Comprehensive Drug-Class Review Framework for improved evidence-based drug policy and formulary modernization.

Formularies are used by payers to optimize access and ensure the appropriate use of medications. Lack of follow-up and re-evaluation can lead to outdated formularies that are not reflective of current evidence. Formulary modernization, an approach to re-align formularies with current evidence has proven successful. The Ontario Drug Policy Research Network (ODPRN) launched a framework for conducting comprehensive drug-class reviews. This commentary describes the individual components of this framework and lessons learned through completion of 12 reviews between 2013 and 2016. We present the ODPRN drug-class review of treatments for chronic hepatitis B as a case example to illustrate the components and impact. The incorporation of foundational health technology assessment components such as economic evaluations and knowledge synthesis with contextualizing evidence such as patient and clinician perspectives (through qualitative studies), real-world evidence (through data analytics), and cross-jurisdictional comparisons (through environmental scans and data analytics), successfully developed jurisdictionally specific policy recommendations grounded in up-to-date evidence. The ODPRN framework for conducting comprehensive drug-class reviews is a robust and feasible approach to conduct formulary modernization. This framework allows for actionable and specific policies which are likely to be considered by decision makers. Adoption of similar frameworks in other jurisdictions may improve uptake of evidence-informed policy recommendations.

Sulfonamide Hypersensitivity: Fact and Fiction.

Sulfonamide antimicrobials are commonly reported as causing drug allergy and have been implicated in a variety of hypersensitivity reactions including immediate IgE-mediated reactions, benign T-cell-mediated rashes, and severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Cross-reactivity is unlikely between sulfonamide antimicrobials and sulfonamide non-antimicrobials. In patients who develop reactions to a sulfonamide non-antimicrobial, there is no evidence to suggest that sulfonamide antimicrobials and other sulfonamide non-antimicrobials would cross-react. Although immediate skin testing can be performed in patients with histories of immediate reactions, they are infrequently positive and wane over time. Delayed skin testing including patch tests to sulfonamides is rarely positive. Drug challenges are a useful tool for patients with both immediate and delayed reactions to sulfonamides. The role of sulfamethoxazole desensitization is controversial as rates of hypersensitivity reactions are similar between desensitization and drug challenge.

Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults.

BACKGROUND AND OBJECTIVES: Rare but potentially life-threatening hypersensitivity reactions can occur during the administration of intravenous iron. To provide guidance to healthcare professionals caring for adults receiving intravenous iron, a panel of 10 Canadian clinical experts developed a practical algorithm for the identification and management of hypersensitivity reactions to intravenous iron. MATERIALS AND METHODS: A systematic search of PubMed to February 2018 was performed. Articles related to hypersensitivity reactions were selected for review. The algorithm was developed during a 1-day live meeting based on the literature review and clinical expertise where evidence was lacking. The algorithm was then refined through an iterative process involving a web-based platform and virtual meetings. RESULTS: The algorithm provides guidance to healthcare professionals in preparing for and administering IV iron, as well as recognizing and managing hypersensitivity reactions to intravenous iron. Considerations for re-challenging patients who have experienced prior reactions are provided. CONCLUSION: Healthcare professionals who are involved in the care of patients receiving intravenous iron should be trained to anticipate, recognize and manage hypersensitivity reactions to intravenous iron to optimize patient care.

Variability in the validity and reliability of outcome measures identified in a systematic review to assess treatment efficacy of cognitive enhancers for Alzheimer's Dementia.

