INTRODUCTION:Sickle cell disease (SCD) is a clinically heterogeneous condition in which individuals experience markedly different disease trajectories. As more people with SCD now survive to adulthood, their disease becomes more complicated due to comorbidities, both related and unrelated to SCD. Thus, a precision-oriented approach is essential when initiating new treatments to ensure the delivery of meaningful and sustained benefits for people with SCD. AREAS COVERED:This expert review examines selected, underrecognized safety concerns related to disease-modifying therapies for SCD as well as for other medications often used in this population. We discuss examples of safety issues involving SCD-modifying therapies, cardiovascular and renal medications, antibiotics, and corticosteroids, highlighting how the unique pathophysiology of SCD may influence drug safety, tolerability, and organ injury. The review is based on a narrative assessment of published clinical trials, observational studies, post-marketing safety reports, registry data, and expert clinical experience. EXPERT OPINION:Although SCD is recognized as a highly heterogeneous condition, this issue is not consistently considered in clinical trial design or when using non-SCD therapies in this population. The recent emergence of new drugs emphasizes the importance of longitudinal monitoring, real-world safety assessment, and multidisciplinary specialist care.
BACKGROUND:Myositis may present as a treatment-related adverse event (TRAE) during immune checkpoint inhibitor (ICI) therapy. In the ARON-MOUSEION-017 meta-analysis, we aimed to assess the frequency of myositis among cancer patients treated with ICIs. RESEARCH DESIGN AND METHODS:The present systematic review and meta-analysis was registered in PROSPERO with ID no. CRD420261278193. Embase, PubMed, Scopus and Web of Science databases were consulted, using Boolean terms and keywords 'Immunotherapy,' 'Myositis' and 'Neoplasms.' RESULTS:For myositis of any grade, 13 studies were included, suggesting that heterogeneity across studies was high and statistically significant (p < 0.001; τ2 = 3.78; I2 = 95.3%, 95% CI [93.1%; 96.7%]), and the pooled proportion of patients affected by any-grade myositis treatment-related adverse events (TRAEs) was 4.2% (95% CI = [1.1%; 14.6%]). CONCLUSIONS:ICI-myositis often appears in concomitance with other immune-mediated conditions, such as myocarditis and myasthenia gravis. These events are clinically relevant, since they are often associated with more severe disease courses and unfavorable outcomes, increasing morbidity and mortality.
INTRODUCTION:Knee osteoarthritis (KOA) is a highly prevalent condition worldwide, resulting in a significant symptom burden and diminished quality of life. Mainstays of KOA management include weight loss, exercise, physical activity, and simple analgesia, with joint replacement as a last resort. Intra-articular injections, especially corticosteroids, have been increasingly used to provide symptomatic relief when simple analgesia fails. However, the efficacy and safety of intra-articular corticosteroid injections (IACS) remain poorly established. AREAS COVERED:This narrative literature review will evaluate the current available literature, outlining evidence on the use of IACS in KOA as well as its clinical efficacy, safety, adverse effects and potential alternative injections. Articles included were sourced from the University of Sydney Library database, Medline via Ovid, and Scopus, between 2000 and 2026. EXPERT OPINION:Overall, while IACS may only provide short-term pain relief, evidence suggests that long-term use should be avoided to prevent chondrotoxicity and further progression of osteoarthritis.
INTRODUCTION:We conducted a systematic review and meta-analysis to evaluate real-world safety outcomes associated with Janus kinase (JAK) inhibitors in patients with moderate-to-severe atopic dermatitis (AD). METHODS:PubMed, Embase, Cochrane Library, and CINAHL were searched through April 2025. Two independent reviewers screened studies and extracted data according to predefined criteria. Risk of bias was assessed using Agency for Healthcare Research and Quality tools. RESULTS:The pooled incidence rates of adverse events (AEs) and serious adverse events (SAEs) with JAK inhibitors were 0.42 (95% CI: 0.35-0.50) and 0.03 (95% CI: 0.01-0.05), respectively. The most common AEs included acne (effect size [ES] = 0.14, 95% CI: 0.12-0.16), skin and subcutaneous tissue infections (ES = 0.17, 95% CI: 0.09-0.26), and herpes virus infections (ES = 0.07, 95% CI: 0.06-0.09). Compared with anti - interleukin-4/interleukin-13 inhibitors, JAK inhibitors were associated with higher risks of acne, anemia, and creatine kinase elevations. CONCLUSIONS:AEs were common but predominantly mild to moderate. Infections, particularly skin and subcutaneous tissue and herpes virus infections, were among the most frequently reported events. The pooled incidence of SAEs, including cardiovascular events, was low within reported follow-up periods. However, heterogeneity and relatively short follow-up limit conclusions regarding long-term risk. PROTOCOL REGISTRATION:CRD42025634423.
