Drugs in Context

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Authors: Stefania Nicola MD, Giovanni Rolla MD, Luisa Brussino MD

The authors wish to make corrections to their article: Nicola S, Rolla G, Brussino L. Breakthroughs in hereditary angioedema management: a systematic review of approved drugs and those under research. Drugs in Context 2019; 8: 212605. DOI: 10.7573/dic.212605

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Authors: Sonia Brugnara MD, Mariacristina Sicher MD, Elena Maria Bonandini MD, Mattia Barbareschi MD, Carlo Renè Girardelli MD, Orazio Caffo MD

Systemic treatment for metastatic melanoma has advanced dramatically in recent years with an impressive increase in the rate of overall survival. The two main different strategies are targeted therapies (i.e. BRAF and MEK inhibitors) and immunotherapy with monoclonal antibodies against the immune checkpoint proteins programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Vitiligo often accompanies immunotherapy in melanoma patients and even correlates with tumor regression after checkpoint blockade. At present, a correlation between vitiligo onset and outcome from immunotherapy is acknowledged; however, evidence of a correlation between vitiligo and efficacy of combination-targeted therapy is lacking. We describe our experience in a patient who received dabrafenib and trametinib and developed vitiligo-like depigmentation after treatment cessation.

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Authors: Donata Galbiati MD, Stefano Cavalieri MD, Salvatore Alfieri MD, Carlo Resteghini MD, Cristiana Bergamini MD, Ester Orlandi MD, Francesca Platini MD, Laura Locati MD, Luca Giacomelli PhD, Lisa Licitra MD, Paolo Bossi MD

Background: Unresectable or metastatic cutaneous squamous cell cancers (cSCCs) are rare but potentially life-threatening diseases. In this setting, systemic therapy has a palliative intent with limited benefit, but there is no established consensus regarding the proper management of this tumour. This retrospective study aimed to review outcomes in patients with non-curable cSCC treated with platinum-based chemotherapy and cetuximab. Methods: We considered 12 consecutive patients treated between June 2010 and March 2016. All patients had received previous treatment for the local disease. Results: The overall response rate was 50%, and the disease control rate was 67%. Median progression-free survival and overall survival were 6.6 (95% confidence interval [CI]: 1.9–8.4) and 14.6 (95% CI: 9.4–20.1) months, respectively. The median duration of response was 4.8 months (95% CI: 1.2–5.9). The most frequent toxicities were skin reactions (58%; grade 3: 25%) and anaemia (10%). No grade 4 toxicities were observed. Conclusions: Cetuximab and platinum-based chemotherapy were shown to be feasible and active in cSCC, with an acceptable toxicity profile, even if with a limited duration of response.

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Authors: Paolo Antonio Ascierto MD, Dirk Schadendorf MD, PhD

Ascierto PA, Schadendorf D. Immunotherapy in non-melanoma skin cancer: updates and new perspectives. Drugs in Context 2019; 8: 212583. DOI: 10.7573/dic.212583

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Authors: José Alexandre Mendonça PhD, Guilherme B Damian MD

Mendonça JA, Damian G. The efficacy of certolizumab pegol in rheumatoid arthritis assessed by gray scale and power Doppler ultrasonography: case reports. Drugs in Context 2019; 8: 212554. DOI: 10.7573/dic.212554

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Authors: Pietro Sollena MD, Maria Mannino MD, Francesco Tassone MD, Maria Alessandra Calegari MD, Ettore D’Argento MD, Ketty Peris MD

Nail toxicities, such as paronychia and pyogenic granuloma-like lesions, are well-recognized side effects of epidermal growth factor receptor inhibitor (EGFR-I) therapy that can significantly impair patient’s quality of life and compliance to anticancer treatment. Numerous therapeutic options are available, with variable rates of success. Recently, topical β-blockers have emerged as a novel, non-invasive treatment strategy. We tested the effectiveness of topical timolol 0.5% gel, twice daily, under occlusion for 30 days, on paronychia and periungual pyogenic granuloma-like lesions in 9 patients being treated with EGFR-I. We also reviewed the available literature on this topic, which is the use of topical β-blockers in the management of EGFR-I-induced nail toxicities. We assessed 25 lesions consistent with the diagnosis of EGFR-I-induced pyogenic granuloma-like lesions and paronychia (21 diagnosed as pyogenic granuloma-like, and four as paronychia). Thirteen of the 25 lesions achieved complete resolution, 9/25 reached at least improvement, and only 3/25 did not respond to the intervention. As for the review, four papers met the scope of our research. The results confirmed at least partial benefit in the majority of treated patients. Among current strategies, high-potency topical corticosteroids are a well-known treatment option especially for paronychia, targeting the inflammatory component of such lesions; nevertheless, the management of pyogenic granuloma-like lesion is often more complex and the success rate is variable. Nail plate avulsion and phenol chemical matricectomy are not highly effective and display some degree of invasiveness. Topical β-blockers seem to be promising alternatives, especially in fragile cancer patients who may be unsuitable candidates for an invasive procedure.

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Authors: Felix Liriano, Candace Hatten MD, Thomas L Schwartz MD

Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.

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Authors: Nicolò Martinelli MD, Vincenzo Curci MD, Antonella Quarantiello MD, Gennaro Saldalamacchia MD

This article is the first part of a literature review concerning diabetic foot ulcers and the use of antimicrobial photodynamic therapy (PDT). Diabetic foot ulcers are associated with high morbidity, mortality, and healthcare costs. Natural healing is often delayed by microbial infection or colonisation, which might lead to serious complications, such as amputation. Furthermore, antibiotic treatment could have limited success because of the development of bacterial resistance and severely limited drug delivery to the ulcer due to vascular damage. PDT has antimicrobial effects and has been used to reduce the total and pathogenic microbial load in diabetic ulcers without inducing bacterial resistance. It is safe and can be used to improve outcomes. A clinical trial demonstrated that PDT with RLP068 reduced the microbial load of diabetic ulcers in 62 patients. This article reports previously published evidence and presents four, unpublished, clinical cases treated in the real-life setting.

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Authors: Olalla Montero-Pérez PharmD, María Beatriz Contreras-Rey PharmD, Ernesto Sánchez-Gómez PhD

Background: Asthma is an inflammatory disease of the airways with symptoms that vary over time and intensity, sometimes leading to disability or even death. Eosinophilic asthma accounts for 25% of cases of severe asthma. It is mediated by eosinophils regulated by interleukin-5 (IL-5), the target of mepolizumab, which has been recently licensed as an add-on treatment of severe refractory eosinophilic asthma. The aim of this study was to evaluate the effectiveness and safety of mepolizumab in clinical practice. Methods: A multicentre, retrospective, and descriptive study covering a year was conducted in a province of Spain with more than 500,000 inhabitants. Every patient prescribed with mepolizumab since its introduction into the hospital was included in the study. Clinical parameters were collected from the pharmacists’ counselling reports from electronic prescription software and electronic patient records. Effectiveness was assessed as a decrease in the exacerbation frequency and/or a reduction in the use of oral corticosteroids (OCS) compared to the previous year. Results: A total of 25 patients were studied, but only 23 could be evaluated by the cut-off date. A decrease in the exacerbation frequency was observed in 19 (82.6%) patients, 11 of them without any exacerbation during the treatment. A relative reduction of 87% in the exacerbation rate per year was obtained. A total of 15 patients were on regular OCS – 9 patients (60%) reduced their average dose, whilst 4 (26.7%) patients completely abandoned OCS. Safety was evaluated based on reported adverse effects. Adverse events were observed in 12 patients, the most common being headache, arthralgia, and dizziness/nausea. Conclusion: Mepolizumab has been shown to be effective based on the high decrease in the exacerbation frequency and reduced use of OCS. Reported adverse effects were mostly mild and appeared in half of the patients; some of the adverse events had not been previously described in pivotal trials.

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Authors: Alpesh Amin MD, MBA, W Richey Neuman MD, MPH, Melissa Lingohr-Smith PhD, Brandy Menges PhD, Jay Lin PhD, MBA

Background: We evaluated whether the duration of hospital stay influences venous thromboembolism (VTE) prophylaxis patterns and VTE risk during hospitalization and post-discharge among patients hospitalized for acute illnesses in the USA. Methods: Patients hospitalized for acute illnesses were identified from the US MarketScan Commercial and Medicare databases (January 1, 2012–June 30, 2015). Patients were stratified by index hospital length of stay (LOS), with study groups with 1–3 day, 4–6 day, and ≥7 day LOSs. Use of VTE prophylaxis and VTE event rates during and after hospitalization (6-month follow-up) were evaluated. Results: Of the overall population, 8647 had a 1–3 day LOS, 5551 had a 4–6 day LOS, and 3697 had a ≥7 day LOS. A greater proportion of patients with a 1–3 day LOS (66.2%) did not receive any VTE prophylaxis in comparison to patients with a 4–6 day LOS (55.0%) and ≥7 day LOS (48.8%; p<0.001). Proportions of patients with VTE events during the index hospitalization increased with longer hospital LOS (1–3 day LOS: 0.5%; 4–6 day LOS: 1.3%; ≥7 day LOS: 5.4%), as did proportions of patients with VTE events during the 6-month follow-up (1–3 day LOS: 2.4%; 4–6 day LOS: 2.7%; ≥7 day LOS: 4.2%). Conclusion: Among this study population of hospitalized acutely ill patients in the USA, VTE pharmacologic prophylaxis was underutilized, regardless of the duration of hospital stay. However, the risk for VTE events was substantial, with nearly 10% of those with a ≥7 day LOS having suffered a VTE event within 6 months.

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Authors: Allan R Brasier MD, Istvan Boldogh DM&B, PhD

Allergic asthma is a chronic inflammatory airway disease whose clinical course is punctuated by acute exacerbations from aeroallergen exposure or respiratory virus infections. Aeroallergens and respiratory viruses stimulate toll-like receptor (TLR) signaling, producing oxidative injury and inflammation. Repetitive exacerbations produce complex mucosal adaptations, cell-state changes, and structural remodeling. These structural changes produce substantial morbidity, decrease lung capacity, and impair quality of life. We will review recent systems-level studies that provide fundamental new insights into how repetitive activation of innate signaling pathways produce epigenetic ‘training’ to induce adaptive epithelial responses. Oxidative stress produced downstream of TLR signaling induces transient oxidation of guanine bases in the regulatory regions of inflammatory genes. The epigenetic mark 8-oxoG is bound by a pleiotropic DNA repair enzyme, 8-oxoguanine DNA glycosylase (OGG1), which induces conformational changes in adjacent DNA to recruit the NFkB·bromodomain-containing protein 4 (BRD4) complex. The NFkB·BRD4 complex not only plays a central role in inflammation, but also triggers mesenchymal transition and extracellular matrix remodeling. Small molecule inhibitors of OGG1-8-oxoG binding and BRD4– acetylated histone interaction have been developed. We present studies demonstrating efficacy of these in reducing airway inflammation in preclinical models. Targeting inducible epigenetic reprogramming pathway shows promise for therapeutics in reversing airway remodeling in a variety of chronic airway diseases.

