The scale of the investigation is striking. The researchers extracted 12,763 adverse event reports involving riociguat from the United States Food and Drug Administration’s Adverse Event Reporting System, known as FAERS, and a further 17,316 reports from VigiAccess, the World Health Organization’s public gateway to global pharmacovigilance data. Together these databases capture hundreds of thousands of reports submitted by healthcare professionals, patients, and manufacturers across dozens of countries, offering a view of drug safety that no single trial can match. Women accounted for the majority of reports in both databases, a pattern consistent with the epidemiology of pulmonary hypertension, which disproportionately affects women, but also a finding that would prove consequential when the team examined sex-specific reactions.

At the heart of the analysis lies a statistical technique called disproportionality analysis, the workhorse of modern pharmacovigilance. Rather than simply counting how often a reaction appears, disproportionality methods ask whether a particular drug-event pair occurs together more often than would be expected by chance, given the overall composition of the database. The team applied multiple established algorithms, including the reporting odds ratio, the proportional reporting ratio, and Bayesian confidence propagation methods, each with defined thresholds for what constitutes a meaningful signal. Requiring agreement across several independent algorithms reduces the risk that a single statistical quirk will be mistaken for a genuine safety concern, a persistent problem in spontaneous reporting data where reporting biases and confounding abound.

The results largely vindicated the drug’s known safety profile. The most frequently reported adverse events were dyspnoea, the medical term for breathlessness, and hypotension, or abnormally low blood pressure. Both are biologically plausible for riociguat: the drug works by enhancing the nitric oxide signalling pathway, relaxing blood vessels and lowering pulmonary vascular resistance, so systemic vasodilation and its consequences are expected effects pushed to an uncomfortable extreme in some patients. The strongest statistical signals included diastolic hypotension and bendopnoea, a subtle symptom in which breathlessness occurs while bending over, such as when putting on shoes. Bendopnoea is increasingly recognized as an early marker of worsening cardiac function, and its emergence as a signal suggests clinicians are documenting it more systematically in this patient population.

The sex-stratified analysis produced some of the study’s most clinically actionable findings. After adjusting for age and body weight, two variables that could otherwise explain differences in drug exposure and metabolism, female patients reported significantly more dyspnoea, headache, nausea, vomiting, and chest pain than male patients. Such gender differences in adverse drug reactions are an area of growing scientific interest, driven by known variations in body composition, hormonal influences, renal and hepatic clearance, and even the historical underrepresentation of women in pivotal trials. For riociguat, the pattern implies that women may need closer monitoring during dose titration, particularly for gastrointestinal intolerance and blood pressure-related symptoms, and that prescribers should not assume trial-derived tolerability data apply uniformly across sexes.

Drug-drug interaction analysis added a second layer of concern. The team identified 30 interaction signals, and the companies of riociguat proved telling: endothelin receptor antagonists accounted for 36.67 percent of the signals and oral anticoagulants for 33.33 percent. Both drug classes are staples of pulmonary hypertension care, meaning the interactions are not exotic edge cases but routine combinations encountered in everyday practice. Endothelin receptor antagonists and riociguat both affect vascular tone, raising questions about additive haemodynamic effects, while anticoagulants are standard in chronic thromboembolic disease and interact with any drug that influences bleeding risk or hepatic metabolism. The authors used multiple signal-detection algorithms for the interaction analysis as well, and their supplementary tables transparently flag which signals were supported by only a single method, an unusually honest approach to the uncertainty inherent in this kind of data mining.

Timing proved to be another revealing dimension. The median time to onset of adverse events was 225 days, with an interquartile range spanning from 47 days to just over 710 days. This long and widely distributed onset window carries a sobering implication: riociguat toxicity is not confined to the initiation period that trials and early monitoring tend to emphasize. A substantial fraction of reactions emerge months or even years into therapy, precisely when patients and clinicians have settled into a sense of security. Sustained vigilance, rather than a brief introductory monitoring burst, appears to be what the data demand, and the late-onset pattern also complicates causal attribution, since comorbid disease progression can mimic drug effects in this progressive illness.

