Integrating novel agents into multiple myeloma treatment - current status in Switzerland and treatment recommendations.

The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.

Ageing with HIV: medication use and risk for potential drug-drug interactions.

OBJECTIVES: To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, ≥ 50 years or <50 years. METHODS: All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database. RESULTS: Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥ 50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups. CONCLUSIONS: The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and response.

Changes over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction.

BACKGROUND: Because of the known relationship between exposure to combination antiretroviral therapy and cardiovascular disease (CVD), it has become increasingly important to intervene against risk of CVD in human immunodeficiency virus (HIV)-infected patients. We evaluated changes in risk factors for CVD and the use of lipid-lowering therapy in HIV-infected individuals and assessed the impact of any changes on the incidence of myocardial infarction. METHODS: The Data Collection on Adverse Events of Anti-HIV Drugs Study is a collaboration of 11 cohorts of HIV-infected patients that included follow-up for 33,389 HIV-infected patients from December 1999 through February 2006. RESULTS: The proportion of patients at high risk of CVD increased from 35.3% during 1999-2000 to 41.3% during 2005-2006. Of 28,985 patients, 2801 (9.7%) initiated lipid-lowering therapy; initiation of lipid-lowering therapy was more common for those with abnormal lipid values and those with traditional risk factors for CVD (male sex, older age, higher body mass index [calculated as the weight in kilograms divided by the square of the height in meters], family and personal history of CVD, and diabetes mellitus). After controlling for these, use of lipid-lowering drugs became relatively less common over time. The incidence of myocardial infarction (0.32 cases per 100 person-years [PY]; 95% confidence interval [CI], 0.29-0.35 cases per 100 PY) appeared to remain stable. However, after controlling for changes in risk factors for CVD, the rate decreased over time (relative rate in 2003 [compared with 1999-2000], 0.73 cases per 100 PY [95% CI, 0.50-1.05 cases per 100 PY]; in 2004, 0.64 cases per 100 PY [95% CI, 0.44-0.94 cases per 100 PY]; in 2005-2006, 0.36 cases per 100 PY [95% CI, 0.24-0.56 cases per 100 PY]). Further adjustment for lipid levels attenuated the relative rates towards unity (relative rate in 2003 [compared with 1999-2000], 1.06 cases per 100 PY [95% CI, 0.63-1.77 cases per 100 PY]; in 2004, 1.02 cases per 100 PY [95% CI, 0.61-1.71 cases per 100 PY]; in 2005-2006, 0.63 cases per 100 PY [95% CI, 0.36-1.09 cases per 100 PY]). CONCLUSIONS: Although the CVD risk profile among patients in the Data Collection on Adverse Events of Anti-HIV Drugs Study has decreased since 1999, rates have remained relatively stable, possibly as a result of a more aggressive approach towards managing the risk of CVD.

Allergologie: 1. Anti-TNFalpha: effets indésirables et implications pratiques [Management of adverse events induced by TNFalpha blocking agents].

TNFalpha blocking agents are effective and essential tools in the management of many inflammatory conditions including rheumatoid arthritis, spondylarthropathies and chronic inflammatory bowel disease. With time, some known side-effects have gained in importance and others have appeared. This article focuses on the potential risks of infection and autoimmunity induced by TNFalpha blocking agents and on the strategy to prevent and treat such adverse events.

The pleiotropic role of lipoxin A4 and its possible therapeutic use in endometriosis

L'endométriose est l'une des principales causes d'infertilité, caractérisée par une croissance ectopique de tissu endométrial. Sa Physiopathologie est encore mal comprise. En utilisant un modèle expérimental murin, nous avons étudié les mécanismes de développement et de progression de l'endométriose ainsi que l'effet d'un traitement systémique avec la lipoxine A4 (LXA4), un médiateur lipidique aux propriétés anti-inflammatoires. Le traitement à la LXA4 réduit de façon significative la taille des lésions endométriotiques et abaisse le taux de cytokines pro-inflammatoires telles que les interleukines (IL)-lß et d'IL-6. Une production aberrante de stéroïdes par les lésions ainsi qu'un contrôle immunitaire défaillant joue un rôle central dans la pathogenèse. LXA4 diminue l'expression du facteur induit par l'hypoxie (HIF)-la et ses gènes cibles, comme le facteur de croissance de Pendothélium vasculaire (VEGF) et la cyclo-oxygénase (COX)-2, qui diminue la production locale de Prostaglandines E2 ce qui résulterait en un environnement hypo-oestrogénique peritonéal. Outre ses effets anti¬inflammatoires, LXA4 régule l'expression des enzymes de remodelage de la matrice tels les métalloprotéinases matricielles (MMP)-2 et -9 ainsi que le facteur de croissance de transformation (TGF)-ß dans les lésions et les cellules du liquide péritonéal. De plus, le traitement à la LXA4 diminue l'expression de l'aromatase (CYP19A1) ainsi que celle du récepteur des oestrogènes (ER)-a qui module la signalisation des oestrogènes et des gènes impliqués dans la prolifération cellulaire (GREB1, cMyc et CCND1). Finalement, lorsque la LXA4 est donnée après l'apparition de la maladie, le traitement est encore efficace sur le contrôle de la croissance des lésions. En conclusion, ces nouvelles découvertes mettent en valeur un répertoire potentiel de cibles pour le traitement de l'endométriose et confirment un effet pléiotrope du traitement à la LXA4 sur la progression de la maladie : en diminuant les médiateurs pro-inflammatoires et angiogéniques, les enzymes de remodelage de la matrice, ainsi que le métabolisme et la signalisation de l'oestrogène, et en intervenant en aval de la cascade de gènes impliqués dans la prolifération. Ainsi, nos résultats désignent LXA4 comme agent thérapeutique potentiel pour le traitement de l'endométriose péritonéale.