INTRODUCTION: Selection of optimal outcome measures is a critical step in a systematic review; inclusion of uncommon or non-validated outcome measures can impact the uptake of systematic review findings. Our goals were to identify the validity and reliability of outcome measures used in primary studies to assess cognition, function, behaviour and global status; and, to use these data to select outcomes for a systematic review (SR) on treatment efficacy of cognitive enhancers for Alzheimer's Dementia (AD). METHODS: Articles fulfilling the eligibility criteria of the SR were included in a charting exercise to catalogue outcome measures reported. Outcome measures were then assessed for validity and reliability. Two independent reviewers abstracted data on outcome measures and validity and reliability reported for cognition, function, behaviour and global status. RESULTS: 129 studies were included in the charting exercise; 57 outcome measures were identified for cognition, 21 for function, 13 for behaviour and 10 for global status. A total of 35 (61%) cognition measures, 10 (48%) functional measures, 8 (61%) behavioural measures and four (40%) of global status measures were only used once in the literature. Validity and reliability information was found for 51% of cognition measures, 90% of function and global status measures and 100% of behavioural measures. CONCLUSIONS: While a large number of outcome measures were used in primary studies, many of these were used only once. Reporting of validity and reliability varied in AD studies of cognitive enhancers. Core outcome sets should be used when available; when they are not available researchers need to balance frequency of reported outcome measures, their respective validity and reliability, and preferences of knowledge users. SYSTEMATIC REVIEW REGISTRATION: CRD#42012001948.

Publicly Funded Oral Chronic Hepatitis B Treatment Patterns in Ontario over 16 Years: An Ecologic Study.

BACKGROUND: Reimbursement for the use of hepatitis B virus (HBV) treatments has not been previously reported for public payers. OBJECTIVE: To describe the number of users and total cost of HBV treatments over the last 16 years among residents of Ontario, Canada, who were covered by the public drug program. METHODS: We conducted a repeated cross-sectional study for HBV treatments reimbursed by the public drug program in Ontario from January 1, 2000, to December 31, 2015. We projected total spending to 2020 based on current utilization trends. RESULTS: HBV drug users per year increased 30-fold, from 132 users in 2000 to 4,035 users in 2015. Total spending on HBV treatments increased 150-fold, from $136,368 annually in 2000 to $21.0 million in 2015. The spending on HBV agents is projected to increase by 65%, with an estimated drug cost of $34.6 million by 2020. CONCLUSIONS: Although not reimbursed as first-line therapy, tenofovir disoproxil fumarate has become the most commonly reimbursed HBV treatment and was associated with an increase in HBV treatment use and total spending. Results of this study found that rapid growth of HBV treatments led to a sustained increase in spending for public payers in Ontario. DISCLOSURES: This study was funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC) and Ontario Strategy for Patient-Orientated Research (SPOR) Support Unit, which is supported by the Canadian Institutes of Health Research and the Province of Ontario. This study was also supported by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario MOHLTC. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed herein are those of the authors and not necessarily those of CIHI. Mamdani has received honoraria from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Bayer. Janssen has received research support, consulting, and/or speaking fees from Gilead, Roche, Merck, AbbVie, Bristol-Myers Squibb, Arbutus, Janssen, and MedImmune. No other authors have any conflicts of interest to declare.

Prior Authorization and Canadian Public Utilization of Direct-Acting Oral Anticoagulants.

PURPOSE: Provincial public drug formularies in Canada have different mechanisms for reimbursement of direct-acting oral anticoagulants (DOACs). We investigate how these differences influence DOAC utilization and expenditure across the country. METHODS: We conducted a population-based, cross-sectional study of all out-patient prescriptions for OACs dispensed to public beneficiaries between January 1, 2010, and June 30, 2015. We calculated quarterly rates of OAC use and expenditures stratified by OAC type and province. RESULTS: The greatest increase in quarterly rates of DOAC utilization occurred in provinces with more liberal mechanism of drug coverage: Ontario by 462%, Alberta by 425% and Quebec by 1,924%. This translated to increased expenditure on overall OAC by 270%, 204% and 390%, respectively. In contrast, provinces with more stringent mechanisms had low rates of DOAC utilization and expenditure. CONCLUSIONS: DOAC utilization and expenditure is considerably different across Canada, associated with provincial difference in reimbursement mechanism.