Crucially, the team did not stop at database mining. They cross-validated their pharmacovigilance signals against the safety data from six riociguat clinical trials, finding general concordance between the real-world reports and the trial evidence for established concerns such as hypotension, gastrointestinal disorders, and peripheral edema. But the databases also yielded signals that trials had not flagged, most notably traumatic fractures and pain in the jaw. Traumatic fractures could plausibly reflect falls precipitated by dizziness or syncope from hypotension, an indirect but clinically important chain of harm, while jaw pain raises questions that will require targeted follow-up. These discrepancies illustrate the complementary nature of the two evidence systems: trials establish causation with rigor but limited statistical power for rare events, while spontaneous reports detect rare and unexpected events but cannot by themselves prove causation.

The practical culmination of the study is a pharmacist-led management framework built on the narrative evidence review and the pharmacovigilance findings. The workflow is organized into three phases: pre-treatment evaluation, treatment initiation, and maintenance, with six core responsibilities assigned to pharmacists. These are drug interaction management, safety signal recognition, patient education, efficacy and safety assessment, professional documentation, and quality indicators. The framework reflects a broader shift in hospital practice, in which pharmacists move from dispensing roles into direct therapeutic management, particularly for high-risk medications like riociguat that demand blood pressure monitoring, careful titration, and constant attention to a patient’s full medication list. Given that the interaction signals cluster around drugs pulmonary hypertension patients take routinely, the pharmacist’s cross-checking role becomes not a luxury but a structural safeguard.

The study carries the usual caveats of spontaneous reporting research. FAERS and VigiAccess suffer from underreporting, inconsistent reporting quality, missing denominators that make incidence rates impossible to calculate, and the reporting biases that come with media attention and litigation. The authors were careful to frame their findings as signals warranting attention rather than proven causal effects, and the ethics declarations note that the use of publicly available, anonymized data required no institutional review board approval. Still, the convergence of evidence from two independent global databases, agreement across multiple statistical algorithms, and validation against six clinical trials gives these findings a weight that single-database studies often lack. For the growing population of patients living with pulmonary hypertension, the message is one of informed vigilance: riociguat remains a valuable therapy, but its safety profile is broader, later-emerging, and more sex-dependent than the label alone suggests, and the pharmacist may be the most important person watching for what the label does not say.

Subject of Research: Post-marketing safety evaluation of the pulmonary hypertension drug riociguat using FAERS and VigiAccess pharmacovigilance databases

Article Title: Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework

Article References: Hong, X., Guo, C., Wang, H., Cai, H., & Zhao, S. (2026). Safety evaluation of riociguat: insights from FAERS and VigiAccess databases, and establishment of pharmacist management framework. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01245-6

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01245-6

Keywords: riociguat, pharmacovigilance, FAERS, VigiAccess, adverse events, pulmonary hypertension, drug-drug interactions, hypotension, pharmacist-led management, drug safety, gender differences, disproportionality analysis

The study’s foundation rests on two of the world’s largest spontaneous reporting repositories. The researchers queried the United States Food and Drug Administration Adverse Event Monitoring System, known as AEMS and commonly referred to in the literature as FAERS, alongside the Japanese Adverse Drug Event Report database, or JADER, covering the period from January 2015 through June 2025. This window captures essentially the entire clinical era of PD-1 and PD-L1 inhibitors, the antibody drugs that block the programmed cell death 1 pathway and its ligand, thereby preventing tumors from co-opting a natural immune checkpoint to shield themselves. Because spontaneous databases record reports submitted by clinicians, pharmacists and patients rather than systematically collected clinical data, they cannot establish incidence rates on their own. What they can reveal, through carefully applied statistical tools, is whether a particular drug-event pairing is reported more often than would be expected by chance, a principle known as disproportionality.

To detect such signals, the team deployed two complementary analytical approaches. The first was the reporting odds ratio, or ROR, a frequentist measure that compares the odds of an immune thrombocytopenia report among patients taking PD-1 or PD-L1 inhibitors against the odds among reports involving all other drugs. The second was a Bayesian framework, which shrinks estimates for drug-event combinations with sparse data and thereby reduces false alarms. By requiring agreement across these methods, the researchers aimed to filter out statistical noise and isolate robust signals. In the American database, they identified 288 reports of immune thrombocytopenia among 157,788 total reports involving PD-1 or PD-L1 inhibitors, a proportion of 0.18 percent. In the Japanese database, the yield was higher: 322 reports among 69,205 relevant reports, or 0.47 percent, a difference that may reflect reporting culture, coding practices, or genuine differences in the treated populations between the two countries.