INTRODUCTION:Dual immune-checkpoint blockade targeting T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and programmed death-ligand 1 (PD-L1) shows synergistic antitumor activity. However, its safety profile remains incompletely defined. Our systematic review and meta-analysis aim to evaluate the safety of tiragolumab in combination with atezolizumab (TA) for the treatment of solid tumors. METHODS:We conducted a comprehensive literature search up to March 2026. Eligible studies were Phase II or III randomized controlled trials (RCTs) comparing TA with atezolizumab-based regimens and reporting adverse events (AEs); pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. RESULTS:Five RCTs involving 1001 patients were included. TA was associated with significantly higher risks of rash (RR 1.66, 95% CI 1.16-2.37), pruritus (RR 2.28, 95% CI 1.65-3.16), and infusion-related reactions (RR 1.80, 95% CI 1.23-2.62). No significant differences were observed for gastrointestinal, hematologic, endocrine, laboratory, or high-grade AEs. Subgroup analyses of TA alone versus atezolizumab alone showed only a significantly higher rash risk (RR 3.85, 95% CI 1.40-10.53). CONCLUSIONS:TA increases rash, pruritus, and infusion-related reactions without a significant rise in severe toxicities. Limited trial numbers and clinical heterogeneity require cautious interpretation and further long-term safety evaluation.
INTRODUCTION:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited treatment options and diverse symptoms necessitating active management. Anticholinergic medications are frequently used in ALS care, particularly for sialorrhea and mood disturbances. Their cumulative effects, termed anticholinergic burden, may pose underrecognized risks in this neurologically vulnerable population. This review highlights a plausible safety signal and outlines priorities for future research. AREAS COVERED:This narrative review synthesizes evidence from non-ALS populations reporting associations between higher anticholinergic burden and cognitive decline, respiratory complications, functional deterioration, and mortality. Evidence was identified through targeted PubMed/MEDLINE and Embase searches with reference chaining, emphasizing recent and seminal studies. Mechanistic overlap with ALS pathophysiology, including neuromuscular junction disruption, impaired cholinergic signaling, and neuroinflammation, supports biological plausibility for harm. Current ALS guidelines do not address cumulative anticholinergic exposure, leaving clinicians without a framework for evaluating risk or deprescribing. EXPERT OPINION:This article proposes a testable hypothesis that anticholinergic burden may represent a clinically relevant yet unmeasured risk factor in ALS. Emerging pharmacoepidemiologic methods and validated burden tools offer approaches to quantify exposure and evaluate relationships with ALS outcomes, supporting safer symptomatic management. Prioritizing longitudinal studies and integrating burden assessment into multidisciplinary care may help clarify risk.
INTRODUCTION:Teprotumumab (Tepezza), a monoclonal antibody targeting the insulin-like growth factor 1 receptor (IGF-IR), was approved in January 2020 by the US Food and Drug Administration for treatment of thyroid-associated ophthalmopathy (TAO). The drug was found to be effective and generally well-tolerated in two registered clinical trials and subsequent post-marketing trials. AREAS COVERED:A search of PubMed and other databases of medical and scientific literature was conducted. Key search terms included 'teprotumumab,' 'Tepezza,' 'thyroid-associated ophthalmopathy treatment,' and 'Graves' disease treatment.' Two adverse events (AEs), auditory abnormalities and hyperglycemia, were the focus of this review. As of 7 December 2025, 392 citations were identified in PubMed using teprotumumab as the search term. Of these, 29 publications primarily reported AEs or safety concerns associated with teprotumumab. The two most consequential AEs, hearing dysfunction and hyperglycemia, were identified in phase 2 and phase 3 clinical trials. EXPERT OPINION:Teprotumumab, the only FDA-approved therapy for TAO, is generally effective. It has been associated with several side effects; the most concerning are hearing dysfunction and hyperglycemia. Due diligence in pretreatment, intra-treatment and post-treatment monitoring is essential. Detailed benefit-risk analysis should be shared with all patients for whom use of the drug is being considered.