Self-Monitoring of Blood Glucose: Impact of Quantity Limits in Public Drug Formularies on Provincial Costs Across Canada.

OBJECTIVES: For most patients with diabetes, routine use of blood glucose test strips (BGTS) has not been shown to be beneficial, yet the economic implications of broad publicly funded reimbursement for BGTS are substantial. We assessed the potential impact of BGTS quantity limits on utilization and costs for 6 publicly funded drug plans across Canada. METHODS: A cross-sectional analysis was conducted in 6 provinces (Alberta, Saskatchewan, Manitoba, Nova Scotia, Newfoundland and Labrador and Prince Edward Island) for patients who received at least 1 prescription for BGTS in 2014 through the public drug program. We determined the number of BGTS that would have exceeded the quantity limits and the associated costs to the provincial drug program. RESULTS: A total of $38,051,026 was spent on BGTS reimbursed through public drug programs among the 6 provinces. In provinces where BGTS use is largely restricted to patients using insulin, the potential annual savings were minimal, ranging from 0.4% to 2.3%, whereas in provinces with more liberal listings, potential savings ranged from 12.4% to 19.8%. Combining these results with data from a previous analysis in Ontario and British Columbia, the cost savings associated with BGTS quantity limits for 8 provinces across Canada (capturing approximately three-quarters of the Canadian population) is estimated to be $30.3 million annually. CONCLUSIONS: The national implementation of a quantity limit policy for BGTS that aligns with evidence of efficacy, optimal prescribing and patient safety can lead to considerable savings for most public drug plans across Canada.

Interprovincial Variation in Antipsychotic and Antidepressant Prescriptions Dispensed in the Canadian Pediatric Population.

OBJECTIVE: Although antidepressants and antipsychotics are valuable medications in the treatment of select psychiatric disorders, there is increasing focus on the balance of risks and benefits of these drugs as prescribed, particularly in the pediatric population. We examined recent national trends and interprovincial variation in dispensing of antipsychotic and antidepressant prescriptions to the Canadian pediatric population. METHOD: We conducted a population-based cross-sectional study of antidepressant and antipsychotic prescriptions dispensed by Canadian pharmacies to the pediatric population (≤18 years) between 2010 and 2013. Prescription volumes were obtained from IMS Health. Analysis was stratified by drug, year, quarter, and province and population-standardized using age-adjusted population estimates. RESULTS: From the first quarter of 2010 to the fourth quarter of 2013, dispensing of antipsychotics to the pediatric population increased 33% (from 34 to 45 prescriptions per 1000) and dispensing of antidepressants increased 63% (from 34 to 55 per 1000). We observed a 1.5-fold interprovincial difference in dispensing rates for antidepressants (range: 189 per 1000 to 275 per 1000) and a 3.0-fold difference for antipsychotics (range: 85 per 1000 to 253 per 1000) in 2013. Among antidepressants, selective serotonin reuptake inhibitors were the most dispensed (76%), with fluoxetine being the leading agent. Among antipsychotics, atypical antipsychotics were the most dispensed (97%), with risperidone being the leading agent. CONCLUSIONS: Antipsychotic and antidepressant dispensing to the Canadian pediatric population increased from 2010 to 2013, with considerable interprovincial variation. Future research is required to explore reasons for observed patterns to optimize care for the Canadian pediatric population.

Variations in costs and use of provincially-funded testosterone replacement therapy across Canada: a population-based study.

INTRODUCTION: Provincial drug-program policies for the reimbursement of testosterone replacement therapy (TRT) vary across Canada, which may result in marked regional variability in use. METHODS: We conducted a population-based cross-sectional analysis of provincially funded TRT spending and utilization in eight provinces across Canada in 2012. We reported the annual cost per user, total cost, and rate of use of TRT overall and by formulation. RESULTS: We identified 23,544 provincially-funded recipients of TRT in 2012 in the eight provinces studied. Average annual cost per person varied by 3-fold, ranging from $173 (Prince Edward Island) to $485 (Ontario). Ontario also had the highest rate of use (1,105 users per 100,000 eligible) and the most liberal listing. Provinces with more restricted access (Alberta, British Columbia, and PEI) had lower annual costs per user ($293, $206, $173, respectively). CONCLUSIONS: Differing reimbursement policies for TRT products across Canada are likely contributing to variation in the rate of use and cost per recipient.