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Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Kam Lun Hon MD, FAAP, FCCM

Background: Motion sickness is a common phenomenon that affects almost everybody at some point in their lifetime. Clinicians should be familiar with the proper management of this condition. Objective: To provide an update on the current understanding of the pathophysiology and management of motion sickness. Methods: A PubMed search was performed with Clinical Queries using the key term ‘motion sickness.’ The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to English literature. The information retrieved from the earlier search was used in the compilation of the present article. Results: Motion sickness is typically triggered by low-frequency vertical, lateral, angular, rotary motion, or virtual stimulator motion, to which an individual has not adapted. Sine qua non for developing motion sickness is when the brain receives conflicting information from different sensors about real body movements or virtual environment. The principal sensors are the eyes, the vestibular apparatus, and proprioceptive receptors. The conflicting information is judged in relation to a pattern of expected associations formed under normal or experienced conditions stored in the brain. Motion sickness typically presents with malaise, anorexia, nausea, yawning, sighing, increased salivation, burping, headache, blurred vision, non-vertiginous dizziness, drowsiness, spatial disorientation, difficulty concentrating, and sometimes vomiting. Simple behavioral and environmental modifications can be effective in the prevention of motion sickness. Medications that are effective in the prophylaxis and/or treatment of motion sickness include anticholinergics, antihistamines, and sympathomimetics. Conclusion: In most cases, motion sickness can be prevented by behavioral and environmental modifications (avoidance, habituation, and minimization of motion stimuli). Pharmacotherapy should be considered in the prevention and/ or treatment of more severe motion sickness and for patients who do not respond to conservative measures. Medications are most effective when combined with behavioral and environmental modifications. Drugs that are effective in the prophylaxis and/or treatment of motion sickness include anticholinergic agents and antihistamines.

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Authors: Manuel Anguita MD, Mariano de la Figuera MD, Alejandro I Pérez Cabeza MD, Carmen Suarez Fernández MD

Aims: To analyze the clinical profile and management of patients with nonvalvular atrial fibrillation taking rivaroxaban in routine practice in Spain. Methods: Clinical data from the observational studies HEROIC (cardiology and hematology; n=1,727), EMIR (cardiology; n=1,493), BRONCE-AP (primary care; n=133), SILVER-AP (primary care; n=457), ALADIN (internal medicine and neurology; n=249), and ESPARTA (internal medicine; n=110) of patients taking rivaroxaban were analyzed. The clinical profile was compared with those of the XANTUS and ROCKET-AF studies. Results: Overall, mean age was 74.9±9.4 years, CHA2DS2-VASc score was 3.7±1.5, and 43.2% had a HAS-BLED score ≥3. Patients included in the HEROIC and EMIR studies were older and more frequently had a creatinine clearance <50 mL/min and a higher thromboembolic risk than those in the XANTUS study, and patients included in the ALADIN study were older and had more prior cerebrovascular disease, but a lower thromboembolic risk than those in the ROCKET-AF trial. In those studies with available data, medication adherence and satisfaction with rivaroxaban were high. Conclusion: Bearing in mind differences according to the clinical setting of each study, atrial fibrillation patients taking rivaroxaban in Spain were elderly and had a high thromboembolic risk. Medication adherence and satisfaction with rivaroxaban were high.

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Authors: Constantine E Kosmas MD, PhD, Andreas Sourlas, Gordon Mallarkey PhD, Delia Silverio MD, Domingo Y Ynoa MD, Peter D Montan MD, Eliscer Guzman MD, Mario J Garcia MD

Cardiovascular disease (CVD) has consistently been the leading cause of death worldwide. Several clinical and epidemiological studies have demonstrated that an elevated plasma concentration of lipoprotein (a) [Lp(a)] is a causative and independent major risk factor for the development of CVD, as well as calcific aortic valve stenosis. Thus, the therapeutic management of hyperlipoproteinemia (a) has received much attention, as significant reductions in Lp(a) levels may, potentially, favorably affect cardiovascular risk. Aspirin, niacin, estrogens, and statins, which act on different molecular pathways, may be prescribed to patients with mild or modest elevations of Lp(a) levels. Other therapeutic interventions, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, Lp(a) apheresis, and the novel antisense oligonucleotides APO(a)-Rx and APO(a)-LRx, which are being evaluated in ongoing clinical trials, have provided some promising results and can potentially be used in severe cases of hyperlipoproteinemia (a). This review aims to present and discuss the current clinical and scientific data pertaining to the therapeutic options for the management of hyperlipoproteinemia (a).

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Authors: Amy C Foulkes BMedSci (Hons), BMBS, MRCP (Derm), PhD, Richard B Warren BSc (Hons), MBChB (Hons), MRCP, PhD

Brodalumab is a recombinant, fully human monoclonal antibody (IgG2) which binds with high affinity to the interleukin (IL) 17 receptor A (IL17R). Brodalumab is now licensed and approved for the treatment of moderate-to-severe chronic plaque psoriasis in North America and Europe. As the third to market in the class of agents targeting IL-17, we review its place in the expanding armamentarium of cytokine-directed therapies for patients with severe psoriasis. Brodalumab is a highly efficacious therapy for psoriasis, whose mechanism of action is separate from other treatments targeting IL-17. Its use is associated with rapid control of the disease. We suggest that brodalumab is likely to be considered in those patients requiring rapid control of disease, where there is no known history of depression or suicidal ideation.

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Authors: Kartikeya Tripathi MD, Joseph D Feuerstein MD

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder that involves any part of the colon starting in the rectum in a continuous fashion presenting typically with symptoms such as bloody diarrhea, abdominal pain, and rectal urgency. UC is diagnosed based on clinical presentation and endoscopic evidence of inflammation in the colon starting in the rectum and extending proximally in the colon. The clinical presentation of the disease usually dictates the choice of pharmacologic therapy, where the goal is to first induce remission and then maintain a corticosteroid-free remission. There are multiple classes of drugs that are available and are used based on the clinical severity of the disease. For mild-to-moderate disease, oral or rectal formulations of 5-aminosalicylic acid are used. In moderate-to-severe UC, corticosteroids are usually used in induction of remission with or without another class of medications such as thiopurines or biologics including anti-tumor necrosis factor, anti-integrins, or Janus kinase inhibitors for maintenance of remission. Up to 15% of the patients may require surgery as they fail to respond to medications and have risk of developing dysplasia secondary to longstanding colitis.

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Authors: Ashutosh M Shukla MD, Aparna Wagle Shukla MD

Several experimental and clinical studies have transformed the traditional antimalarial role of chloroquine (CHQ) and related structural analogues to potent therapeutic agents for a host of nonmalarial indications. The expanding clinical applicability for these drugs includes rheumatological and cardiovascular disorders (CVD), chronic kidney disease (CKD), oncology, and a variety of nonmalarial infections. These clinical advancements are primarily related to pleiotropic pharmacological actions of these drugs, including immunomodulation, anti-inflammatory properties, and capabilities of inducing autophagy and apoptosis at a cellular level. Historically, many clinical benefits in nonmalarial indications were first recognized through serendipitous observations; however, with numerous ongoing systematic clinical studies, the clinical horizons of these drugs have a promising future.

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Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Kam Lun Hon MD, FAAP, FCCM

Background: Gastroesophageal reflux is a common disorder in pediatrics. Clinicians should be familiar with the proper evaluation and management of this condition. Objective: To provide an update on the current understanding, evaluation, and management of gastroesophageal reflux in children. Methods: A PubMed search was performed with Clinical Queries using the key term ‘gastroesophageal reflux’. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. The search was restricted to the English literature and the pediatric age group. Results: Regurgitation is the most frequent symptom of gastroesophageal reflux and is present in nearly all cases. Gastroesophageal reflux occurs normally in infants, is often physiological, peaks at 4 months of age, and tends to resolve with time. Gastroesophageal reflux disease occurs when gastric contents reflux into the esophagus or oropharynx and produce troublesome symptom(s) and/or complication(s). A thorough clinical history and a thorough physical examination are usually adequate for diagnosis. When the diagnosis is ambiguous, diagnostic studies may be warranted. A combined esophageal pH monitoring and multichannel intraluminal esophageal electrical impedance device is the gold standard for the diagnosis of gastroesophageal reflux disease if the diagnosis is in doubt. In the majority of cases, no treatment is necessary for gastroesophageal reflux apart from reassurance of the benign nature of the condition. Treatment options for gastroesophageal reflux disease are discussed. Conclusion: In most cases, no treatment is necessary for gastroesophageal reflux apart from reassurance because the condition is benign and self-limiting. Thickened feedings, postural therapy, and lifestyle changes should be considered if the regurgitation is frequent and problematic. Pharmacotherapy should be considered in the treatment of more severe gastroesophageal reflux disease for patients who do not respond to conservative measures. Proton pump inhibitors are favored over H2-receptor antagonists because of their superior efficacy. Antireflux surgery is indicated for patients with significant gastroesophageal reflux disease who are resistant to medical therapy.

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Authors: Luis Miguel Juárez-Salcedo MD, Viraj Desai BA, Samir Dalia MD

The emergence of targeted therapy for patients with hematological diseases has permanently altered the therapeutic landscape. Immunochemotherapy regimes are now more and more being replaced by targeted therapies due to superior efficacy and better safety profiles. However, evolution and selection of subclones with continuous treatment leads to disease relapse and resistance toward these novel drugs. Venetoclax, the highly selective BCL-2 inhibitor (ABT-199), has an acceptable safety profile. To date, it has been approved for the treatment of first-line and relapsed/refractory chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, extension of indications can be expected in monotherapy and in combination regimens with promising outcomes in other hematological diseases. In this article, we describe the mechanism of action that stands behind the efficacy of venetoclax and provide a summary of available results from clinical trials.