Allergologie: 2. Mastocytose systémique--nouvelles stratégies thérapeutiques [Systemic mastocytosis--new therapeutic strategies].

Systemic mastocytosis is characterized by an excessive proliferation of mast cells and their accumulation in different organs. Avoidance of trigger factors leading to anaphylaxis is a general measure valid for all forms of mastocytosis. A premedication is necessary in case of surgery, anesthesia or administration of radiocontrast agents. Symptomatic treatment comprises antihistamines, anti-leukotrienes, proton pump inhibitors and topical corticosteroids. Indolent mastocytosis with refractory symptoms, the rare cases of aggressive mastocytosis with organ dysfunction and the even rarer mast cell leukemia require cytoreductive therapy. First-line agents are interferon alpha 2b and imatinib, a tyrosine kinase inhibitor. To date there is no curative treatment.

CD4+CD25+Foxp3+ regulatory T cells: from basic research to potential therapeutic use.

Regulatory T cells control immune responses to self- and foreign-antigens and play a major role in maintaining the balance between immunity and tolerance. This article reviews recent key developments in the field of CD4+CD25+Foxp3+ regulatory T (TREG) cells. It presents their characteristics and describes their range of activity and mechanisms of action. Some models of diseases triggered by the imbalance between TREG cells and effector pathogenic T cells are described and their potential therapeutic applications in humans are outlined.

Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment.

Despite a low positive predictive value, diagnostic tests such as complete blood count (CBC) and C-reactive protein (CRP) are commonly used to evaluate whether infants with risk factors for early-onset neonatal sepsis (EOS) should be treated with antibiotics. We investigated the impact of implementing a protocol aiming at reducing the number of diagnostic tests in infants with risk factors for EOS in order to compare the diagnostic performance of repeated clinical examination with CBC and CRP measurement. The primary outcome was the time between birth and the first dose of antibiotics in infants treated for suspected EOS. Among the 11,503 infants born at ≥35 weeks during the study period, 222 were treated with antibiotics for suspected EOS. The proportion of infants receiving antibiotics for suspected EOS was 2.1% and 1.7% before and after the change of protocol (p = 0.09). Reduction of diagnostic tests was associated with earlier antibiotic treatment in infants treated for suspected EOS (hazard ratio 1.58; 95% confidence interval [CI] 1.20-2.07; p <0.001), and in infants with neonatal infection (hazard ratio 2.20; 95% CI 1.19-4.06; p = 0.01). There was no difference in the duration of hospital stay nor in the proportion of infants requiring respiratory or cardiovascular support before and after the change of protocol. Reduction of diagnostic tests such as CBC and CRP does not delay initiation of antibiotic treatment in infants with suspected EOS. The importance of clinical examination in infants with risk factors for EOS should be emphasised.

Coping with an HIV infection. A multicenter qualitative survey on HIV positive adolescents' perceptions of their disease, therapeutic adherence and treatment.

HIV-positive adolescents face a number of challenges in dealing with their disease and its treatment. In this qualitative study, twenty-nine HIV-positive adolescents aged 13 to 20 years (22 girls), who live in Switzerland, were asked, in a semi-structured interview (duration of 40-110 minutes), to describe their perceptions and experiences with the disease itself and with therapeutic adherence. While younger adolescents most often thought of their disease as fate, older adolescents usually knew that they had received it through vertical transmission, although the topic appeared to be particularly difficult to discuss for those living with their HIV-positive mothers. Based on their attending physician's assessment, 18 subjects were judged highly adherent, 4 fairly and 7 poorly adherent. High adherence appeared linked with adequate psychological adjustment and effective coping mechanisms, as well as with the discussion and adoption of explicit medication-taking strategies. The setting and organisation of health care teams should allow for ongoing discussions with HIV-positive adolescents that focus on their perceptions of their disease, how they cope with it and with the treatment, and how they could improve their adherence.