Factors that may be influencing the rise in prescription testosterone replacement therapy in adult men: a qualitative study.

OBJECTIVE: To explore and describe the factors that may be influencing the rise of prescribing and use of testosterone replacement therapy (TRT) in adult men. DESIGN: A rapid qualitative research design using semi-structured interviews with providers and patients. SETTING: Ontario, Canada. PARTICIPANTS: Nine men who have used TRT (referred to as "patients"), and six primary care clinicians and seven specialists (collectively referred to as "providers") who prescribed or administered TRT. METHOD: Patients' and providers' perspectives were investigated through semi-structured interviews. A purposive sampling approach was used to recruit all participants. We conducted qualitative analysis using the framework approach for applied health research. MAIN FINDINGS: Participants perceived the following factors to have influenced TRT prescriptions and use in adult men: provider factors (diagnostic ambiguity of age-related hypogonadism and beliefs about appropriateness of TRT) and patient factors (access to information on TRT and drug seeking behavior). They perceived that these factors have perpetuated a rise in prescription in the absence of clear clinical guidelines and unclear research evidence on the safety and efficacy of TRT. CONCLUSION: The findings of this study highlight that much work still needs to be done to improve diagnostic accuracy and encourage appropriate TRT prescription in adult men. In addition, both patients and providers need more information about the risks and long-term effects of TRT in men.

Access to Triptans for Acute Episodic Migraine: A Qualitative Study.

OBJECTIVE: Our study aims to examine factors related to access of triptans among multiple stakeholder groups. BACKGROUND: Triptans are a cornerstone of pain management for the acute treatment of migraine, but actual utilization of triptans is lower than ideal. Initial and continued access to triptans may be an important clinical issue in the acute treatment of migraines, but factors affecting access at the patient, provider, and health-care system levels have not been comprehensively explored. METHODS: A qualitative study was conducted in Ontario, Canada, between August 2013 and January 2014. Three participant groups were recruited to the qualitative study: (1) migraineurs who have experience accessing triptans; (2) physicians, including primary care physicians (PCPs) and neurologists, who have prescribed triptans; and (3) pharmacists who have dispensed triptans. Qualitative data were collected through one-on-one, semi-structured telephone interviews. The framework approach was used for data collection and analysis. RESULTS: Data collected from 19 migraineurs, 6 physicians, and 8 pharmacists were included in the analysis. Study participants discussed various factors that facilitate or hinder access to triptans, which were synthesized into four themes that emerged at the patient, provider, and health-care systems levels: (1) awareness; (2) apathy; (3) advocacy; and (4) affordability. Across all participant groups, awareness of available treatments and coverage policies for those treatments were potential factors relating to timely drug provision. Participants describe apathy in terms of patients' health-seeking behaviors and physicians' lack of concern toward migraine, which were seen as factors that could delay diagnosis and provision of appropriate treatment. Patients engaging in self-advocacy enhanced their ability to seek timely and appropriate provision of triptans at the patient level. At the health-care provider level, pharmacists were identified by patients as advocates for receiving more effective treatments for their migraines; pharmacists also self-identified with the advocate role. The affordability of triptans was a key concern impacting access at the systems level, but coverage limitations (eg, quantity limits) were also described to influence the appropriateness of prescribed migraine treatment. CONCLUSION: This study fills a gap in knowledge about access to triptans and how this may be impacted by patient, provider, and health-care systems barriers. Overall, our study sheds light on the experiences of prescribing, dispensing, and accessing triptans for migraine treatment, and unveils important information that can impact how patients access these drugs.