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Authors: Ahmet Koyuncu MD, Ezgi İnce MD, Erhan Ertekin MD, Raşit Tükel MD

Comorbid disorders are highly prevalent in patients with social anxiety disorder, occurring in as many as 90% of patients. The presence of comorbidity may affect the course of the disease in several ways such as comorbidity in patients with social anxiety disorder (SAD) is related to earlier treatment-seeking behavior, increased symptom severity, treatment resistance and decreased functioning. Moreover, comorbidities cause significant difficulties in nosology and diagnosis, and may cause treatment challenges. In this review, major psychiatric comorbidities that can be encountered over the course of SAD as well as comorbidity associated diagnostic and therapeutic challenges will be discussed.

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Authors: Seyda Cankaya MD, Baris Cankaya MD, Ulkan Kilic PhD, Ertugrul Kilic PhD, Burak Yulug MD

Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson’s disease (PD), Huntington’s disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD.

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Authors: Matteo Bassetti MD, PhD, Daniele Roberto Giacobbe MD, Antonio Vena MD, PhD, Adrian Brink MMed

Antimicrobial stewardship programmes have been playing an important role in patient care and hospital policies. These programmes are now recognised as formal strategies for curbing the upward trend in antibiotic resistance and for improving the appropriate antimicrobial and antifungal use. The role of such programs in the era of antimicrobial resistance presents several unique challenges and opportunities, most notably in the diagnostic and therapeutic setting. Controversies remain regarding the most effective interventions and the appropriate design to evaluate their impact. In this review, based on rounds of discussion, we explain the most important challenges faced by antibiotic stewardship and antifungal stewardship programmes. We also try to suggest areas for further research.

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Authors: Marco Caminati MD, Francesco Menzella MD, Lucia Guidolin MD, Gianenrico Senna MD

Recent research in the field of bronchial asthma has mainly focused on eosinophilic disease phenotype. Several trials proved the efficacy and safety profile of eosinophils and interleukin (IL)-5 targeting molecules, currently approved for severe asthma and available on the market. They include mepolizumab and reslizumab, IL-5 blocking molecules, and benralizumab, targeting the IL-5 receptor and eliciting a NK cell-mediated antibody-dependent cellular cytotoxicity against eosinophils. Eosinophilic inflammation represents the common pathophysiological background of several conditions, providing the rationale for the use of the same biologics beyond asthma. Although with different evidence grade, from clinical trials to case reports, anti-IL-5 biologics have been investigated in eosinophilic granulomatosis with polyangitis, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, nasal polyposis, hypereosinophilic syndrome, and eosinophilic esophagitis. However, non-negligible differences between asthma and other eosinophilic diseases, particularly in eosinophils homing (blood and/or tissues), target organs and thus clinical features, probably account for the different response to the same drug in different clinical conditions and highlights the need for tailoring the therapeutic approach by modulating the drug dose and/or by combination therapy with multiple drugs. The optimal safety and tolerability profile of anti-IL-5 drugs warrants further and larger experimental and real-life investigations, which are needed especially in the field of non-asthma eosinophilic diseases. This review aims at summarizing the rationale for the use of biologics in eosinophilic diseases and their mechanisms of action. The current efficacy and safety evidence about eosinophils and IL-5 targeting molecules in asthma and in eosinophilic conditions beyond bronchi is also discussed.

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Authors: Daniela Barraco MD, Margherita Maffioli MD, Francesco Passamonti MD

Myelofibrosis (MF) is a heterogeneous disorder characterized by splenomegaly, constitutional symptoms, ineffective hematopoiesis, and an increased risk of leukemic transformation. The ongoing research in understanding the pathophysiology of the disease has allowed for the development of targeted drugs optimizing patient management. Furthermore, disease prognostication has significantly improved. Current therapeutic interventions are only partially effective with only allogeneic stem cell transplant potentially curative. Ruxolitinib is the only approved therapy for MF by the US Food and Drug Administration. However, despite efficacy in reducing splenomegaly and controlling symptomatology, it is not associated with consistent molecular or pathologic responses. Drug discontinuation is associated with a dismal outcome. The therapeutic landscape in MF has significantly improved, and emerging drugs with different target pathways, alone or in combination with ruxolitinib, seem promising.

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Authors: Daniele Orsucci MD, Elena Caldarazzo Ienco MD, Gabriele Siciliano MD, PhD, Michelangelo Mancuso MD, PhD

Mitochondrial disorders are a group of metabolic conditions caused by impairment of the oxidative phosphorylation system. There is currently no clear evidence supporting any pharmacological interventions for most mitochondrial disorders, except for coenzyme Q10 deficiencies, Leber hereditary optic neuropathy, and mitochondrial neurogastrointestinal encephalomyopathy. Furthermore, some drugs may potentially have detrimental effects on mitochondrial dysfunction. Drugs known to be toxic for mitochondrial functions should be avoided whenever possible. Mitochondrial patients needing one of these treatments should be carefully monitored, clinically and by laboratory exams, including creatine kinase and lactate. In the era of molecular and ‘personalized’ medicine, many different physicians (not only neurologists) should be aware of the basic principles of mitochondrial medicine and its therapeutic implications. Multicenter collaboration is essential for the advancement of therapy for mitochondrial disorders. Whenever possible, randomized clinical trials are necessary to establish efficacy and safety of drugs. In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.

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Authors: Melissa E Badowski PharmD, MPH, Bradley Burton PharmD, Kristy M Shaeer PharmD, MPH, John Dicristofano BS, PharmD Candidate

The rise in non-AIDS defining cancers (NADCs) is emerging as a leading cause of death for HIV and cancer patients. To address this, current literature and guidelines suggest the continuation of antiretroviral therapy (ART) with oral oncolytic agents to prevent adverse complications associated with HIV disease progression. However, such an approach has the potential for drug–drug interactions and adverse events for patients on such therapy. Further, recommendations on how to adjust these medications, when used concomitantly, are limited. As such, our purpose is to evaluate existing literature through such means as drug databases (e.g. Micromedex, Lexi-Comp, etc.) and package inserts along with PubMed/Medline, Embase, and Google Scholar databases to develop a reference tool for providers to utilize when there is a decision to treat a patient with ART and oral oncolytic agents concurrently. Our findings suggest that there are many drug interactions that should be taken into consideration with dual therapy. Metabolism is a key determinant of dose adjustment, and many oncolytic agents and ART agents must have their dose adjusted as such. Most notably, several tyrosine kinase inhibitors require dose increases when used with non-nucleoside reverse transcriptase inhibitors (NNRTIs) but must be decreased when used concomitantly with protease inhibitors (PIs) and cobicistat. Further findings suggest that certain agents should not be used together, which include, but are not limited to, such combinations as bosutinib with NNRTIs, cobicistat, or PIs; idelalisib with maraviroc or PIs; neratinib with NNRTIs, cobicistat, or PIs; and venetoclax with NNRTIs. Overall, the most prominent oncolytic drug interactions were discovered when such agents were used concomitantly with PIs, cobicistat-boosted elvitegravir, or NNRTIs. Future studies are necessary to further evaluate the use of these agents together in disease therapy to generate absolute evidence of such findings. However, from the studies evaluated, much evidence exists to suggest that concomitant therapy is not without drug interactions. As such, clinical decisions regarding concomitant therapy should be evaluated in which the risk and benefit of dual therapy are assessed. Dose adjustments must be made accordingly and in consultation with both HIV and oncology clinicians and pharmacists to reduce the risk for adverse outcomes and disease progression for those with cancer and HIV/AIDS.

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Authors: Rechelle Tull MD, William D Hoover III MD, Jacqueline F De Luca MD, William W Huang MD, MPH, Joseph L Jorizzo MD

Eosinophilic fasciitis is an uncommon connective tissue disorder that affects patients of all ages, resulting in significant morbidity. Systemic corticosteroids can induce remission of disease. However, there is no universally accepted treatment ladder for eosinophilic fasciitis. This case series evaluates treatment efficacy in patients with eosinophilic fasciitis seen at Wake Forest University Department of Dermatology outpatient clinics. Patient charts were screened using ICD-9 diagnosis code 710.9 (unspecified diffuse connective tissue disease) to identify patients with eosinophilic fasciitis (n=10) seen at our institution. Patients were treated for an average 24 months with a combination of methotrexate and prednisone therapy, unless one or both were contraindicated, with each medication tapered conservatively to prevent disease flares. Alternate treatments included mycophenolate mofetil with prednisone, azathioprine with prednisone, prednisone monotherapy, and methotrexate monotherapy. Disease remission off therapy and on low-dose therapy was 66 and 70%, respectively. Our first-line therapy of concomitant methotrexate and prednisone is well-tolerated and effective for managing patients with eosinophilic fasciitis. Our study was limited to cases seen at a single academic institution.

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Authors: Sonia Brugnara, Mariacristina Sicher, Elena Maria Bonandini, Davide Donner, Franca Chierichetti, Mattia Barbareschi, Carlo Renè Girardelli, Orazio Caffo

Here, we report the case of a patient, diagnosed with BRAFV600E-mutated metastatic malignant melanoma M1a, who achieved a complete metabolic response after 7 months of treatment with the combination of dabrafenib and trametinib. After 31 months, the treatment was interrupted for patient’s decision. To date October 2017, 18 months after the interruption of the treatment with the combination of dabrafenib and trametinib, follow-up Positron Emission Tomography (PET) scans are still documenting complete metabolic response.

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Authors: Mariane Teodoro Fernandes MD, Jacob J Adashek BA, Carmelia Maria Noia Barreto MD, Ana Cláudia Barbin Spinosa MD, Barbara de Souza Gutierres MSc, Gilberto Lopes MD, MBA, FAMS, Auro del Giglio MD, PhD, Pedro Nazareth Aguiar Jr MD, MSc

In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2- advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor.

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Authors: Sanjay Kalra, Gagan Priya

While lipids are an integral part of the endocrine clinic, the opposite is not necessarily true. The lipocrinology framework addresses this lacuna, by highlighting the similarities and multiple relationships between lipid and endocrine function. It reinforces the need to screen (clinically or biochemically) all dyslipidemic patients for endocrine disease and appropriate endocrine patients for dyslipidemia. Thus, it aims to improve clinical care for persons with lipid abnormalities as well as endocrine disease.