New Algorithm for Managing Childhood Illness Using Mobile Technology (ALMANACH): A Controlled Non-Inferiority Study on Clinical Outcome and Antibiotic Use in Tanzania.

INTRODUCTION: The decline of malaria and scale-up of rapid diagnostic tests calls for a revision of IMCI. A new algorithm (ALMANACH) running on mobile technology was developed based on the latest evidence. The objective was to ensure that ALMANACH was safe, while keeping a low rate of antibiotic prescription. METHODS: Consecutive children aged 2-59 months with acute illness were managed using ALMANACH (2 intervention facilities), or standard practice (2 control facilities) in Tanzania. Primary outcomes were proportion of children cured at day 7 and who received antibiotics on day 0. RESULTS: 130/842 (15∙4%) in ALMANACH and 241/623 (38∙7%) in control arm were diagnosed with an infection in need for antibiotic, while 3∙8% and 9∙6% had malaria. 815/838 (97∙3%;96∙1-98.4%) were cured at D7 using ALMANACH versus 573/623 (92∙0%;89∙8-94∙1%) using standard practice (p<0∙001). Of 23 children not cured at D7 using ALMANACH, 44% had skin problems, 30% pneumonia, 26% upper respiratory infection and 13% likely viral infection at D0. Secondary hospitalization occurred for one child using ALMANACH and one who eventually died using standard practice. At D0, antibiotics were prescribed to 15∙4% (12∙9-17∙9%) using ALMANACH versus 84∙3% (81∙4-87∙1%) using standard practice (p<0∙001). 2∙3% (1∙3-3.3) versus 3∙2% (1∙8-4∙6%) received an antibiotic secondarily. CONCLUSION: Management of children using ALMANACH improve clinical outcome and reduce antibiotic prescription by 80%. This was achieved through more accurate diagnoses and hence better identification of children in need of antibiotic treatment or not. The building on mobile technology allows easy access and rapid update of the decision chart. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201011000262218.

Use of asthma medication during pregnancy and risk of specific congenital anomalies: A European case-malformed control study.

BACKGROUND: Pregnant women with asthma need to take medication during pregnancy. OBJECTIVE: We sought to identify whether there is an increased risk of specific congenital anomalies after exposure to antiasthma medication in the first trimester of pregnancy. METHODS: We performed a population-based case-malformed control study testing signals identified in a literature review. Odds ratios (ORs) of exposure to the main groups of asthma medication were calculated for each of the 10 signal anomalies compared with registrations with nonchromosomal, nonsignal anomalies as control registrations. In addition, exploratory analyses were done for each nonsignal anomaly. The data set included 76,249 registrations of congenital anomalies from 13 EUROmediCAT registries. RESULTS: Cleft palate (OR, 1.63; 95% CI, 1.05-2.52) and gastroschisis (OR, 1.89; 95% CI, 1.12-3.20) had significantly increased odds of exposure to first-trimester use of inhaled β2-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled β2-agonists were found for spina bifida, cleft lip, anal atresia, severe congenital heart defects in general, or tetralogy of Fallot. None of the 4 literature signals of exposure to inhaled steroids were confirmed (cleft palate, cleft lip, anal atresia, and hypospadias). Exploratory analyses found an association between renal dysplasia and exposure to the combination of long-acting β2-agonists and inhaled corticosteroids (OR, 3.95; 95% CI, 1.99-7.85). CONCLUSIONS: The study confirmed increased odds of first-trimester exposure to inhaled β2-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting β2-agonists and inhaled corticosteroids. Use of inhaled corticosteroids during the first trimester of pregnancy seems to be safe in relation to the risk for a range of specific major congenital anomalies.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients.

Patients with a solid organ transplant have increased in numbers and in individual survival in Switzerland over the last decades. As a consequence of long-term immunosuppression, skin cancer in solid organ recipients (SOTRs) has been recognized as an important problem. Screening and education of potential SOTRs about prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, SOTRs should be seen by a dermatologist yearly for repeat education as well as early diagnosis, prevention and treatment of skin cancer. Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in the setting of long-term immunosuppression. Sun protection by behaviour, clothing and daily sun screen application is the most effective prevention. Cumulative sun damage results in field cancerisation with numerous in-situ SCC such as actinic keratosis and Bowen's disease which should be treated proactively. Invasive SCC is cured by complete surgical excision. Early removal is the best precaution against potential metastases of SCC. Reduction of immunosuppression and switch to mTOR inhibitors and potentially, mycophenolate, may reduce the incidence of further SCC. Chemoprevention with the retinoid acitretin reduces the recurrence rate of SCC. The dermatological follow-up of SOTRs should be integrated into the comprehensive post-transplant care.