Triptans for Acute Migraine: Drug Class Review to Help Inform Policy Decisions.

BACKGROUND/OBJECTIVE: In Ontario, triptans are publicly funded through the Ontario Drug Benefit's Exceptional Access Program, a prior authorization program. However, it was unclear whether this listing aligned with current evidence of safety and effectiveness for triptans in migraine. Using a comprehensive and novel drug class review framework, we describe our review of triptans for the management of acute migraine to evaluate the appropriateness of triptan listing on the public drug formulary in Ontario. METHODS: This supplement in Headache highlights four key components of the triptan drug class review, including findings from a qualitative analysis of patient and clinician perspectives, a systematic review and network meta-analysis of clinical trial evidence, a pharmacoepidemiologic analysis comparing utilization trends across Canada, and a reimbursement-based economic analysis. RESULTS: We found that triptans were efficacious and safe for the treatment of acute migraine. However, Ontario has among the lowest rates of publically funded triptan use in Canada, which may be due to the highly restrictive nature of access to triptans in Ontario. Expanding access to triptans via a less restrictive listing (eg, Limited Use) would potentially increase use by 20-fold, with increase in costs of approximately 220%. CONCLUSION: Based on findings from our multi-faceted review and after stakeholder review and input from the Citizens' Panel, two policy options for triptans were recommended for Ontario's publically funded drug program: Limited Use access or coverage via the Exceptional Access Program, both options including quantity limits of 12 units per month.

Public Drug Coverage and Its Impact on Triptan Use Across Canada: A Population-Based Study.

BACKGROUND: Public drug coverage for triptan medications varies across jurisdictions in Canada, which may lead to differences in usage patterns and patient risk for medication overuse headache. METHODS: We conducted a population-based, cross-sectional analysis of publicly funded triptan use in seven provinces across Canada from January 1, 2012 to December 31, 2012. All patients who had filled at least one prescription for a triptan during the study period were included. We defined quantity limits of 6, 12, and 18 triptan units per month to assess the prevalence of high volumes of triptan use, which may place patients at risk for medication overuse headaches, and compared this prevalence between provinces with different funding restrictions. RESULTS: We identified 14,085 publicly funded users of triptans in 2012 in the seven provinces studied, 82.5% of whom were aged less than 65 years (N = 11,631). The prevalence of triptan use ranged substantially by province, from 0.04% in Ontario to a maximum of 1.0% in Manitoba (P < .001). Furthermore, the percentage of patients in each province using more than 6, 12, or 18 units per month differed significantly between provinces (P < .001). In particular, the percentage of patients treated with more than 6 units per month ranged from as low as 2.1% in Saskatchewan to 43.8% in Ontario. CONCLUSIONS: Differing public drug reimbursement criteria for triptans may be one contributing factor that has led to our observation of considerable variation in both prevalence of triptan prescribing and potential overuse of these medications. We offer that monthly quantity limits may be considered as a tool to decrease risks for medication overuse headache.

Application of a trigger tool in near real time to inform quality improvement activities: a prospective study in a general medicine ward.