The headline statistical finding is unambiguous. Every individual PD-1 and PD-L1 inhibitor examined in the study generated a significant disproportionality signal for immune thrombocytopenia in the American database, indicating that the association is not driven by a single agent but is a class effect spanning the entire therapeutic family. In JADER, the overall reporting odds ratio was 3.57, with a 95 percent confidence interval of 3.13 to 4.06, meaning that reports of immune thrombocytopenia were roughly three and a half times more likely to involve these checkpoint inhibitors than other drugs. The American analysis produced an even stronger estimate. Crucially, the researchers recognized that Japanese reports appear in both databases, since Japanese cases can be submitted to the FDA system as well, and they therefore repeated the American analysis after excluding reports originating from Japan. The signal not only survived but remained strong, with a reporting odds ratio of 5.72 and a confidence interval of 4.83 to 6.77, demonstrating that the association is not an artifact of duplicated data flowing between the two national systems.

Beyond confirming that the signal exists, the study probed when these events occur, and the timing analysis yielded one of the most clinically actionable insights. The median time to onset in the American database was 43 days, with an interquartile range stretching from 13 to 126 days, meaning that half of all reported cases arose within roughly six weeks of starting treatment. To characterize the underlying hazard pattern, the team fitted a Weibull distribution to the time-to-onset data and calculated a shape parameter of 0.70, with a 95 percent confidence interval of 0.64 to 0.80. Because this value falls below 1, the distribution follows what safety researchers call an early-failure pattern: the risk of an immune thrombocytopenia report is concentrated in the early phase of treatment and gradually declines thereafter. This statistical signature echoes what has been observed for other immune-related adverse events of checkpoint inhibitors, many of which cluster in the first weeks to months of therapy when the newly unleashed immune response is at its most volatile.

Yet the Weibull analysis also carried a cautionary note. Although reports clustered early, they did not stop early. Cases continued to be recorded well beyond the initial treatment period, with the upper reaches of the interquartile range extending past four months and a tail of reports arriving even later. For clinicians, this means that vigilance for platelet counts cannot be confined to the first few infusion cycles. A patient who has tolerated a PD-1 inhibitor for half a year can still develop immune-mediated platelet destruction, and the study’s data suggest that the hazard, while front-loaded, never fully disappears during the treatment period. The authors frame this as a call for continued clinical vigilance throughout the course of immune checkpoint inhibitor therapy, with particular attention to platelet measurements in the early weeks but without assuming that later courses of treatment are risk-free.

To explore which patients might be most susceptible, the researchers conducted an exploratory multivariable logistic regression on the report-level data from the American database. This analysis adjusted for multiple characteristics simultaneously and identified two factors associated with a higher likelihood of an immune thrombocytopenia report: age between 65 and 85 years, and body weight of 75 kilograms or less. Both findings are biologically plausible. Older patients tend to have more dysregulated immune systems, a phenomenon sometimes described as immunosenescence, and lower body weight may correlate with altered drug exposure, comorbidity burdens, or baseline hematological vulnerability. The authors are careful to characterize this regression as exploratory, since spontaneous reporting data are subject to confounding, reporting biases and missing information, and the analysis identifies patterns in reports rather than causal risk factors in patients. Even so, the results give clinicians a concrete profile to watch: older, lighter patients early in the course of checkpoint inhibitor therapy.

The demographic picture of the reports themselves adds further texture. In the American database, men accounted for 53.8 percent of the immune thrombocytopenia reports, and individuals aged 65 or older accounted for 58.4 percent, a distribution that mirrors both the demographics of the cancer populations receiving these drugs and the age-related patterns of immune-related adverse events more broadly. Immune thrombocytopenia itself is not a trivial complication. Depending on severity, it can present as petechiae, bruising, mucosal bleeding or, in the worst cases, life-threatening hemorrhage, and it may force interruption or discontinuation of an otherwise effective cancer therapy. Because checkpoint inhibitors are now given to hundreds of thousands of patients worldwide across lung cancer, melanoma, renal cell carcinoma, head and neck cancer and many other indications, even a rare event translates into a meaningful absolute number of affected individuals.