INTRODUCTION:Pulmonary arterial hypertension (PAH) has responded favorably to the new fusion protein named sotatercept. This study aimed to evaluate the safety and efficacy of sotatercept in PAH. METHODS:The online databases like PubMed/Medline, Cochrane Library, and ClinicalTrials.gov were searched until 15 September 2024 for studies comparing sotatercept to placebo using keywords such as "sotatercept, pulmonary arterial hypertension, and 'fusion protein.' RESULTS:Of the 213 titles searched, after removing duplicates, 142 studies were evaluated for eligibility. Two RCTs were finally included. Subgroup analysis was conducted for the two doses (0.7 mg/kg and 0.3 mg/kg). In the safety analysis, there were no significant differences in total adverse events [RR = 1.03 (0.95, 1.12), I2 = 0, p = 0.50], serious adverse events [RR = 0.96 (0.38, 2.42), I2 = 56, p = 0.93], and mortality [RR = 0.39 (0.01, 11.81), I2 = 61%, p = 0.59]. However, a significant difference was observed with non-serious adverse events [RR = 1.15 (1.03-1.30), I2 = 0%, p = 0.02], telangiectasia [RR = 3.34 (1.26-8.83), p = 0.02], thrombocytopenia [RR = 3.69 (1.23-11.0), I2 = 0%, p = 0.02] and epistaxis [RR = 5.58 (2.20-14.13), p = 0.0003]. No significant difference was observed with headache, nasopharyngitis, hypotension, neutropenia, nausea, diarrhea, rash, anemia, and dizziness. A significant change was observed with the majority of efficacy parameters, like Pro BNP [MD = -1150.38 (-1846.44, -454.32), I2 = 79, p = 0.001], pulmonary vascular resistance [MD = -234.40 (-325.30, -143.51), I2 = 72, p < 0.00001], pulmonary arterial wedge pressure (p = 0.007) and improvement in WHO functional class [OR = 3.23 (1.25, 8.34), I2 = 61, p = 0.02]. CONCLUSION:This study demonstrates that sotatercept is more effective than placebo in treating PAH and has a fair safety profile. CLINICALTRIAL.GOV:Identifier numbers: NCT04576988 and NCT03496207 PROSPERO: CRD42024534695.
INTRODUCTION:Tirzepatide, a dual GIP and GLP-1 receptor agonist, offers unprecedented efficacy for type 2 diabetes and obesity. Due to its rapid global adoption, understanding its complete safety spectrum is urgently needed to guide responsible prescribing and mitigate public health risks. AREAS COVERED:A literature search was conducted using PubMed and other public databases available to evaluate current evidence on the efficacy, safety, and metabolic impact of tirzepatide. The research discussed encompasses clinical trials and real-world data detailing the glycemic and weight reduction benefits of the drug. We examine its overall tolerability, covering common gastrointestinal events, including its high comparative risk for severe gastrointestinal events and treatment discontinuation, rare risks such as gallbladder and thyroid disorders, and the complex impact of the drug on skeletal muscle mass. EXPERT OPINION:While tirzepatide represents a paradigm shift in metabolic therapy, clinical management must evolve toward precision phenotyping to individualize patient risk-benefit trajectories. Future research must prioritize long-term functional outcomes to ensure that disease-modifying benefits are not offset by treatment-induced sarcopenia.
INTRODUCTION:Biologic therapies have changed the management of moderate-to-severe psoriasis by targeting key immunologic pathways. With increasing real-world use, long-term safety profiles are important for clinical decision-making. AREAS COVERED:The objective of this research is to provide an update on the safety of biologics over the past five years in psoriasis, including infection risk, malignancy, immunogenicity, and long-term outcomes. An informal literature review through PubMed was done using key search terms from 2020 to 2025. EXPERT OPINION:Biologic therapies are safe compared to older systemic drugs. Despite the minor risk for more common colds, which may be due to greater social interactions, the benefits far outweigh the risks. Biologics have facilitated improving psoriasis care, providing greater clearance with less risk of severe side effects.