BACKGROUND: Retrospective record review using trigger tools remains the most widely used method for measuring adverse events (AEs) to identify targets for improvement and measure temporal trends. However, medical records often contain limited information about factors contributing to AEs. We implemented an augmented trigger tool that supplemented record review with debriefing front-line staff to obtain details not included in the medical record. We hypothesised that this would foster the identification of factors contributing to AEs that could inform improvement initiatives. METHOD: A trained observer prospectively identified events in consecutive patients admitted to a general medical ward in a tertiary care academic medical centre (November 2010 to February 2011 inclusive), gathering information from record review and debriefing front-line staff in near real time. An interprofessional team reviewed events to identify preventable and potential AEs and characterised contributing factors using a previously published taxonomy. RESULTS: Among 141 patients, 14 (10%; 95% CI 5% to 15%) experienced at least one preventable AE; 32 patients (23%; 95% CI 16% to 30%) experienced at least one potential AE. The most common contributing factors included policy and procedural problems (eg, routine protocol violations, conflicting policies; 37%), communication and teamwork problems (34%), and medication process problems (23%). However, these broad categories each included distinct subcategories that seemed to require different interventions. For instance, the 32 identified communication and teamwork problems comprised 7 distinct subcategories (eg, ineffective intraprofessional handovers, poor interprofessional communication, lacking a shared patient care, paging problems). Thus, even the major categories of contributing factors consisted of subcategories that individually related to a much smaller subset of AEs. CONCLUSIONS: Prospective application of an augmented trigger tool identified a wide range of factors contributing to AEs. However, the majority of contributing factors accounted for a small number of AEs, and more general categories were too heterogeneous to inform specific interventions. Successfully using trigger tools to stimulate quality improvement activities may require development of a framework that better classifies events that share contributing factors amenable to the same intervention.

Cost and Resource Use of Pemphigus and Pemphigoid Disorders Pre- and Post-Rituximab.

BACKGROUND: Rituximab (RTX) is increasingly used for the treatment of pemphigus and pemphigoid disorders. The high cost of RTX frequently limits its use and access. OBJECTIVE: To determine the health system resources and costs associated with RTX treatment of pemphigus and pemphigoid. METHODS: Health system resources and costs attributed to a convenience sample of 89 patients with either pemphigus or pemphigoid were identified, quantified, and valued 6 months prior to and following RTX initiation between May 2006 and August 2012. Overall cohort costs and costs per patient were calculated (2013 Can$). RESULTS: The overall cohort cost for 6 months pre-RTX was $3.8 million and for 6 months post-RTX was $2.6 million. The average cost per patient decreased from $42,231 to $29,423 (30.3% decrease). The main cost driver was intravenous immunoglobulin. CONCLUSIONS: Our findings suggest that RTX is effective in reducing health system resources and the costs associated with the treatment of pemphigus and pemphigoid.

Safety of 5-Aminosalicylic Acid Derivatives in Patients with Sensitivity to Acetylsalicylic Acid and Nonsteroidal Anti-inflammatory Drugs.

BACKGROUND: One of the cornerstones of the management of inflammatory bowel disease is the use of 5-aminosalicylic acid (5-ASA) compounds for treatment of flares and as maintenance therapy during remission. There are concerns about using 5-ASA in patients with a history of hypersensitivity to acetylsalicylic acid (ASA). OBJECTIVE: To assess the literature with respect to the safety of 5-ASA compounds in patients with documented sensitivity to ASA or nonsteroidal anti-inflammatory drugs (NSAIDs). DATA SOURCES: A literature search was conducted in the MEDLINE and Embase databases, using various search terms, including "aminosalicylic acids", "non-steroidal anti-inflammatory agents," "hypersensitivity", and "allergy". The search was limited to articles (of any study design) published in English. Abstracts, full articles, and reference lists from retrieved articles were assessed to identify further relevant literature. STUDY SELECTION AND DATA EXTRACTION: Of 485 citations identified in the initial search, 4 case reports were relevant to the study objective and were analyzed in detail. DATA SYNTHESIS: Three of the case reports described the successful use of 5-ASA compounds in patients with prior sensitivity to ASA or an NSAID. The fourth report described a reaction to 5-ASA in a patient who had previously tolerated ASA. All of the reports were limited by lack of investigation into the validity of the reported sensitivity to ASA or 5-ASA. CONCLUSIONS: There is a dearth of evidence demonstrating cross-reactivity between ASA or NSAID and 5-ASA. This lack of information may relate to the mechanism of action of 5-ASA. This agent controls inflammation by inhibiting prostaglandin E2 and leukotrienes. In contrast, ASA-induced or NSAID-induced reactions are due to inhibition of the cycloxygenase-1 enzyme and subsequent release of histamine and synthesis of leukotrienes. Further reports describing the safety of 5-ASA use in patients with sensitivity to ASA or NSAIDs are needed before safety in this situation can be definitively determined. In patients with sensitivity to ASA or NSAID who require 5-ASA, a test dose of 5-ASA (to rule out potential cross-reactivity) or further investigation of the ASA or NSAID sensitivity is recommended.