The study’s limitations are those inherent to pharmacovigilance databases, and the authors acknowledge them directly. Spontaneous reports lack denominators, so the 0.18 and 0.47 percent figures represent proportions of reports rather than true incidence rates among treated patients. Reporting is subject to stimulated surveillance, media attention and regulatory alerts, and misclassification of events is possible. The regression findings are exploratory and cannot establish causation. Nevertheless, the convergence of evidence across two independent national databases, two statistical methodologies, a class-wide signal covering every individual drug, a sensitivity analysis that controlled for cross-database duplication, and a coherent early-failure timing pattern gives the findings substantial weight. The authors position their work as a foundation for active-surveillance studies, which follow patients prospectively and can measure true incidence, and they emphasize that the practical message for oncology teams is straightforward: monitor platelet counts with particular care in the first weeks of PD-1 or PD-L1 inhibitor treatment, remain alert throughout therapy, and pay special attention to older patients of lower body weight, so that this rare but potentially serious immune complication can be caught and managed before it becomes dangerous.

Subject of Research: Immune thrombocytopenia associated with PD-1/PD-L1 inhibitor therapy assessed through real-world pharmacovigilance database analysis

Article Title: A multidimensional assessment of immune thrombocytopenia reports involving PD-1/PD-L1 inhibitors: a real-world pharmacovigilance study using AEMS and JADER databases

Article References: Li, Y., Yang, Q., Pan, Y., & Mai, H. (2026). A multidimensional assessment of immune thrombocytopenia reports involving PD-1/PD-L1 inhibitors: a real-world pharmacovigilance study using AEMS and JADER databases. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01246-5

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01246-5

Keywords: PD-1 inhibitors, PD-L1 inhibitors, immune thrombocytopenia, immune checkpoint inhibitors, pharmacovigilance, FAERS, JADER, disproportionality analysis, immune-related adverse events, drug safety, platelets, immunotherapy

Diabetes affects roughly one in 200 cats, making it one of the most common endocrine diseases in the species. Traditional management relies on insulin, but success depends heavily on an owner’s ability to give injections reliably, recognize signs of poor glycemic control, and perform home blood glucose monitoring. For many owners, the financial cost, the stress of handling an unwilling cat, and the disruption of daily routines prove overwhelming; previous research has found that up to 10 percent of owners elect euthanasia rather than pursue treatment. Against that backdrop, once-daily oral SGLT2 inhibitors represented a genuine breakthrough. In clinical trials, bexagliflozin achieved a treatment success rate of 84.0 percent by day 56, while velagliflozin reached 88.4 percent by day 30, and a randomized non-inferiority trial showed that once-daily velagliflozin matched twice-daily insulin in glycemic control without episodes of clinical hypoglycemia.

Yet both drugs carry an FDA-mandated Boxed Warning for diabetic ketoacidosis (DKA) and euglycemic DKA, a life-threatening metabolic complication that has appeared in a small but clinically meaningful proportion of treated cats. Pre-market trials also documented gastrointestinal effects such as vomiting, diarrhea, and anorexia, along with other drug-specific events listed in the prescribing information. Because spontaneous reporting systems can capture safety signals that emerge only after a drug reaches a much broader population, the research team, led by Xiaoheng Lai and Maohua Chen of China, turned to the ADAE database maintained by the FDA Center for Veterinary Medicine. The database serves as an early warning system, collecting reports from veterinarians and owners about suspected adverse drug events in animals across the United States.

The researchers extracted every adverse event report submitted for cats receiving bexagliflozin between the fourth quarter of 2022 and the second quarter of 2025, and for velagliflozin between the third quarter of 2023 and the second quarter of 2025. After deduplication and merging of follow-up reports, the dataset contained 34,187 adverse event reports for cats in total, of which 2,876 involved bexagliflozin and 2,776 involved velagliflozin. Each report was coded using the Veterinary Dictionary for Drug Regulatory Activities terminology, a four-tiered hierarchy that organizes events from broad system organ classes down to specific low-level terms. The study followed the READUS-PV reporting guidelines to ensure transparent and standardized conduct of the disproportionality analysis.

