Philippe Musette

First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial

BACKGROUNDnHigh doses of corticosteroids are considered the standard treatment for pemphigus. Because long-term corticosteroid treatment can cause severe and even life-threatening side-effects in patients with this disease, we assessed whether first-line use of rituximab as adjuvant therapy could improve the proportion of patients achieving complete remission off-therapy, compared with corticosteroid treatment alone, while decreasing treatment side-effects of corticosteroids.nnnMETHODSnWe did a prospective, multicentre, parallel-group, open-label, randomised trial in 25 dermatology hospital departments in France (Ritux 3). Eligible participants were patients with newly diagnosed pemphigus aged 18-80 years being treated for the first time (not at the time of a relapse). We randomly assigned participants (1:1) to receive either oral prednisone alone, 1·0 or 1·5 mg/kg per day tapered over 12 or 18 months (prednisone alone group), or 1000 mg of intravenous rituximab on days 0 and 14, and 500 mg at months 12 and 18, combined with a short-term prednisone regimen, 0·5 or 1·0 mg/kg per day tapered over 3 or 6 months (rituximab plus short-term prednisone group). Follow-up was for 3 years (study visits were scheduled weekly during the first month of the study, then monthly until month 24, then an additional visit at month 36). Treatment was assigned through central computer-generated randomisation, with stratification according to disease-severity (severe or moderate, based on Harmans criteria). The primary endpoint was the proportion of patients who achieved complete remission off-therapy at month 24 (intention-to-treat analysis). This study is registered with ClinicalTrials.gov, number NCT00784589.nnnFINDINGSnBetween May 10, 2010, and Dec 7, 2012, we enrolled 91 patients and randomly assigned 90 to treatment (90 were analysed; 1 patient withdrew consent before the random assignment). At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38·4-71·7; p<0·0001. This difference corresponded to a relative risk of success of 2·61 (95% CI 1·71-3·99, p<0·0001), corresponding to 1·82 patients (95% CI 1·39-2·60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3-4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1·20 [SD 1·25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0·59 [1·15]; p=0·0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]).nnnINTERPRETATIONnData from our trial suggest that first-line use of rituximab plus short-term prednisone for patients with pemphigus is more effective than using prednisone alone, with fewer adverse events.nnnFUNDINGnFrench Ministry of Health, French Society of Dermatology, Roche.

Traitement par rituximab d’un purpura thrombopénique immunologique au cours d’un lupus systémique

Resume Introduction Le purpura thrombopenique immunologique est une maladie auto-immune dont le traitement repose en premiere intention sur la corticotherapie generale. Le traitement peut etre difficile, en particulier en cas de contre-indication aux traitements classiques : corticoides, splenectomie ou immunosuppresseurs. Nous rapportons le cas d’une malade lupique dont le purpura thrombopenique immunologique a ete traite avec succes par rituximab (anticorps anti-CD20) du fait d’une tuberculose disseminee contre-indiquant l’utilisation des traitements classiques. Le rituximab (Mabthera®) a obtenu une AMM dans le traitement des lymphomes folliculaires chimioresistants ou en rechute. Observation Une femme de 31 ans, d’origine maghrebine, etait atteinte depuis 10 ans d’un lupus erythemateux systemique traite par prednisone, hydroxychloroquine, methotrexate et anti-inflammatoires non-steroidiens. Trois mois apres l’introduction d’une quadritherapie antituberculeuse pour une miliaire tuberculeuse disseminee survenait un purpura thrombopenique grave (plaquettes : 4G/l). La malade etait initialement traitee sans succes par trois cures d’immunoglobulines. La thrombopenie restant inferieure a 5 G/l, la malade recevait 4 perfusions hebdomadaires de rituximab (Mabthera®) : 375 mg/m2. La thrombopenie regressait apres la troisieme perfusion. Parallelement, les anticorps anti-ADN natifs initialement tres eleves se normalisaient. Aucun effet secondaire n’etait observe. La malade n’avait pas de rechute de son purpura, ni de son lupus, 29 mois apres la derniere perfusion. Commentaires Le rituximab semble representer une alternative interessante dans le traitement du purpura thrombopenique immunologique en cas d’inefficacite ou de contre-indication aux traitements conventionnels.

New Approaches to Investigate Drug-Induced Hypersensitivity

The workshop on New Approaches to Investigate Drug-Induced Hypersensitivity was held on June 5, 2014 at the Foresight Center, University of Liverpool. The aims of the workshop were to (1) discuss our current understanding of the genetic, clinical, and chemical basis of small molecule drug hypersensitivity, (2) highlight the current status of assays that might be developed to predict potential drug immunogenicity, and (3) identify the limitations, knowledge gaps, and challenges that limit the use of these assays and utilize the knowledge gained from the workshop to develop a pathway to establish new and improved assays that better predict drug-induced hypersensitivity reactions during the early stages of drug development. This perspective reviews the clinical and immunological bases of drug hypersensitivity and summarizes various experts views on the different topics covered during the meeting.