INTRODUCTION:Asthma treatment has undergone a substantial change since monoclonal antibodies have been approved as treatment. IL-5 is a crucial player within the immunological pathways underlying asthma pathobiology. Selectively targeting IL-5 and its receptor demonstrated on long-term observations an optimal safety and efficacy profile in asthma patients. However, in some special populations, the evidence related to the safety data is still limited. AREAS COVERED:The present review summarizes the currently available literature on the overall safety of anti-IL-5 compounds, including a focus on partial vs complete blood eosinophil depletion in response to the different therapies. Furthermore, data on anti-IL-5 antibodies in children, pregnant patients and old people in terms of safety profile have been critically reviewed. EXPERT OPINION:Limited data are available in children, pregnant women and elderly. The last two categories are usually excluded by the clinical trials enrollment, and a few randomized studies are available for children. However, the real-world evidence, aligned with the highly selective mechanism of action, supports the implementation of the anti-IL-5 therapies in the three subgroups mentioned above. Of course, an individualized approach carefully evaluating the risk-benefit balance and a close monitoring are highly recommended in those patients.
INTRODUCTION:Dravet syndrome is an early-onset developmental and epileptic encephalopathy in which management must extend beyond seizure control to include the monitoring and treatment of neurodevelopmental and systemic comorbidities. AREAS COVERED:Well-established treatments, together with recently approved agents, are discussed alongside under-reported therapies. Safety profiles, clinically relevant pharmacokinetic interactions, and practical aspects of dose titration and monitoring are reviewed. Emerging targeted pharmacological and genetic strategies are also briefly considered as potential disease-modifying approaches. EXPERT OPINION:In clinical practice, valproate-based regimens remain central to seizure management, with adjunctive therapies tailored to seizure type, comorbidities, tolerability, and drug interactions. While stiripentol, clobazam, fenfluramine, and cannabidiol are supported by the strongest evidence, less frequently reported therapies, including perampanel, topiramate, levetiracetam, cenobamate, and ketogenic dietary therapies, may benefit selected patients but require cautious use due to heterogeneous efficacy and safety data. The complexity of available options highlights the need for individualized, dynamic treatment strategies. Although emerging targeted and genetic therapies may represent a future paradigm shift beyond symptomatic seizure control, their clinical impact remains to be established, warranting careful implementation and long-term safety evaluation.
INTRODUCTION:Acute ischemic stroke (AIS) is currently the leading cause of morbidity and mortality globally, and despite progress that has been made in treatment and prevention over the last 30 years, its burden is expected to increase in future decades, due to the growth and aging of the populations. Therein, a greater access and delivery of safe and effective better drugs will be needed to improve AIS management. AREAS COVERED:This review highlights the current AIS care strategies, focusing on the efficacy and safety of antithrombotic drugs. EXPERT OPINION:Regarding AIS, reperfusion through IV thrombolysis remains the cornerstone of treatment, alongside mechanical thrombectomy in eligible patients. International guidelines recommend Alteplase within 4.5 hours of symptom onset; however, advanced neuroimaging may allow for the extension of this treatment window in selected patients. Tenecteplase, with its favorable pharmacokinetics and simplified administration, is emerging as an alternative. Early secondary prevention is strictly dependent on stroke etiology and consists of antiplatelets, oral anticoagulants, and aggressive risk factor control. Cardioembolic strokes require timely oral anticoagulation, while noncardioembolic minor ischemic strokes or high-risk transient ischemic attacks benefit from short-term dual antiplatelet therapy.