At the heart of the study lies a statistical technique called disproportionality analysis, which asks a deceptively simple question: does a particular adverse event appear more often in reports for a given drug than would be expected if that drug were no more likely than any other to cause it? The team employed a case/non-case design in which the reporting proportion of each adverse event for the target drug was compared with the reporting proportion for all other drugs in the database. Four separate algorithms were applied in parallel: the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS). Crucially, a signal was only accepted when all four algorithms met their threshold criteria simultaneously, a conservative standard designed to suppress false positives arising from sparse data or multiple testing.

The results revealed striking differences between the two drugs. Bexagliflozin-related adverse events spanned 22 system organ classes, with statistically significant signals at the organ-class level for investigations, endocrine system disorders, and renal and urinary disorders. Among the 25 positive preferred terms, the strongest signals included weight fluctuation, glucosuria, and abnormal serum protein. Velagliflozin-related events covered 19 system organ classes, with significant signals for endocrine system disorders and investigations, and its 19 positive preferred terms were led by ketonuria, hypochloremia, and acid-base disorders. In a head-to-head comparison restricted to the overlapping reporting period, bexagliflozin showed stronger signals for diabetic ketoacidosis (ROR 7.40 versus 5.53) and ketosis (9.54 versus 7.16), while velagliflozin displayed markedly stronger signals for ketonuria (30.89 versus 7.27) and hypochloremia (8.18 versus 4.75). Ketosis was the most frequently reported event for both drugs, appearing in 1,290 bexagliflozin reports and 927 velagliflozin reports.

Timing proved to be another point of divergence. The median time-to-onset of adverse events was 9 days for bexagliflozin compared with 5 days for velagliflozin, and the median duration was 14 days versus 8 days. More than half of the events for both drugs emerged within the first 10 days of treatment, but velagliflozin showed a higher proportion of very early events, with 63.16 percent occurring within the first week compared with 16.00 percent for bexagliflozin. Stratified analysis showed that for both drugs, diabetic ketoacidosis, diarrhea, and ketosis were rapid-onset events, while bexagliflozin was additionally associated with several prolonged-duration events, including polydipsia with a median duration of 420 days and polyuria lasting a median of 90 days. The authors caution, however, that increased thirst and urination are also classic signs of diabetes itself, so those extended durations may reflect underlying disease progression rather than direct drug effects.

The mechanistic explanation for the shared ketosis signal lies in the physiology of SGLT2 inhibition. These drugs work by blocking glucose reabsorption in the kidney, causing excess glucose to be excreted in urine, but monotherapy relies on sufficient residual endogenous insulin production. When insulin is inadequate, metabolism can shift toward ketone production and ultimately ketoacidosis. SGLT2 inhibitors also stimulate glucagon secretion, further promoting ketogenesis. Notably, euglycemic DKA can occur without marked hyperglycemia, which risks diagnostic delay if owners and clinicians are not alert to the possibility. The study reinforces existing recommendations that blood beta-hydroxybutyrate concentrations be assessed at baseline and monitored closely during the first 14 days of therapy, with values above 2.4 mmol/L typically necessitating insulin and values between 1.0 and 2.4 mmol/L warranting reassessment within two to three days.

Beyond the metabolic risks, the analysis identified significant signals for urinary tract infection with both drugs, consistent with clinical trials in which positive urine cultures were among the most frequently reported events for velagliflozin, and for pancreatitis or elevated pancreatic enzymes, a finding complicated by the fact that diabetes itself is a common risk factor for feline pancreatitis. Electrolyte disturbances, particularly hypochloremia, hypokalemia, hyponatremia, and hypophosphatemia with velagliflozin, also emerged prominently, possibly arising secondarily from gastrointestinal fluid losses. An unexpected signal for hypoglycemia appeared with bexagliflozin despite its absence from the product label, prompting the authors to suggest that prescribing information and post-marketing studies be updated. The descriptive data showed predominantly male, older, heavier cats among reported cases, with euthanasia reported in roughly 7 percent of reports for both drugs and death in 1.77 percent of each.