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Authors: Sarah L Anderson PharmD, Joel C Marrs PharmD

Hypertension (HTN) is a common disease state associated with extensive morbidity and mortality worldwide. It is often difficult for patients with HTN to achieve and maintain a goal blood pressure (BP), despite there being many effective treatment options available. Sacubitril/valsartan is a first-inclass angiotensin receptor neprilysin inhibitor (ARNI) that has garnered approval by the US Food and Drug Administration and the European Medicines Agency as a first-line treatment for heart failure with reduced ejection fraction. During clinical trials for heart failure as well as in independent trials for HTN, sacubitril/valsartan has demonstrated safety and efficacy when it comes to BP lowering, making it a promising antihypertensive agent. Most trials of sacubitril/valsartan were 8 to 12 weeks in length and demonstrated a clinically relevant BP lowering that was frequently more significant than its comparators. While more data are needed to confirm its role as an antihypertensive agent, the data available are promising and it is anticipated that sacubitril/valsartan will gain an indication of HTN.

8

Authors: Matteo Santoni MD, Francesco Massari MD, Vincenzo Di Nunno MD, Alessandro Conti MD, Alessia Cimadamore MD, Marina Scarpelli MD, Rodolfo Montironi PhD, Liang Cheng PhD, Nicola Battelli MD, Antonio Lopez-Beltran PhD

Advances in understanding the mechanisms of tumour-induced immunosuppression have led to the development of immune-checkpoint inhibitors in cancer patients, including those with renal cell carcinoma (RCC). The optimal combination between immunotherapy and targeted agents (as well as the possible favourable sequential therapy of these two classes of drugs) remains an open question at this moment. Several trials are currently underway to assess the combination of anti-programmed-death 1 (PD-1) or anti-PD-ligand(L)1 agents with other immunotherapies or with anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). In this editorial, we described the results of the most recent clinical trials on the use of immunotherapies in RCC and the emerging data on the research for reliable biomarkers of tumour response in this setting. In addition, we have focused on the role of the gut microbiome and tumour microenvironment in the development of future therapeutic strategies for RCC patients.

9

Authors: Marisa C Liu MD, MPH, Krishnansu S Tewari MD

Over the last decade, new therapeutics in the form of anti-angiogenic treatment, synthetic lethality, and checkpoint inhibition have offered new options for the treatment of ovarian cancer. This review summarizes studies related to these treatment modalities and additionally novel combinations that offer a veritable therapeutic matrix for clinicians to choose from.

9

Authors: Marija Vavlukis MD, PhD, FESC, Ana Vavlukis MSc

Background: Statins are the hypolipemic treatment of choice for hyperlipidemia with confirmed atherosclerotic cardiovascular disease (ASCVD) protective effect, proven even in normolipemic patients. But in rare situations, even with a high-dose treatment regimen, or maximally tolerated statin dose treatment, treatment targets of low-density lipoprotein cholesterol (LDL-C), according to the risk profile of the patient, cannot be achieved. Combination therapy with ezetimibe is an effective treatment choice, as it is one of the few hypolipemic drugs with proven ASCVD protective effect. Aim: In this review, we address the question of therapeutic efficacy and safety of ezetimibe in combination therapy with statins, as expressed through its hypolipemic and vasoprotective effects and its potential side effects. Methods: We conducted a literature review of English articles through PubMed, PubMed Central, and Cochrane for randomized clinical trials, retrospective analyses, meta-analyses, and review articles by using key words: ezetimibe, statins, combination therapy, adverse effects. We analyzed data on ezetimibe–statin combination therapy in terms of hypolipemic efficacy, ASCVD risk reduction, and adverse effects. Results: Statins have been proven to be very effective in reducing ASCVD risk, with no apparent threshold at which LDL-C lowering is not associated with reduced risk. Yet, a significant ontreatment residual risk of major cardiovascular (CV) events still exists according to meta-analyses of statin trials. Findings like this point to the unmet needs of the patients on statin treatment. The unmet needs in terms of LDL-C targets and ASCVD risk reduction raise the question of statin combination therapy. Ezetimibe is a cholesterol-lowering drug from the class of cholesterol absorption inhibitors, with the potency to decrease LDL-C by about 10–18% and Apo B by 11–16%, while in combination therapy with statins, an additional LDL-C lowering of 25% or total LDL-C lowering of 34–61% is observed. The effects on LDL-C and other lipoprotein (LP) fractions are translated by ASCVD risk reduction. Ezetimibe is one of the few hypolipemic medications that leads to additional ASCVD risk reduction when added to statin therapy. Present data on ezetimibe support the existence of pleotropic anti-inflammatory and antioxidative effects, in addition to its hypolipemic effect, which are responsible for this added ASCVD risk reduction on top of statin monotherapy. Ezetimibe, in combination therapy with a maximal or maximally tolerated statin therapy, is used in patients who fail to achieve target LDL-C levels with statin monotherapy. In combination with low-to-moderate statin dose treatment, or with second- or thirdline statins, ezetimibe is used in situations of statin-associated muscle symptoms. The combination therapy is relatively safe. Conclusion: Ezetimibe add-on to statin combination therapy is an effective treatment option that leads to additional LDL-C lowering – recommended in situations where, with a maximal or maximally tolerated statin monotherapy treatment regimen, LDL-C targets cannot be achieved. It leads to additional ASCVD risk reduction, without raising significant safety concerns.

9

Authors: Constantine E Kosmas MD, PhD, Ian Martinez MD, Andreas Sourlas, Kyriaki V Bouza MD, Frederick N Campos MD, Verenisse Torres MD, Peter D Montan MD, Eliscer Guzman MD

Several prospective epidemiological studies have shown that there is a clear inverse relationship between serum highdensity lipoprotein-cholesterol (HDL-C) concentrations and risk for coronary heart disease (CHD), even at low-density lipoprotein-cholesterol (LDL-C) levels below 70 mg/dL. However, more recent evidence from genetic studies and clinical research has come to challenge the long-standing notion that higher HDL-C levels are always beneficial, while lower HDL-C levels are always detrimental. Thus, it becomes apparent that HDL functionality plays a much more important role in atheroprotection than circulating HDL-C levels. HDL cholesterol efflux capacity (CEC) from macrophages is a key metric of HDL functionality and exhibits a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease (CAD), independent of the HDL-C level. Thus, extensive research is being conducted to identify new agents with a favorable side effect profile, which would be able to enhance CEC, improve HDL functionality and potentially decrease cardiovascular risk. This review aims to present and discuss the current clinical and scientific evidence pertaining to the significance of HDL functionality over the actual HDL-C concentration in mediating the favorable effects on the cardiovascular system. Thus, we conducted a PubMed search until December 2017 through the English literature using the search terms ‘HDL function/ functionality’, ‘HDL properties’, ‘cardiovascular risk’ and ‘cholesterol efflux capacity’. We also included references from the articles identified and publications available in the authors’ libraries.

10

Authors: Pedro Luis Gonzalez MD, MT, Urania Rappo MD, Karthik Akinapelli MS, Jennifer S McGregor RPh, Sailaja Puttagunta MD, Michael W Dunne MD

Background: Persons who inject drugs (PWID) are at increased risk of acute bacterial skin and skin structure infections (ABSSSIs), a growing healthcare concern. Multiple medical, social, and economic issues, including adherence and comorbidities, complicate the medical care of the PWID population, adversely affecting patient outcomes. Methods: We assessed demographics and outcomes for the PWID population in a double-blind trial of 698 patients randomized to dalbavancin 1500 mg as a single intravenous (IV) infusion or as a 2-dose regimen (1000 mg IV on day 1; 500 mg IV on day 8) for ABSSSI. The primary endpoint was ≥20% reduction in erythema at 48–72 hours in the intent-to-treat population; clinical status was also assessed at days 14 and 28. Results: There were 212/698 (30.4%) patients with a history of injection drug use in this clinical trial. Dalbavancin efficacy was similar between the single- and 2-dose therapy groups in the PWID and non-PWID populations at all timepoints. Dalbavancin was well tolerated in the PWID population, with similar rates of adverse events as the non-PWID population. Conclusion: Dalbavancin as a single-dose or 2-dose regimen had similar efficacy for the treatment of ABSSSI at all timepoints in the PWID and non-PWID populations. A single 30-minute IV infusion would eliminate the need for indwelling IV access. The convenience of a single dose supervised in a health setting may also optimize treatment adherence in the PWID population.

10

Authors: Nicola Personeni MD, Tiziana Pressiani MD, Armando Santoro MD, Lorenza Rimassa MD

Over the past ten years, sorafenib, a multikinase inhibitor, has been the only systemic agent approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Whereas only recently lenvatinib was shown to be noninferior to sorafenib, in terms of survival, all other agents previously tested failed to prove noninferiority (or superiority) when compared with sorafenib. Similarly, in a second-line setting, most investigational drugs have failed to provide better survival outcomes than placebo. However, in 2016, data from the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Overall, side-effects were in line with the known safety profile of regorafenib. More recently, the survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with cabozantinib in the frame of the phase 3 CELESTIAL trial. As HCC seems to be an attractive target for immunotherapy, a phase 1/2 trial reported promising efficacy signals from nivolumab, and results of a larger phase 3 trial with another checkpoint inhibitor, namely, pembrolizumab, are still pending. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and immunotherapy that will likely change the treatment scenario of HCC.

10

Authors: Ariana Papier BA, Lindsay C Strowd MD

Background: Atopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative. Method: We performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy. Results: Sixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that longterm studies are not yet available for the novel PDE4 inhibitor. Discussion: Topical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed.

11

Authors: Constantine E Kosmas MD, PhD, Delia Silverio MD, Andreas Sourlas, Frank Garcia MD, Peter D Montan MD, Eliscer Guzman MD

There is extensive evidence demonstrating that there is a clear inverse correlation between plasma high density lipoprotein cholesterol (HDL-C) concentration and cardiovascular disease (CVD). On the other hand, there is also extensive evidence that HDL functionality plays a very important role in atheroprotection. Thus, genetic disorders altering certain enzymes, lipid transfer proteins, or specific receptors crucial for the metabolism and adequate function of HDL, may positively or negatively affect the HDL-C levels and/or HDL functionality and subsequently either provide protection or predispose to atherosclerotic disease. This review aims to describe certain genetic disorders associated with either low or high plasma HDL-C and discuss their clinical features, associated risk for cardiovascular events, and treatment options.