BACKGROUND:Compounded versions of tirzepatide are widely available in the U.S. in the form of fixed‑dose combinations of tirzepatide and various analogs of vitamin B12. These combinations are mass marketed in the U.S. and other countries as comparable to FDA‑approved tirzepatide products even though they undergo no evaluation of their potency or impurity profiles. RESEARCH DESIGN AND METHODS:Samples of compounded tirzepatide combined with B12 obtained from various sources in the U.S. market were tested using various analytical methods. Samples were assessed for unacceptable levels of peptide-related impurities. RESULTS:Our testing identified a widespread and previously unidentified impurity in compounded tirzepatide-B12 products resulting from a chemical reaction between tirzepatide and certain analogs of B12. CONCLUSION:Despite the presence of this impurity, these products continue to be mass marketed as 'personalized' treatments. Our findings underscore the importance of testing and FDA approval before new drugs are marketed and highlight potential risks for patients associated with untested combinations. A novel impurity, present at substantial levels in compounded tirzepatide/B12 products, highlights risks inherent in marketing complex therapies outside the drug‑approval framework. Although clinical effects of this impurity are unknown, the identification of a widespread impurity adds to the existing quality concerns presented by compounded tirzepatide.
BACKGROUND:This study aimed to assess the safety and effectiveness of vonoprazan, a potassium-competitive acid blocker, as long-term maintenance therapy in patients with healed reflux esophagitis (RE) in real-world settings. RESEARCH DESIGN AND METHODS:This prospective, observational study enrolled patients with healed RE from 122 sites in Japan. Patients received daily oral vonoprazan 10 mg as maintenance treatment for 12 months. Safety was assessed by monitoring adverse events (AEs) and adverse drug reactions (ADRs), and effectiveness was evaluated by endoscopic RE recurrence and symptom severity. RESULTS:Of the 1237 enrolled patients, 1174 were included in the safety analysis. ADRs were reported in 2.3% of patients. ADRs included diarrhea, constipation, and abnormal hepatic function. The severity of symptoms improved over time, and of those with endoscopic findings, the RE recurrence was 4.0% (17/425). A total of four serious ADRs were reported in two patients, which led to death, comprising pneumonia, acute leukemia, myelodysplastic syndrome, and decreased platelet count. CONCLUSIONS:This study demonstrates the effectiveness of vonoprazan in preventing RE recurrence during maintenance treatment in clinical practice. The incidence of ADRs was low, and no new safety signals were identified, supporting the established safety profile of vonoprazan.Clinical trial registration: NCT03214081; jRCT1080223147.
INTRODUCTION:Sjögren's disease (SjD) carries an increased risk of B-cell lymphoma, yet drug treatment strategies are largely extrapolated from general lymphoma care. This study summarizes available evidence on the efficacy and safety of drug therapies in SjD-associated lymphomas. AREAS COVERED:A PubMed and Embase search (January 1995-August 2025) identified studies evaluating the efficacy and safety of pharmacologic treatment for SjD-associated non-Hodgkin B-cell lymphomas (English language, ≥5 patients). Rituximab (anti-CD20) monotherapy achieved reliable early disease control in localized, low-burden lymphoma with limited toxicity. In more disseminated or aggressive lymphoma types, particularly diffuse large B-cell lymphoma, immunochemotherapy (rituximab plus chemotherapy) remains standard. In indolent disease, immunochemotherapy combination regimens can improve lymphoma control. However, regimen-specific safety data are limited and inconsistently reported. EXPERT OPINION:Current evidence supports a pragmatic, individualized approach. Rituximab remains the foundation of SjD-associated lymphoma therapy, typically combined with chemotherapy. However, current evidence is limited by small, heterogeneous cohorts, with pooled reporting across lymphoma types/regimens and limited safety reporting. Prospective SjD-specific studies, with regimen-level reporting of efficacy and safety are needed. Uniform endpoints that capture both hematologic and autoimmune activity, and lymphoma-type stratification should be applied.
INTRODUCTION:Statins' widespread use in cardiovascular disease management raises concerns about adverse drug reactions (ADRs). Comparative ADR profiles across different statin types remain lacking, necessitating further investigation to refine patient management. AREAS COVERED:The FDA Adverse Event Reporting System (FAERS) database (2004Q1-2024Q2) was leveraged to extract healthcare professional reports where statins were the 'principal suspected' causative agent. A systematic analysis of ADRs for statins (Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Pitavastatin) was performed using Ratio of Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). Intersection analysis delineated similarities and differences in ADR profiles across various statin types. EXPERT OPINION:This study identified common ADRs across all statin types, including elevated Blood Creatine Phosphokinase, Chromaturia, and elevated Hepatic Enzymes. Furthermore, a shared ADR of elevated Blood Urea was observed across all statins except Pitavastatin. Specific ADRs, potentially attributable to their distinct pharmacokinetic properties and chemical structures, including hearing loss associated with Atorvastatin, skeletal-related ADRs with Rosuvastatin, and premature labor with Pravastatin. This pharmacovigilance study utilizing spontaneous reporting data revealed previously underrecognized statins safety signals. Findings suggest distinct reporting patterns among statins, warranting dedicated investigations into their clinical considerations.