The authors are careful to acknowledge the limitations inherent in spontaneous reporting systems. Under-reporting, reporting bias, variable data quality, and the lack of detailed clinical narratives mean that disproportionality signals represent statistical associations and hypotheses, not established causation or true incidence rates. The absence of a disease-matched comparator, such as insulin reports, may have inflated signals tied to diabetes severity itself. Nevertheless, a sensitivity analysis confirmed that the core signals were robust, and the study provides veterinarians with actionable, drug-specific guidance: vigilant ketone monitoring in the first two weeks regardless of the drug chosen, electrolyte surveillance especially with velagliflozin, and particular attention to weight changes and persistent urinary signs with bexagliflozin. As oral SGLT2 inhibitor use expands in feline practice, this real-world evidence offers a data-driven foundation for individualized treatment decisions and tailored safety monitoring in the management of feline diabetes.

Subject of Research: Post-marketing pharmacovigilance of SGLT2 inhibitors for feline diabetes using the FDA Animal Drug Adverse Events database

Article Title: Post-marketing safety monitoring of sodium-glucose cotransporter 2 inhibitors for diabetes in cats: a pharmacovigilance study based on the FDA ADAE database

Article References: Post-marketing safety monitoring of sodium-glucose cotransporter 2 inhibitors for diabetes in cats: a pharmacovigilance study based on the FDA ADAE database. (n.d.). https://doi.org/10.1093/jvimsj/aalag193

Image Credits: AI Generated

DOI: 10.1093/jvimsj/aalag193

Keywords: bexagliflozin, velagliflozin, SGLT2 inhibitors, feline diabetes, pharmacovigilance, FDA ADAE database, disproportionality analysis, diabetic ketoacidosis, ketosis, adverse events, veterinary internal medicine, drug safety

Hand-foot syndrome, or PPE, is far more than a cosmetic nuisance. The condition typically begins with tingling, numbness and redness on the palms of the hands and soles of the feet, and can progress in severe cases to swelling, blistering, ulceration and intense pain that makes walking, gripping objects or even buttoning a shirt difficult. Because these symptoms strike exactly the functions patients rely on for daily life, PPE is a leading cause of dose reductions, treatment interruptions and outright abandonment of otherwise effective cancer regimens. Oncologists have long recognized it as a hallmark toxicity of certain targeted therapies and chemotherapy agents, but the true breadth of drugs implicated — and the timing of onset — has remained surprisingly poorly mapped.

To build that map, the researchers turned to FAERS, the FDA’s sprawling spontaneous reporting database, which collects adverse event submissions from healthcare professionals, manufacturers and patients across the United States. They extracted reports spanning the first quarter of 2004 through the first quarter of 2025, removed duplicate submissions, and then applied a family of statistical techniques known as disproportionality analysis. Rather than proving causation in the way a clinical trial would, disproportionality analysis asks a subtler question: does a particular drug appear in reports of a given side effect more often than would be expected by chance? Four complementary algorithms were used to answer that question — the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network and multi-gamma Poisson shrinkage. Requiring agreement across all four methods helps filter out spurious associations that can arise in self-reported data.

The results were striking in both their scale and their specificity. Protein kinase inhibitors — the targeted drugs that block enzymes driving cancer cell growth and tumor blood vessel formation — and antimetabolites, the classic chemotherapy agents that interfere with DNA and RNA synthesis, emerged as the dominant drug classes. Among individual agents, the oral kinase inhibitor regorafenib, the multi-kinase blocker sorafenib and the fluoropyrimidine prodrug capecitabine produced the strongest safety signals. These three drugs are mainstays of treatment for colorectal cancer, hepatocellular carcinoma, renal cell carcinoma and other hard-to-treat malignancies, meaning the toxicity burden is concentrated in some of oncology’s most vulnerable populations. The finding that hundreds of other drugs also appeared in PPE reports underscores that the syndrome is not confined to a short list of notorious culprits.

Perhaps the most clinically actionable discovery concerns timing. The vast majority of PPE cases — 83.4 percent — occurred within the first 90 days of starting treatment, with many surfacing within the initial weeks. This early-onset pattern carries an important message for oncology teams: the highest-risk window for hand-foot syndrome opens almost immediately after a patient begins therapy. The authors argue that this argues for proactive patient education at the very first prescription, so that patients recognize the earliest tingling or redness and report it before it escalates into blistering lesions. It also supports intensified skin assessment during the initial phases of treatment with high-risk drugs, when a timely dose adjustment can often prevent progression without compromising cancer control.