11

Authors: Daniel I G Cubero MD, PhD, Beatrice Martinez Zugaib Abdalla MD, Jean Schoueri, Fabio Iazetti Lopes, Karine Corcione Turke, Jose Guzman MD, Auro Del Giglio MD, PhD, Carlos D’Apparecida Santos Machado Filho MD, PhD, Vanessa Salzano MD, Dolores Gonzalez Fabra MD

Background: Currently, molecularly targeted drugs are part of the therapeutic arsenal for the treatment of many neoplasms and are responsible for improvements in the quality of life and survival of patients. Although they act on proteins and components within biochemical pathways that are expressed to a greater extent in neoplastic cells, these drugs can also interfere with the activity of normal cells. Scope: This article reviews the cutaneous side effects of main molecularly targeted cancer therapies for solid tumors. Findings: The use of these drugs causes side effects, and the skin is one of the most commonly affected organs. In this literature review, we discuss the adverse cutaneous effects caused by molecularly targeted drugs. Conclusion: The identification of these reactions is important to both dermatologists and oncologists so that they properly diagnose the reaction and administer adequate treatment, which would allow greater adherence to the oncological treatment and improve patients’ quality of life.

12

Authors: Kam Lun Hon MBBS, MD (CUHK), FAAP, FCCM, Kin Fon Leong MBBS, MRCPCH, Theresa Leung MBBS, FRCPCH, FHKAM(Paed), FHKCPaed, Alexander KC Leung MBBS, FRCPC, FRCP(UK & Irel), FRCPCH, FAAP

Background: Eczema or atopic dermatitis (AD) is a common relapsing childhood dermatologic illness. Treatment of AD is primarily topical with emollients and corticosteroid/calcineurin inhibitor, which is efficacious for the majority of patients. However, AD is often complicated and difficult to manage in many Asian cities. Effective therapy is impeded by fallacies in the following aspects: (1) mistrust and unrealistic expectations about Western medicine, (2) skin care and allergy treatment, (3) ambiguity about optimal bathing and moisturizing, (4) hesitation and phobias about the usage of adequate topical corticosteroid and immunomodulatory therapies, (5) food and aeroallergen avoidance and dietary supplementation, and (6) complementary and alternative therapies. Methods and Results: Eleven anonymized case scenarios are described to illustrate issues associated with these fallacies. A literature review is performed and possible solutions to handle or dismiss these fallacies are discussed. Conclusions: The first step in patient care is to accurately assess the patient and the family to evaluate possible concerns, anxiety, and phobias that could impede therapeutic efficacy. Education about the disease should be individualized. Conflicting recommendations on the usage of topical steroid have a detrimental effect on management outcomes, which must be avoided.

12

Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Kam Lun Hon MD, FAAP, FCCM, Theresa NH Leung MBBS, FRCPCH, FHKAM (Paed)

Background: Febrile seizures are the most common neurologic disorder in childhood. Physicians should be familiar with the proper evaluation and management of this common condition. Objective: To provide an update on the current understanding, evaluation, and management of febrile seizures. Methods: A PubMed search was completed in Clinical Queries using the key terms ‘febrile convulsions’ and ‘febrile seizures’. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Results: Febrile seizures, with a peak incidence between 12 and 18 months of age, likely result from a vulnerability of the developing central nervous system to the effects of fever, in combination with an underlying genetic predisposition and environmental factors. The majority of febrile seizures occur within 24 hours of the onset of the fever. Febrile seizures can be simple or complex. Clinical judgment based on variable presentations must direct the diagnostic studies which are usually not necessary in the majority of cases. A lumbar puncture should be considered in children younger than 12 months of age or with suspected meningitis. Children with complex febrile seizures are at risk of subsequent epilepsy. Approximately 30–40% of children with a febrile seizure will have a recurrence during early childhood. The prognosis is favorable as the condition is usually benign and self-limiting. Intervention to stop the seizure often is unnecessary. Conclusion: Continuous preventative antiepileptic therapy for the prevention of recurrent febrile seizures is not recommended. The use of intermittent anticonvulsant therapy is not routinely indicated. Antipyretics have no role in the prevention of febrile seizures.

14

Authors: Alexander KC Leung MBBS, FRCPC, FRCP (UK and Irel), FRCPCH, FAAP, Benjamin Barankin MD, FRCPC, Kin Fon Leong MBBS, MRCPCH, Kam Lun Hon MD, FAAP, FCCM

Background: Penile warts are the most common sexually transmitted disease in males. Clinicians should be familiar with the proper evaluation and management of this common condition. Objective: To provide an update on the current understanding, evaluation, and management of penile warts. Methods: A PubMed search was completed in Clinical Queries using the key terms ‘penile warts’ and ‘genital warts’. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Results: Penile warts are caused by human papillomavirus (HPV), notably HPV-6 and HPV-11. Penile warts typically present as asymptomatic papules or plaques. Lesions may be filiform, exophytic, papillomatous, verrucous, hyperkeratotic, cerebriform, fungating, or cauliflower-like. Approximately one-third of penile warts regress without treatment and the average duration prior to resolution is approximately 9 months. Active treatment is preferable to watchful observation to speed up clearance of the lesions and to assuage fears of transmission and autoinoculation. Patient-administered therapies include podofilox (0.5%) solution or gel, imiquimod 3.75 or 5% cream, and sinecatechins (polypheron E) 15% ointment. Clinician-administered therapies include podophyllin, cryotherapy, bichloroacetic or trichloroacetic acid, oral cimetidine, surgical excision, electrocautery, and carbon dioxide laser therapy. Patients who do not respond to first-line treatments may respond to other therapies or a combination of treatment modalities. Second-line therapies include topical/intralesional/ intravenous cidofovir, topical 5-fluorouracil, and topical ingenol mebutate. Conclusion: No single treatment has been shown to be consistently superior to other treatment modalities. The choice of the treatment method should depend on the physician’s comfort level with the various treatment options, the patient’s preference and tolerability of treatment, and the number and severity of lesions. The comparative efficacy, ease of administration, adverse effects, cost, and availability of the treatment modality should also be taken into consideration.

14

Authors: Montserrat Casamayor MD, PhD, Karen DiDonato MSN, RN, Marc Hennebert MBA, MS, Luca Brazzi MD, PhD, Gregor Prosen MD, FEBEM

Background: Acute pain is among the leading causes of referral to the emergency department (ED) in industrialized countries. Its management mainly depends on intensity. Moderateto- severe pain is treated with intravenous (IV) administered opioids, of which morphine is the most commonly used in the ED. We have estimated the burden of IV administration of morphine in the five key European countries (EU5) using a micro-costing approach. Scope: A structured literature review was conducted to identify clinical guidelines for acute pain management in EU5 and clinical studies conducted in the ED setting. The data identified in this literature review constituted the source for all model input parameters, which were clustered as analgesic (morphine), material used for IV morphine administration, nurse workforce time and management of morphine-related adverse events and IV-related complications. Findings: The cost per patient of IV morphine administration in the ED ranges between €18.31 in Spain and €28.38 in Germany. If costs associated with the management of morphine-related adverse events and IV-related complications are also considered, the total costs amount to €121.13–€132.43. The main driver of those total costs is the management of IV-related complications (phlebitis, extravasation and IV prescription errors; 73% of all costs) followed by workforce time (14%). Conclusions: IV morphine provides effective pain relief in the ED, but the costs associated with the IV administration inflict an economic burden on the respective national health services in EU5. An equally rapid-onset and efficacious analgesic that does not require IV administration could reduce this burden.

14

Authors: Youngjung Kim, Laura Hack, Elizabeth S Ahn, Jungjin Kim

Alcohol use disorder (AUD) is commonly encountered in clinical practice. A combination of psychosocial intervention and pharmacotherapy is the cornerstone of AUD treatment. Despite their efficacy, safety and cost-effectiveness, clinicians are reluctant to prescribe medications to treat individuals with AUD. Given the high rate of relapse with psychosocial intervention alone, increasing patient access to this underutilized treatment has the potential to improve clinical outcome in this difficult-to-treat population. Herein, we provide practical pharmacotherapy strategies to improve treatment outcome for AUD. We review the efficacy and side effects of both on- and off-label agents with a particular focus on clinical applicability. Recommendations are supported by findings from randomized controlled trials (RCT) and meta-analyses selected to be representative, where possible, of current treatment guidelines. The goal of this paper is to help readers use pharmacotherapy with greater confidence when treating patients with AUD.

15

Authors: Milena M McLaughlin PharmD, MSc, Aimee J Guerrero BS, Andrew Merker PharmD

A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse effects and antiretroviral therapy is most robust with protease inhibitors, specifically atazanavir and indinavir, and includes reports of crystalluria, leukocyturia, nephritis, nephrolithiasis, nephropathy and urolithiasis. Several case reports describe potential nephropathy (including Fanconi syndrome) secondary to administration of abacavir, didanosine, lamivudine and stavudine. Case reports documented renal events such as acute renal failure, nephritis, proteinuria and renal stones with efavirenz administration. Regarding rilpivirine, a small increase of serum creatinine levels (SCr) was found in clinical trials; however, the clinical significance and impact on actual renal function is unknown. The integrase strand transfer inhibitors and enfuvirtide have a relatively safe renal profile, although studies have shown dolutegravir and raltegravir cause mild elevations in SCr without an impact on actual renal function. This is similar to the reaction observed with cobicistat, the pharmacokinetic enhancer frequently given with elvitegravir.

17

Authors: Margarita SaizSatjes, Francisco Javier Martinez-Martin

Antihypertensive treatment of patients with diabetes should include those drugs with a positive effect on metabolic parameters. Most patients with diabetes require at least two antihypertensive agents. Combining a dihydropyridine calcium channel blocker with a renin-angiotensin-aldosterone system inhibitor is a rational approach. However, not all dihydropyridines are equal with respect to their effects on metabolic parameters. Thus, manidipine exerts a positive effect on insulin resistance. However, this effect has not been observed with amlodipine. On the other hand, the excessive activation of sympathetic nervous system has been related with an increase of insulin resistance, pulse pressure, and ankle edema rates. Compared with amlodipine, manidipine activates sympathetic nervous system to a lesser extent. As a result, treatment with manidipine represents a good option in hypertensive patients with diabetes.