INTRODUCTION:Older patients with hypertension have unique clinical challenges based on age-related physiological changes, multimorbidity, and vulnerability to drug side effects. The 2017 American College of Cardiology/American Heart Association guidelines propose initiating antihypertensive therapy at a systolic blood pressure threshold of 130 mm Hg for non-institutionalized ambulatory adults over the age of 65. They also recommended individualized treatment for adults with advanced frailty or high risk of adverse events. AREAS COVERED:This article reviews evolving paradigms and strategies in blood pressure therapy in elderly individuals, based on shifting the approach from stringent treatment targets toward individualized management. Step-care management is one such strategy that involves prudent introduction of low doses of antihypertensives with regular follow-up to avoid side effects. Deprescribing is increasingly being promoted as a key intervention in reducing polypharmacy and maximizing safety in at-risk groups of patients. EXPERT OPINION:There is an increased need to incorporate frailty and functional assessments into routine practice and clinical trials. Despite growing evidence, there are still implementation challenges such as insufficient robust long-term data for frail populations. Pragmatic trials, adoption of digital solutions, and implementation of individualized goals must be the targets of future research.
INTRODUCTION:Drug utilization studies (DUS) provide important insights on how medications are used in routine clinical practice and can identify gaps between real-world use and existing evidence and guidance. While DUS are relevant across all therapeutic areas, they are particularly valuable in pediatrics as a substantial proportion of prescribing occurs off-label or with limited trial data. AREAS COVERED:This paper describes five domains where pediatric DUS can contribute to improving safe and rational use of medications: (i) setting research priorities, (ii) supporting drug surveillance and stewardship, (iii) identifying and reducing unwarranted variation, (iv) assessing prescriber behavior, and (v) evaluating the impact of regulatory actions and clinical guidelines. The five domains are illustrated using examples of Danish register-based pediatric DUS. EXPERT OPINION:Despite their value, pediatric DUS remain underused in clinical and regulatory decision-making. DUS should be systematically integrated into the development and revision of clinical guidelines on medication use and used routinely to evaluate the effects of major regulatory initiatives. Establishing near-real-time monitoring systems and extending DUS to inpatient settings would further strengthen their ability to impact clinical practice and support safer and more evidence-based prescribing for children and adolescents.
INTRODUCTION:SGLT-2 inhibitors improve type 2 diabetes and heart failure outcomes, yet representation of key demographic and clinical subgroups remains unclear. We aimed to quantify their representation in phase 3/4 trials. METHODS:We searched CENTRAL, MEDLINE, and Embase (inception-5 May 2025) for trials (≥300 participants) reporting subgroup enrollment. We estimated pooled prevalence using random-effects meta-analyses and calculated exploratory Participation-to-Prevalence Ratios (PPRs) against real-world U.S. disease burden. RESULTS:Across 91 RCTs, type 2 diabetes prevalence was: females 43.8% (95% CI 42.0%-45.7%), eGFR < 60 32.5% (13.1%-55.6%), older adults 31.8% (25.7%-38.2%), and Black participants 4.9% (4.3%-5.6%). In heart failure, prevalence was: older adults 68.7% (59.9%-76.8%), females 34.1% (27.8%-40.7%), and Black participants 7.6% (5.7%-9.7%). Exploratory PPRs indicated underrepresentation of Black participants (0.3 diabetes; 0.5 heart failure), older adults in diabetes (0.7), and females in heart failure (0.7). Data for liver disease and children/adolescents were insufficient. CONCLUSIONS:Prevalence was low for Black participants in both populations, older adults in diabetes trials, and females in heart failure trials. These disparities, alongside the exclusion of children and adolescents, may limit safety data generalizability, underscoring the need for inclusive recruitment. PROTOCOL REGISTRATION:www.crd.york.ac.uk/prospero identifier is CRD42024561154.