The analysis also uncovered differences in reporting patterns between female and male patients. For two drugs in particular — the HER2-targeted breast cancer therapy lapatinib and capecitabine — PPE signals were stronger in women. The researchers are careful to caution against overinterpreting this finding. Sex-related differences in spontaneous reports can arise from prescribing patterns, with some drugs used predominantly in diseases that affect one sex more than the other, as well as from possible biological factors such as differences in skin structure, drug metabolism or hormonal influences. Disentangling genuine biological susceptibility from the artifacts of who receives which drug and who reports which symptom remains an open challenge for pharmacovigilance, and the authors explicitly call for cautious interpretation and further study.

Mechanistically, hand-foot syndrome is thought to arise from the unique biology of the skin on the palms and soles. These regions are rich in eccrine sweat glands, experience high mechanical pressure and friction, and express high levels of the molecular targets — such as vascular endothelial growth factor receptor and platelet-derived growth factor receptor — that protein kinase inhibitors are designed to block. When those signaling pathways are inhibited in the skin’s blood vessels, capillary damage and local inflammation can follow, and the repeated trauma of walking and gripping amplifies the injury. For antimetabolites like capecitabine, which is converted to 5-fluorouracil inside the body, the toxicity reflects the drug’s interference with rapidly dividing cells, with the concentration of the activating enzyme thymidine phosphorylase particularly high in palm and sole tissue. The convergence of drug exposure and mechanical stress explains why the syndrome has such a distinctive anatomical fingerprint.

The scale of the new study gives it particular weight in a field where much of the evidence comes from small clinical trials that may not capture rare or slowly accumulating toxicities. By pooling more than two decades of real-world reports, the analysis captures the experience of a far more diverse patient population than any single trial — patients with comorbidities, concurrent medications and varying ethnic backgrounds. At the same time, the authors and pharmacovigilance experts alike emphasize the inherent limitations of spontaneous reporting: not all adverse events are reported, reporting rates are influenced by media attention and litigation, and the database cannot establish how frequently PPE occurs relative to the total number of patients treated. Disproportionality signals are a starting point for hypothesis generation, not a verdict on causation.

Even with those caveats, the study’s implications for clinical practice are concrete. Oncologists prescribing regorafenib, sorafenib or capecitabine now have robust, data-driven backing for early and sustained skin monitoring, and the identification of 427 drugs with PPE reports should prompt awareness beyond the usual suspects, particularly as newer kinase inhibitors reach the market. For patients, the message is empowering: symptoms in the hands and feet during cancer treatment should never be dismissed as minor, because early recognition opens the door to dose modification, topical therapies, cooling measures and supportive care that can keep treatment on track. The research team concludes that enhanced vigilance and tailored monitoring schedules — matched to each drug’s risk profile and to the early onset window — are the most promising route to reducing the burden of this debilitating toxicity while preserving the anticancer benefits of the drugs patients depend on.

Subject of Research: Drug-induced palmar-plantar erythrodysaesthesia syndrome associated with antineoplastic agents identified through FDA adverse event reporting data

Article Title: Antineoplastic agent-induced palmar-plantar erythrodysaesthesia syndrome: insights from the FDA adverse event reporting system

Article References: Cheng, H., Li, Q., Hong, X., Zhang, Z., Chen, L., Yang, X., Wang, S., & Pan, W. (2026). Antineoplastic agent-induced palmar-plantar erythrodysaesthesia syndrome: insights from the FDA adverse event reporting system. Journal of Cancer Research and Clinical Oncology. https://doi.org/10.1007/s00432-026-06547-0

Image Credits: AI Generated

DOI: 10.1007/s00432-026-06547-0

Keywords: hand-foot syndrome, palmar-plantar erythrodysaesthesia, FAERS, pharmacovigilance, protein kinase inhibitors, capecitabine, regorafenib, sorafenib, antineoplastic agents, disproportionality analysis, adverse drug reactions, oncology