19

Authors: Carlos Blanco MD, PhD, Raphaelle Bazire MD, Laura Argiz MD, Jenaro Hernández-Peña MD, PhD

The objective of the systematic review is to provide complete and updated information on efficacy and safety of sublingual immunotherapy (SLIT) formulations for the treatment of allergic respiratory diseases (ARDs). The literature search was conducted on PubMed database, involving double-blind, randomized clinical trials published between January 1992 and 2018, written in English, and performed in humans. The number of articles finally selected for review was 112. Data from the majority of properly controlled clinical trials demonstrate that SLIT is effective not only with short-term use (first year) but also with long-term use (up to the third year of active therapy), for treating ARDs in children and adults. Both continuous and discontinuous schemes of administration showed significant reductions in symptom and medication scores. Moreover, a SLITinduced disease-modifying effect has been documented mainly with grass pollen extracts, since improvement is maintained during at least 2 years of follow-up after a 3-year treatment period. Additionally, allergen immunotherapy should also be considered a preventive strategy, especially for decreasing bronchial asthma incidence in children and adolescents with allergic rhinitis treated with SLIT. This therapy is also safe, producing only a few mainly local and mild-to-moderate adverse events, and usually self-limited in time. The registration and authorization of allergen SLIT preparations (grasses and house-dust mite tablets) as drugs by regulatory agencies, such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), has represented a landmark in allergy immunotherapy research. Further long-term studies, specially designed with allergens other than grass pollen or house-dust mites, not only in allergic rhinoconjunctivitis but also on asthmatic subjects, as well as studies comparing different administration schedules and/or routes, are required in order to continue the progress in the modern development of this particularly promising therapy.

21

Authors: Elizabeth S Nakasone MD, PhD, Sara A Hurvitz MD, Kelly E McCann MD, PhD

Breast cancer is the most prevalent malignancy in women and the second most common cause of cancer-related death worldwide. Despite major innovations in early detection and advanced therapeutics, up to 30% of women with nodenegative breast cancer and 70% of women with node-positive breast cancer will develop recurrence. The recognition that breast tumors are infiltrated by a complex array of immune cells that influence their development, progression, and metastasis, as well as their responsiveness to systemic therapies has sparked major interest in the development of immunotherapies. In fact, not only the native host immune system can be altered to promote potent antitumor response, but also its components can be manipulated to generate effective therapeutic strategies. We present here a review of the major approaches to immunotherapy in breast cancers, both successes and failures, as well as new therapies on the horizon.

1

Authors: Christophe Sapin, Ann Hartry, Siddhesh A Kamat, Maud Beillat, Ross A Baker, Anna Eramo

The authors wish to make the following corrections to their article: Sapin C, Hartry A, Kamat SA, Beillat M, Baker RA, Eramo A. Pharmacoeconomic comparison of aripiprazole once-monthly and paliperidone palmitate from a head-to-head clinical trial in schizophrenia: a US analysis. Drugs in Context 2016; 5: 212301. DOI: 10.7573/dic.212301

5

Authors: S. Morelli, E. Puxeddu

Lenvatinib, a multikinase inhibitor, is approved for the treatment of patients with radioiodine-refractory metastatic thyroid cancer on the basis of a Phase III, prospective, double-blind, randomized, placebo-controlled trial that showed longer progression-free survival in the drug-treated arm. Here, we report the case of a young papillary thyroid cancer patient, pretreated with three other kinase inhibitors, who achieved a long-term clinical benefit from lenvatinib in the fourth-line setting.

8

Authors: Sabrina Rossi, Alessandra Cassano, Antonia Strippoli, Giovanni Schinzari, Ettore D’Argento, Michele Basso, Carlo Barone

Background: Eribulin mesylate is currently approved in the United States and Europe for the treatment of metastatic breast cancer (MBC). Scope: The objective of this retrospective study is to find specific predictive criteria related to patient or tumor characteristics in order to select patients that might benefit the most from eribulin and define the correct treatment sequence. Findings: Forty-four patients with MBC who received eribulin in third or subsequent lines of therapy in a single Italian center were considered eligible. Patients were stratified by body mass index, hormonal/HER2 status, and previous therapies. Primary endpoint was progression free survival (PFS), whereas secondary endpoint was disease control rate (DCR). A longer PFS was found in patients with hormone-positive tumors (p=0.0051), in HER2-negative cases (p=0.037), and in overweight patients (p=0.0015). No difference in efficacy was observed when eribulin was administered in third or subsequent lines of therapy. Significantly longer PFS (p<0.0001) and higher DCR (p=0.035) were achieved by patients previously treated with paclitaxel-bevacizumab in comparison to those pretreated with other drug combinations or with anthracyclines. Prior treatment with nab-paclitaxel seems to have a detrimental effect on PFS (p=0.0008). Conclusion: Hormone and HER2 status seems a good predictive and prognostic indicator of response to eribulin. Efficacy seems independent from the number of prior therapies, and it is not influenced by prior endocrine treatments and anthracyclines-containing regimens. On the other hand, sensitivity to a prior treatment with paclitaxel-bevacizumab might be predictive of response to eribulin.

10

Authors: Nirmish R Shah

Iron overload is a concern for patients who require repeated red-blood-cell transfusions due to conditions such as sickle cell disease, thalassemia, or myelodysplastic syndromes. The recommended treatment for removing excess iron in these patients is iron chelation therapy. Currently available iron chelators include deferoxamine, which is administered by injection, and deferasirox and deferiprone, both of which are administered orally. Adherence to iron chelator therapy is an important consideration and may be affected by side effects. A new formulation of deferasirox, a film-coated tablet (FCT), has the potential to improve adherence by offering greater flexibility in administration compared with the original formulation of deferasirox, a dispersible tablet (DT) for oral suspension. This review provides an overview of the currently available iron chelator formulations, with a focus on a comparison between deferasirox DT for oral suspension and deferasirox FCT. The new formulation may be associated with fewer side effects and has increased bioavailability. In addition, alternative strategies for iron chelation, such as combining two different iron chelators, will be discussed.

12

Authors: Rosamund J Wilson, J Brian Copley

Background: Calcium-based and non-calcium-based phosphate binders have similar efficacy in the treatment of hyperphosphatemia; however, calcium-based binders may be associated with hypercalcemia, vascular calcification, and adynamic bone disease. Scope: A post hoc analysis was carried out of data from a 16- week, Phase IV study of patients with end-stage renal disease (ESRD) who switched to lanthanum carbonate monotherapy from baseline calcium acetate/calcium carbonate monotherapy. Of the intent-to-treat population (N=2520), 752 patients with recorded dose data for calcium acetate (n=551)/calcium carbonate (n=201) at baseline and lanthanum carbonate at week 16 were studied. Elemental calcium intake, serum phosphate, corrected serum calcium, and serum intact parathyroid hormone levels were analyzed. Findings: Of the 551 patients with calcium acetate dose data, 271 (49.2%) had an elemental calcium intake of at least 1.5 g/day at baseline, and 142 (25.8%) had an intake of at least 2.0 g/day. Mean (95% confidence interval [CI]) serum phosphate levels were 6.1 (5.89, 6.21) mg/dL at baseline and 6.2 (6.04, 6.38) mg/dL at 16 weeks; mean (95% CI) corrected serum calcium levels were 9.3 (9.16, 9.44) mg/dL and 9.2 (9.06, 9.34) mg/dL, respectively. Of the 201 patients with calcium carbonate dose data, 117 (58.2%) had an elemental calcium intake of at least 1.5 g/day, and 76 (37.8%) had an intake of at least 2.0 g/day. Mean (95% CI) serum phosphate levels were 5.8 (5.52, 6.06) mg/dL at baseline and 5.8 (5.53, 6.05) mg/dL at week 16; mean (95% CI) corrected serum calcium levels were 9.7 (9.15, 10.25) mg/dL and 9.2 (9.06, 9.34) mg/dL, respectively. Conclusion: Calcium acetate/calcium carbonate phosphate binders, taken to control serum phosphate levels, may result in high levels of elemental calcium intake. This may lead to complications related to calcium balance.

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Authors: Amalia Leceta, Ander Sologuren, Román Valiente, Cristina Campo, Luis Labeaga

Background: Bilastine is a safe and effective commonly prescribed non-sedating H1-antihistamine approved for symptomatic treatment in patients with allergic disorders such as rhinoconjunctivitis and urticaria. It was evaluated in many patients throughout the clinical development required for its approval, but clinical trials generally exclude many patients who will benefit in everyday clinical practice (especially those with coexisting diseases and/or being treated with concomitant drugs). Following its introduction into clinical practice, the Medical Information Specialists at Faes Farma have received many practical queries regarding the optimal use of bilastine in different circumstances. Data sources and methods: Queries received by the Medical Information Department and the responses provided to senders of these queries. Results: The most frequent questions received by the Medical Information Department included the potential for drug-drug interactions with bilastine and commonly used agents such as anticoagulants (including the novel oral anticoagulants), antiretrovirals, antituberculosis regimens, corticosteroids, digoxin, oral contraceptives, and proton pump inhibitors. Most of these medicines are not usually allowed in clinical trials, and so advice needs to be based upon the pharmacological profiles of the drugs involved and expert opinion. The pharmacokinetic profile of bilastine appears favourable since it undergoes negligible metabolism and is almost exclusively eliminated via renal excretion, and it neither induces nor inhibits the activity of several isoenzymes from the CYP 450 system. Consequently, bilastine does not interact with cytochrome metabolic pathways. Other queries involved specific patient groups such as subjects with renal impairment, women who are breastfeeding or who are trying to become pregnant, and patients with other concomitant diseases. Interestingly, several questions related to topics that are well covered in the Summary of Product Characteristics (SmPC), which suggests that this resource is not being well used. Conclusions: Overall, this analysis highlights gaps in our knowledge regarding the optimal use of bilastine. Expert opinion based upon an understanding of the science can help in the decision-making, but more research is needed to provide evidence-based answers in certain circumstances.

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Authors: Adam Ioannou, Sofia Metaxa, George Kassianos, Constantinos G Missouris

Objective: Our aim was to assess whether the recommendations and guidelines for thromboprophylaxis in patients with atrial fibrillation (AF) have been adopted in general practice (GP). Methods: We conducted a retrospective study using the GP computer database (Hatfield, UK) on all 9400 patients to assess the quality of anticoagulation in patients with a recorded diagnosis of AF. Results: Of the 180 patients with a diagnosis of AF, 107 (59.4%) were treated with warfarin, 19 (10.6%) with a novel oral anticoagulant (NOAC), 31 (17.2%) with aspirin or clopidogrel, and 23 (12.8%) received none. Thirty-seven patients (34.6%) who were taking warfarin had a time in the therapeutic range (TTR) of less than 65%. Forty-five (27.6%) of the 163 patients who had a CHA2DS2VASc score of two or more were not prescribed a vitamin K antagonist (VKA) or a NOAC. None had a HAS-BLED greater than the CHA2DS2VASc score. Conclusion: Our study demonstrates that one in four patients with non-valvular AF, at risk of a stroke, is not being adequately treated with an oral anticoagulant in primary care. The majority were treated with warfarin, a third of which had a low TTR. A high proportion of patients are prescribed antiplatelet therapy instead. This is despite overwhelming evidence that VKAs and NOACs, and not aspirin or clopidogrel, improve outcome in patients with non-valvular AF. We suggest that a review of GP practice databases should be considered to identify patients with non-valvular AF, at risk of a disabling or fatal event, and measures taken to initiate anticoagulant therapy.