CONTEXTE: L'un des éléments essentiels du traitement des maladies inflammatoires de l'intestin est l'utilisation de préparations d'acide 5-aminosalicylique (5-ASA) pour traiter les poussées inflammatoires et comme traitement d'entretien pendant la rémission. En revanche, certaines inquiétudes existent quant à l'utilisation de préparations de 5-ASA chez les patients qui présentent une hypersensibilité à l'acide acétylsalicylique (AAS). OBJECTIF: Analyser la littérature portant sur l'innocuité des préparations de 5-ASA chez les patients qui souffrent d'une sensibilité attestée à l'AAS ou aux anti-inflammatoires non stéroïdiens (AINS). SOURCES DES DONNÉES: Une recherche documentaire a été effectuée dans les bases de données MEDLINE et Embase. Les termes utilisés pour la recherche comprenaient entre autres : « acides aminosalicyliques ¼, « anti-inflammatoires non stéroïdiens ¼, « hypersensibilité ¼ et « allergie ¼. La recherche se limitait aux articles publiés en anglais, sans égard au plan de l'étude. Les résumés, les articles complets et les listes de références des articles recensés ont été évalués afin de repérer toute autre littérature pertinente. SÉLECTION DES ÉTUDES ET EXTRACTION DES DONNÉES: Des 485 articles recensés lors de la recherche initiale, quatre observations cliniques étaient applicables à l'objectif de la présente étude et ont été examinées en détail. SYNTHÈSE DES DONNÉES: Trois des quatre observations cliniques décrivaient une utilisation positive de préparations de 5-ASA chez des patients ayant des antécédents de sensibilité à l'AAS ou à un AINS. La quatrième observation rendait compte d'une réaction au 5-ASA chez un patient n'ayant jamais eu d'intolérance à l'AAS auparavant. L'ensemble de ces observations cliniques présentait des lacunes découlant de l'absence de vérification quant à la validité de la sensibilité à l'AAS ou au 5-ASA qui avait été signalée. CONCLUSIONS: Il existe très peu de données permettant de démontrer la réactivité croisée entre l'AAS ou les AINS et les préparations de 5-ASA. Ce manque d'information peut avoir comme source le mécanisme d'action du 5-ASA. La capacité de ce dernier à réduire l'inflammation réside dans son pouvoir d'inhibition de la production de la prostaglandine E2 et de leucotriènes, un mécanisme différent de celui qui cause les réactions produites par l'AAS ou les AINS, car ces médicaments inhibent l'enzyme cyclo-oxygénase-1 et subséquemment la libération d'histamine et la synthèse de leucotriènes. D'autres observations décrivant l'innocuité du 5-ASA chez les patients présentant une sensibilité à l'AAS ou aux AINS doivent être effectuées avant de pouvoir déterminer définitivement si l'emploi de préparations de 5-ASA est sûr chez ces patients. Chez les patients qui souffrent d'une sensibilité à l'AAS ou aux AINS, il est recommandé d'administrer une dose d'essai de 5-ASA (afin d'exclure une réaction croisée possible) ou de vérifier plus soigneusement leur sensibilité à l'AAS ou aux AINS. [Traduction par l'éditeur].

Durable remission of pemphigus with a fixed-dose rituximab protocol.