Lymphangiosarcome traité par doxorubicine liposomale (Caelyx

Resume Introduction Le lymphangiosarcome est une tumeur de mauvais pronostic. Son traitement chimiotherapique repose principalement sur les anthracyclines, dont l’utilisation est difficile chez les malades âges du fait de leur toxicite. Nous rapportons l’observation d’une femme âgee dont le lymphangiosarcome a, dans un premier temps, repondu a la doxorubicine (Caelyx ® ), anthracycline de moindre toxicite. Observation Une femme de 70 ans ayant un lymphœdeme sequellaire d’une neoplasie mammaire a developpe un lymphangiosarcome du bras et de la region pectorale realisant une enorme tumeur saignotante. Un traitement par doxorubicine (50 mg/m 2 ) etait instaure. Des la premiere cure, on notait une diminution de la masse tumorale et des saignements. Une regression de 90 p. 100 de la tumeur et une recuperation partielle de la fonction du membre superieur gauche etaient obtenues apres cinq cures. Deux mois apres l’arret du traitement, le lymphangiosarcome recidivait et la malade decedait. Discussion Le Caelyx ® a entraine une regression tumorale importante ainsi qu’un excellent effet antalgique et hemostatique avec une bonne tolerance. Une remission complete par le Caelyx ® d’un angiosarcome du cuir chevelu a ete recemment rapportee. Ce traitement pourrait etre une alternative therapeutique dans les lymphangiosarcomes inoperables notamment chez les malades âges.

Syndrome d’hypersensibilité médicamenteuse à l’imatinib

BACKGROUNDnImatinib (Glivec) is a tyrosine kinase inhibitor used to treat certain cases of leukaemia. We report a case of a drug-induced reaction with eosinophilia and systemic symptoms (DRESS) caused by imatinib.nnnCASE-REPORTnA 77-year-old woman with a chronic myeloid leukaemia was treated with imatinib and allopurinol. Nineteen days after the start of treatment, the patient presented fever with a generalized polymorphous rash associated with oral erosions, facial oedema, diffuse lymphadenopathy and blood hypereosinophilia. Histological analysis of skin biopsy specimens suggested a drug-induced reaction. The outcome was favourable two weeks after discontinuation of treatment. Three months later, imatinib was reintroduced because of progression of the patients chronic myeloid leukaemia, and recurrence of the skin rash and fever was observed within 12 hours.nnnDISCUSSIONnAllopurinol was stopped definitively because of its more frequent imputability. Imatinib was reintroduced after considering the benefit-risk ratio and in full knowledge of the existence of cutaneous reactions to imatinib, despite there being only one recent report of DRESS following treatment with imatinib. According to the causality criteria of Bégaud et al. regarding imatinib, inherent causality of the drug in our patient was initially possible (I2) and appeared likely (I3) after the rechallenge test. This case clearly illustrates that imatinib is a potential cause of DRESS.

Cas cliniqueSyndrome d’hypersensibilité médicamenteuse à l’imatinibImatinib-induced DRESS

BACKGROUNDnImatinib (Glivec) is a tyrosine kinase inhibitor used to treat certain cases of leukaemia. We report a case of a drug-induced reaction with eosinophilia and systemic symptoms (DRESS) caused by imatinib.nnnCASE-REPORTnA 77-year-old woman with a chronic myeloid leukaemia was treated with imatinib and allopurinol. Nineteen days after the start of treatment, the patient presented fever with a generalized polymorphous rash associated with oral erosions, facial oedema, diffuse lymphadenopathy and blood hypereosinophilia. Histological analysis of skin biopsy specimens suggested a drug-induced reaction. The outcome was favourable two weeks after discontinuation of treatment. Three months later, imatinib was reintroduced because of progression of the patients chronic myeloid leukaemia, and recurrence of the skin rash and fever was observed within 12 hours.nnnDISCUSSIONnAllopurinol was stopped definitively because of its more frequent imputability. Imatinib was reintroduced after considering the benefit-risk ratio and in full knowledge of the existence of cutaneous reactions to imatinib, despite there being only one recent report of DRESS following treatment with imatinib. According to the causality criteria of Bégaud et al. regarding imatinib, inherent causality of the drug in our patient was initially possible (I2) and appeared likely (I3) after the rechallenge test. This case clearly illustrates that imatinib is a potential cause of DRESS.