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Authors: Ivelina Gueorguieva, Ann Cleverly, Durisala Desaiah, Analia Azaro, Joan Seoane, Irene Braña, Elisabet Sicart, Colin Miles, Michael M Lahn, Malcolm I Mitchell, Jordi Rodon

Objective: Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor β (TGFβ) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations. Methods: Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. Results: Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-∞) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. Conclusions: In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation.

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Authors: Teerha Piratvisuth, Piyawat Komolmit, Henry LY Chan, Tawesak Tanwandee, Wattana Sukeepaisarnjaroen, Mário G Pessoa, Eduardo Fassio, Suzane K Ono, Fernando Bessone, Jorge Daruich, Stefan Zeuzem, Michael Manns, Alkaz Uddin, Yuhong Dong, Aldo Trylesinski

Background: A 2-year roadmap study was conducted to evaluate the efficacy and safety of tenofovir intensification at Week 24 in patients with chronic hepatitis B (CHB) receiving telbivudine. Scope: A prospective multicenter study was conducted in treatment-naive patients with hepatitis B e antigen (HBeAg)- positive CHB. All patients received telbivudine (600 mg/day) until Week 24. Thereafter, patients with detectable hepatitis B virus (HBV) DNA (≥300 copies/mL) were administered tenofovir (300 mg/day) plus telbivudine, and patients with undetectable HBV DNA continued telbivudine monotherapy until Week 104. The primary endpoint was the proportion of patients with undetectable HBV DNA (<300 copies/mL) at Weeks 52 and 104. Findings: A total of 105 patients were enrolled in the trial, of which 100 were eligible for efficacy analysis. Undetectable HBV DNA levels were observed at Week 24 in 55 patients who continued on with telbivudine monotherapy. The remaining 45 patients with detectable HBV DNA received tenofovir add-on therapy. With monotherapy, 100% (55/55) and 94.5% (52/55) of patients achieved HBV DNA <300 copies/mL at Weeks 52 and 104, respectively; the corresponding values for patients with add-on therapy were 84.4% (38/45) and 93.3% (42/45). Overall, undetectable HBV DNA (<300 copies/mL) was found in 93% (93/100) and 94% (94/100) of patients at Weeks 52 and 104, respectively. HBeAg seroconversion rate was 44.4% (44/99) at Week 104 for the overall patient population. One patient in the monotherapy group and six in the intensification group demonstrated HBsAg clearance at Week 104. HBsAg seroconversion was observed in four patients at Week 104, all belonged to the tenofovir intensification group. Eight patients sustained HBsAg loss during a posttreatment follow-up period of 16 weeks. Alanine aminotransferase (ALT) normalization was constant in the telbivudine monotherapy group, whereas a progressive improvement was observed in the tenofovir intensification group. Two patients in the monotherapy and none in the intensification group experienced viral breakthrough by Week 104. There were no reports of myopathy in either group. The mean changes in estimated glomerular filtration rate (eGFR), estimated using the Modification of Diet in Renal Disease (MDRD) formula, from baseline to Week 104 were +6.145 mL/min/1.73 m2 (p=0.0230) and +7.954 mL/min/1.73 m2 (p=0.0154) in the telbivudine monotherapy and tenofovir intensification groups, respectively. The incidence of serious AEs was four in the telbivudine monotherapy and two in the tenofovir intensification group. The main limitation of this study was limited sample size, which made the power of the observation low, and the absence of a comparative subgroup to assess the progression of patients with detectable HBV DNA without treatment intensification. Conclusions: Data from this 2-year roadmap study confirmed that telbivudine with add-on tenofovir was effective and well tolerated in patients with CHB. Telbivudine was associated with an improvement in eGFR from baseline in both the groups.

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Authors: Paul Harper, Emmanuel J Favaloro, Julie Curtin, Chris Barnes, Scott Dunkley

Human plasma-derived factor VIII/von Willebrand factor complex concentrates are used to control bleeding in patients with von Willebrand disease (VWD) or haemophilia A (HA). The properties of these haemostatic factor concentrates vary widely, which can have significant clinical implications. This review provides an extensive overview of the molecular properties, in addition to pharmacokinetic, efficacy and safety data, and case studies of clinical experience of one such concentrate, Biostate. These data are discussed in the context of various therapeutic applications and compared with other factor concentrate products. Data are presented from data on file from the manufacturer; product information and published experimental and clinical pharmacokinetic, safety and efficacy study data; and example case studies of clinical experience. The data discussed herein demonstrate that Biostate has well-established efficacy profiles in the treatment of patients with VWD or HA, with the control of bleeding rated as ‘excellent’, ‘good’ or ‘moderate’ in >90% of patients. In an immune-tolerance induction setting, 73% of patients achieved a complete response following treatment with Biostate. Biostate was generally well tolerated in patients with HA or VWD, with infrequent minor adverse events reported and no reported cases of clinically relevant thrombosis.

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Authors: Vinod Dasa, Mitch DeKoven, Kainan Sun, Allan Scott, Sooyeol Lim

Background: Intra-articular injection of hyaluronic acid (HA) for knee osteoarthritis (OA) effectively reduces pain and delays total knee replacement (TKR) surgery; however, little is known about relative differences in clinical and cost outcomes among different HA products. Objective: To compare disease-specific costs and risk of TKR among patients receiving different HA treatments in a commercially insured cohort of patients with knee OA in the USA. Method: Retrospective analyses using IMS Health’s PharMetrics Plus Health Plan Claims Database were conducted by identifying knee OA patients with claims indicating initiation of HA treatment at an ‘index date’ during the selection period (2007–2010). Patients were required to be continuously enrolled in the database for 12 months preindex to 36 months postindex. A generalized linear model (GLM) with a gamma distribution and log-link function was used to model aggregate patient-based changes in disease-specific costs. A Cox proportional hazards model (PHM) was used to model the risk of TKR. Both multivariate models included covariates such as age, gender, comorbidities, and preindex healthcare costs. Results: 50,389 patients with HA treatment for knee OA were identified. 18,217 (36.2%) patients were treated with HA products indicated for five injections per treatment course (Supartz and Hyalgan). The remainder were treated with HA products indicated for fewer than five injections per treatment course, with 20,518 patients (40.7%) receiving Synvisc; 6,263 (12.4%), Euflexxa; and 5,391 (10.7%), Orthovisc. Synvisc- and Orthovisc-injected patients had greater disease-specific costs compared to Supartz/Hyalgan (9.0%, p<0.0001 and 6.8%, p=0.0050, respectively). Hazard ratios (HRs) showed a significantly higher risk of TKR for patients receiving Synvisc compared to Supartz/Hyalgan (HR=1.069, p=0.0009). Patients treated with Supartz/Hyalgan, Euflexxa, and Orthovisc had longer delays to TKR than those treated with Synvisc. Conclusion: Analysis of administrative claims data provides real-world evidence that meaningful differences exist among some HA products in disease-specific cost and time to knee replacement surgery.

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Authors: Ivar S Jensen, Emily Zacherle, Christopher M Blanchette, Jie Zhang, Wes Yin

Background: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22–53% with progression-free survival (PFS) in the range of 4.8–8.8 months. Recently, combination targeted therapies have improved response rates to about 66–69%, PFS to 11.0–12.6 months and overall survival (OS) to 25.1–25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19–29% with monotherapies and improved PFS of 11.7 compared with 4.4–5.8 months with monotherapies, the OS benefit is yet to be established in phase 3 trials. As healthcare costs continue to rise, US payers have a predominant interest in assessing the value of available treatments. Therefore, a cost-benefit model was developed to evaluate the value of treating BRAF+ advanced melanoma with two combination therapies: nivolumab + ipilimumab (N+I) and dabrafenib + trametinib (D+T). Scope: The model was used to estimate total costs, total costs by expenditure category, cost per month of PFS and cost per responder for the payer, and societal perspectives of treating advanced melanoma patients with the BRAF V600 mutation using combination targeted therapy (D+T) or combination immunotherapy (N+I). The model followed patients from initiation of treatment to the point of progression or death. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results and to understand the dispersion of simulated results. Findings: Based on a hypothetical payer with one million covered lives, it was expected that fourteen metastatic melanoma patients with the BRAF V600 mutation would be treated each year. Cost-benefit with N+I and D+T was simulated from the payer perspective. The cost per month of PFS for N+I was $22,162, while that for D+T was $17,716 (–$4,446 cost difference); the cost per responder for N+I was $388,746 and that for D+T was $282,429 (–$106,316 cost difference). The cost per month of PFS and per responder from the societal perspective resembled the patterns observed from the payer’s perspective: the cost per month of PFS for N+I was $22,843, while that for D+T was $18,283 (–$4,560 cost difference). The cost per responder for N+I was $400,695 and that for D+T was $291,473 (–$109,222 cost difference). The totals of travel and treatment time for N+I and D+T were 58 hours and 3.9 hours per patient, respectively, of which total infusion time for N+I accounted for a majority – 59% – of the 58 hours. Sensitivity analyses indicated that results were most sensitive to model inputs for median PFS, body weight, and drug cost. Moreover, D+T is likely associated with a lower cost per month of PFS and cost per responder than N+I, except at low body weights (less than 57 kg). Conclusion: The model presented in this study was used to analyze the clinical and economic benefit of using combination therapies in advanced melanoma patients with the BRAF V600 mutation. This analysis suggests D+T therapy is associated with less patient time and lower costs relative to N+I to gain similar PFS and overall response rate (ORR) benefits.

5

Authors: Molly R Belkin, Thomas L Schwartz

Clonidine and guanfacine are alpha-2 receptor agonists that decrease sympathetic outflow from the central nervous system. Posttraumatic stress disorder (PTSD) is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system. Currently, the only US Food and Drug Administration (FDA)-approved medications for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. Sometimes use of the SSRIs may not lead to full remission and symptoms of hyperarousal often persist. This article specifically reviews the literature on alpha-2 receptor agonist use for the treatment of PTSD and concludes that while the evidence base is limited, these agents might be considered useful when SSRIs fail to treat symptoms of agitation and hyperarousal in patients with PTSD.