IMPORTANCE: Rituximab induces B-lymphocyte apoptosis by targeting CD20 antigen and has shown efficacy in antibody-mediated autoimmune disease. Rituximab is increasingly being acknowledged as an effective and safe treatment option for pemphigus. OBJECTIVE: To assess the clinical response of patients with pemphigus to rituximab using a modified fixed-dose rheumatoid arthritis protocol (1 g intravenously on days 1 and 15, followed by 500 mg intravenously if clinically warranted at 6-month intervals or repeated full dosing). DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted using records from a tertiary referral center for autoimmune bullous disorders. Participants included 92 patients (pemphigus vulgaris, 84 [91%], and pemphigus foliaceus, 8 [9%]) who received rituximab treatment between May 1, 2006, and August 30, 2012. MAIN OUTCOMES AND MEASURES: The primary outcomes were time to relapse and achievement of a complete response with or without treatment at the end of the study. RESULTS: Median time to relapse after the first treatment cycle was 15 months (95% CI, 10.3-19.7). All patients experienced improvement. Complete remission rates with or without adjuvant treatment at final follow-up were 89% (56 patients [61%] were in complete remission without treatment and 26 patients [28%] were in complete remission during adjuvant treatment). No serious infectious adverse events occurred. CONCLUSIONS AND RELEVANCE: The fixed-dose, modified rheumatoid arthritis protocol for rituximab was efficacious and well tolerated in patients with pemphigus. Patients who do not achieve remission after 1 cycle or patients who experience relapse benefit from further cycles of rituximab. Our results need to be confirmed in larger and controlled trials.

Anticonvulsant hypersensitivity syndrome: an update.

INTRODUCTION: Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening adverse drug reaction, primarily associated with phenytoin, phenobarbital and carbamazepine. It is characterized by a triad of fever, skin eruption and internal organ involvement (usually liver), which occur two to eight weeks after the initiation of therapy. Anticonvulsant hypersensitivity syndrome has been estimated to occur between 1 and 1000 and 1 in 10,000 exposures; however, its true incidence is unknown because of the variable presentation and inaccurate reporting. AREAS COVERED: This paper presents the incidence, epidemiology and pathogenesis of AHS, along with recommendations for its diagnosis and management. EXPERT OPINION: Avoidance of all aromatic anticonvulsants is recommended in patients who develop AHS with one of these agents, as there is a high degree of crossreactivity among all these agents. There are no universally recognized tests for the prediction of AHS due to aromatic anticonvulsants or lamotrigine. Yet genetic testing in a predictive sense would help guide the choice of an appropriate anticonvulsant medication. Other tests, using cellular surrogates, such as lymphocytes or platelets, have been used primarily for diagnostic testing and do not have the universal practicality afforded to genetic tests.

Effect of a single-cycle alternative dosing regimen for rituximab for recalcitrant pemphigus: a case series of 9 patients.

BACKGROUND: There is increasing evidence that a single cycle of rituximab (375 mg per square meter [corrected] of body surface area once weekly for 4 weeks) is efficacious in patients with severe pemphigus. The approved protocol in rheumatoid arthritis is 1 g on days 1 and 15. We report herein on the efficacy and safety of this latter protocol for rituximab in 9 patients with pemphigus. OBSERVATIONS: Nine patients with recalcitrant pemphigus were treated with prednisone, immunosuppressive agents, and/or intravenous immunoglobulin. Rituximab, 1 g, was infused on days 1 and 15. Each patient was observed for a minimum of 6 months. Reepithelialization of at least 50% of the affected areas occurred in all patients within 16 weeks. Three of 6 patients (50%) discontinued intravenous immunoglobulin therapy. A significant decrease in the pemphigus severity score and the mean dosage of prednisone was observed at 3 and 6 months. Relapses were observed in 4 patients between 5 and 13 months after rituximab treatment; these patients completed a second cycle of rituximab. There were no serious adverse effects observed during the follow-up period. CONCLUSIONS: A single cycle of rituximab, 1 g on days 1 and 15, is an effective treatment for pemphigus. Further studies are needed to determine the efficacy and safety of repeated treatment courses in patients who experience recurrences.