSSION: Our review of the literature individualized a group of 8 compounds where the diagnosis of aphthous ulcers was plausible and another group of 21 compounds where the diagnosis of aphthous ulcers requires confirmation. The clinical relevance and limitations of this analysis are discussed. CONCLUSION: Drug-induced aphthosis is probably a real phenomenon. Causality of the 8 compounds in the first group is simply more fully documented than for the 21 compounds in the second group. A low evidence level may not confirm these hypotheses. Some drugs may have been incorrectly ruled out due to lack of information.
[Pretibial epidermolysis bullosa and hypothyroidism].
BACKGROUND: We report a case of primary non-autoimmune hypothyroidism causing pretibial epidermolysis bullosa. CASE REPORT: A 70-year-old man with primary non-autoimmune hypothyroidism developed blisters of different ages on the lateral aspect of both legs. Pathology reported blisters with subepidermal cleavage. Direct immunofluorescence was negative. Electron microscope examination showed a variable cleavage level and diffuse infiltration of a granulous and amorphous microfibrillar substance. After hormone replacement therapy, euthyroidism was associated with a reduction in the number of bullae and finally complete remission. After 12 months follow-up, the patient has not experienced recurrence. DISCUSSION: Recurrence-free clinical improvement after hormone replacement therapy suggests the diagnosis of hypothyroidism pretibial epidermolysis bullosae. Mochizuki et al. described a similar case which rapidly regressed after hormone therapy but where the electron microscope showed a different cleavage level. These bullae appear to result from a mechanical mechanism due to their localization in areas exposed to friction and also to the presence of bullae of different ages. This hypothesis is confirmed by the presence of a variable level of cleavage and a substance dense to electrons at electron microscopy as well as by the skin weakness. Our case confirms the reality of hypothyroidism pretibial epidermolysis bullosa. Thyroid hormones should be assayed in patients presenting pretibial bullae.
Leg ulcers and hydroxyurea: forty-one cases.
BACKGROUND: Hydroxyurea is an antitumor agent used to treat chronic myeloproliferative disorders. Leg ulcerations have been reported in patients undergoing long-term hydroxyurea therapy for myeloproliferative diseases. To better define this dermatological adverse effect of hydroxyurea therapy and to try to understand the pathophysiological process of this disease, we collected medical information for such patients in a multicenter retrospective study. OBSERVATIONS: Forty-one patients (mean age, 67 years) developed leg ulcerations while undergoing hydroxyurea therapy (mean therapy duration, 5 years). The sex ratio was 1, and there was no underlying vascular disease. Hematologic abnormalities were identified. Complete recovery from the ulcerations occurred quickly after withdrawal of treatment in 33 (80%) of the cases. CONCLUSIONS: This longest-reported series of patients confirms the role of hydroxyurea therapy in the onset of leg ulcerations. Healing or improvement requires cessation of treatment. Cutaneous atrophy and impaired wound healing may explain the relationship between hydroxyurea and leg ulcers. In addition, the megaloblastic erythrocytes resulting from the presence of hydroxyurea may circulate poorly through the capillary network. A prospective study in hematologic centers would be valuable.
Photosensitivity with sulfasalazopyridine hypersensitivity syndrome.
Five weeks after the start of treatment with an association of sulfasalazopyridine and piroxicam, a 30-year-old woman presented with an eczematous eruption in light-exposed areas, hepatomegaly and fever (38 degrees C). Laboratory studies showed leukocytosis, eosinophilia and hepatic cytolysis. Treatment consisted of withdrawing the two drugs and topical steroids. The clinical signs regressed in 6 days. An increase in eosinophilia and hepatic cytolysis was observed until the tenth day, after which the trend reversed. Laboratory parameters were normal on the twentieth day. One month later, photopatch testing was performed. A patch test with sulfanilamide irradiated with UVA was positive. Clinical and laboratory findings were highly suggestive of drug hypersensitivity syndrome. The positive result from the UVA photopatch test with sulfanilamide suggests that sulfasalazopyridine was involved in the occurrence of hypersensitivity syndrome in our patient. We conclude that photodistributed eruptions can be observed in drug hypersensitivity syndrome with photosensitizing drugs.