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Authors: Marco Turini, Vittoria Piovesana, Pierfrancesco Ruffo, Claudio Ripellino, Nazarena Cataldo

Background: Chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as one of the most distressing adverse effects among treated patients with cancer. Inadequately treated, CINV can lead to increased resource utilization and severely impair patients’ daily functioning and quality of life. Direct costs include acquisition cost of antiemetic drugs and rescue medication, administration devices, add-on treatments, such as hydration, and additional patient care, that is, nursing and physician time, unscheduled office visits, emergency room admissions, and, in some cases, extended hospitalization or readmission. There are many reports on the cost-effectiveness of antiemetic drugs, but information on the total cost per patient associated with CINV is limited. The costs associated with severe CINV episodes are considered responsible for the most significant part of the expenditures. Scope: The aim of this study was to investigate the management of CINV episodes in three European health-care environments and to estimate direct costs associated with severe CINV episodes. Methods: An online survey addressed to Italian, German, and French oncologists and oncology nurses was performed. The survey included 41 questions about the management and the resource utilization for patients experiencing any CINV episode during the 6-month period preceding the survey. Furthermore, the cost associated with severe CINV episode management was estimated by adopting the National Health Service’s perspective. Findings: A large proportion of patients receiving chemotherapy experienced a CINV episode (34.4% in Italy, 50.2% in France, and 40.4% in Germany); among those, 8.8% in Italy, 11.6% in France, and 19.2% in Germany experienced a severe CINV episode. Compared with Italy, Germany and France presented a greater hospitalization rate following an unplanned visit to the oncology ward or an emergency room access due to CINV. In Italy, the mean cost per patient with a severe CINV episode resulted in approximately €389, about half of the mean cost in France (€750) and a third of the mean cost in Germany (€1,017). Conclusions: Severe CINV episodes requiring hospitalization, day hospital, or hospitalization extension involve a significant cost for the National Health Services; additional studies should be conducted in order to evaluate potential ways to offset these expenses.

7

Authors: Sarah L Scarpace

Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. Immunotherapies directed at the programmed cell death-1 receptor (PD-1) or its ligand (PD-L1) (nivolumab and pembrolizumab) have demonstrated efficacy in both nonsquamous and squamous cell NSCLC. Because of their similar mechanism of action against the PD-L1/PD-1 pathway, both drugs have similar toxicity profiles related to immune-mediated adverse reactions that can generally be monitored and managed with oral corticosteroids. This paper provides an overview of drug therapy options for squamous cell NSCLC with a focus on the evidence and clinical application of the anti-PD1 therapies. A comparison of the dosing, administration, indications, and differences in the measurement of PD-L1 expression in the clinical trials of nivolumab and pembrolizumab is also provided.

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Authors: George Kassianos

Uptake of vaccination against seasonal influenza in healthcare workers (HCWs) is, in general, low (vaccine coverage of 6–54%), as is awareness of its importance, and has been decreasing in most European Union (EU) countries in recent years. By virtue of their working environment, HCWs are at an increased risk of influenza infection and of subsequently transmitting the virus to vulnerable patients, in whom disease burden is significant. It could be argued that a similar or higher target vaccination rate to that recommended for older age groups and people with chronic medical conditions (75%) should be applied to HCWs, and the European Council recommends Member States to improve vaccination coverage in this population. In this context, better education of HCWs is needed to increase awareness and highlight the importance of HCW vaccination for the benefit of public health, particularly for their patients, who may be at risk of serious complications that could lead to disability or death. Secondary to these professional responsibilities, personal benefits (as well as benefits to close family and friends) should also be emphasised. Misconceptions that create barriers to vaccination need to be discussed openly and objections placed in the context of public health.

10

Authors: Saleh al-Alaiyan, Paul Pollack, Gerard F Notario

Background: The peak season of respiratory syncytial virus (RSV) infections in warmer climates may extend beyond the typical five-month RSV season of temperate regions. Additional monthly doses of palivizumab may be necessary in warmer regions to protect children at high risk for serious infection by the RSV. Methods: In a Phase II, single-arm, single-center, noncomparative, open-label, prospective study conducted in Saudi Arabia, children at high risk for RSV infection received up to seven monthly injections of palivizumab (15 mg/kg) during the 2000–2001 RSV season. Key enrollment criteria were no previous exposure to palivizumab and gestational age ≤35 weeks, ≤6 months of age at enrollment, or chronic lung disease and ≤24 months of age at enrollment. We wished to assess the safety, immunogenicity, and pharmacokinetics of palivizumab as an extended seven-dose regimen. Results: Of 18 enrolled patients, 17 patients received seven palivizumab injections. Seven adverse events (AEs) occurred in five patients. Bronchiolitis was the most commonly reported AE. Six serious AEs occurred in four patients. No AEs were considered related to palivizumab. Trough levels of palivizumab in serum were >40 μg/mL in most patients after the first injection and in 16/18 and 14/17 patients after the fourth and sixth injections, respectively. Except for one patient at one visit, the anti-palivizumab titer was <1:10 at all visits. Conclusion: These data suggest that an extended palivizumab regimen of up to seven monthly doses during the RSV season exhibited an acceptable safety profile in children at high risk for RSV infection in Saudi Arabia.

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Authors: Daniel Santarsieri, Thomas L Schwartz

Prescribing of antidepressant treatment (ADT) for major depressive disorder (MDD) has increased in quantity and popularity over the last two decades. This is likely due to the approval of safer medications, better education of clinicians and their patients, direct-to-consumer marketing practices, and less stigma associated with those taking ADT. This trend has also been met with some controversy, however, as the ongoing safety and effectiveness of these treatments have at times been called into question. This paper discusses the differing levels of evidence that support the use of ADT based on (A) Food and Drug Administration approvals, (B) data from randomized controlled trials or meta-analyses and, where these are not available, the authors discuss and apply, (C) theoretical pharmacodynamic principles to justify antidepressant choice in the treatment of MDD patients. The final section discusses standard psychopharmacology guideline approaches to better alert the reader as to which practices are commonplace compared with those which are more outside of the standard of care.

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Authors: Allicia C Girvan, Gebra C Carter, Li Li, Anna Kaltenboeck, Jasmina Ivanova, Maria Koh, Jessi Stevens, Eleanor Hayes-Larson, Michael M Lahn

Background: Glioblastoma (GB) treatment remains challenging because of recurrence and poorly defined treatment options after first-line therapy. To better understand real-world application of treatment paradigms and their impact on outcomes, we describe patterns of treatment, outcomes, and use of cancer-related healthcare resource for glioblastoma in the USA. Methods: A retrospective, online chart-abstraction study was conducted; each participating oncologist contributed ≤5 charts. Patients were ≥18 years with biopsy-confirmed primary or secondary newly diagnosed GB on or after 1 January 2010, had received first- and second-line therapies, and had information collected for ≥3 months after initiation of second-line therapy or until death. Assessments were descriptive and included Kaplan–Meier analyses from initiation to end of second-line therapy, disease progression, or death. Results: One hundred sixty physicians contributed information on 503 patient charts. During first-line therapy, patients most commonly underwent temozolomide monotherapy (76.5%). During second-line therapy, patients most commonly underwent bevacizumab monotherapy (58.1%). Median duration of second-line therapy was 130 days; median time to disease progression was 113 days. Median survival was 153 days. Use of supportive care was observed to be numerically higher in first- compared with second-line therapy except for anti-depressants, growth factors, and stimulants. Frequently used resources included corticosteroids (78.8% of patients in first-line and 62.6% in second-line therapies), anti-epileptics (45.8% and 41.5%) and narcotic opioids (45.3% and 41.4%). Conclusions: Most GB patients received temozolomide during first-line therapy and bevacizumab monotherapy or combination therapy during second-line therapy. Use of supportive care appeared to be higher in first- compared with second-line therapy for some agents.

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Authors: Richard Brice, Sharon Shelley, Pankaj Chaturvedi, Divina Glah, Donna Ashley, Monica Hadi

Introduction: Management of type 2 diabetes mellitus (T2DM) often requires intervention with oral and injectable therapies. Across National Health Service (NHS) England, injectable therapies may be initiated in secondary, intermediate or primary care. We wished to understand resource utilization, pathways of care, clinical outcomes, and experience of patients with T2DM initiated on injectable therapies. Method: We conducted three service evaluations of initiation of injectable therapies (glucagon-like peptide–1 receptor agonists (GLP-1 RAs) or basal insulin) for T2DM in primary, secondary and intermediate care. Evaluations included retrospective review of medical records and service administration; prospective evaluation of NHS staff time on each episode of patient contact during a 3-month initiation period; patient-experience survey for those attending for initiation. Data from each evaluation were analysed separately and results stratified by therapy type. Results: A total of 133 patients were included across all settings; 54 were basal-insulin initiations. After initiation, the mean HbA1c level fell for both types of therapies, and weight increased for patients on basal insulin yet fell for patients on GLP-1 RA. The mean cost of staff time per patient per initiation was: £43.81 for GLP-1 RA in primary care; £243.49 for GLP-1 RA and £473.63 for basal insulin in intermediate care; £518.99 for GLP-1 RA and £571.11 for basal insulin in secondary care. Patient-reported questionnaires were completed by 20 patients, suggesting that patients found it easy to speak to the diabetes team, had opportunities to discuss concerns, and felt that these concerns were addressed adequately.

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Authors: Christopher M Blanchette, Caihua Liang, Deborah P Lubeck, Britt Newsome, Sandro Rossetti, Xiangmei Gu, Benjamin Gutierrez, Nancy D Lin

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. Methods: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/2000–2/28/2013 and ≥6 months of previous continuous enrollment (baseline) within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD) patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. Results: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. Conclusions: These results suggest that distribution of patients by age at transition to next stage may be useful for identification of ADPKD patients at risk of rapid progression. The results also suggest that medical claims with diagnosis codes for “unspecified PKD”, in absence of a diagnosis code for autosomal recessive polycystic kidney disease, may be a good proxy for ADPKD.

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Authors: Julia M Kasprzak, Yaohul G Xu

Lentigo maligna is a melanocytic neoplasm occurring on sun-exposed skin, usually on the head and neck, of middle-aged and elderly patients. It is thought to represent the in situ phase of lentigo maligna melanoma. The ill-defined nature and potentially large size of lesions can pose significant diagnostic and treatment challenges. The goal of therapy is to cure the lesions in order to prevent development of invasive disease, and surgical excision is the treatment of choice to achieve clear histological margins. Nonsurgical treatment modalities have been reported; however, evidence is lacking to support their use. Age, general health, and comorbidities need to be taken into account when deciding the right treatment modality for each individual patient.