Background Multiple sclerosis (MS) is a leading cause of non-traumatic neurological disability in young adults. We assessed 20-year trends in MS prevalence, incidence and mean age at death in Lombardy, Italy, using population-wide linked administrative data. Methods We conducted a retrospective population-based cohort study including all regional residents aged 18 years or older between 2005 and 2024. MS cases were identified through an administrative algorithm. Annual crude and age-standardised incidence and prevalence rates were calculated overall and by sex and age group, using the 2025 WHO World Standard Population, including female-to-male ratios. Mean age at death was computed and stratified by sex. Temporal trends were analysed using joinpoint regression. Findings Among 10 million residents, MS incidence and prevalence increased from 8.2 (95%CI, 7.6–8.8) to 10.9 (10.2–11.6) and from 71.6 (70.0–73.2) to 152.4 (150.1–154.8) per 100,000 population, respectively, over the period 2005–2024. MS incidence was consistently higher among females and rose most markedly among adults 18–29-year +43.9%, from 12.4 (10.5–14.5; n = 153) to 17.8 (15.5–20.4; n = 217) per 100,000 and 30–39-year +42.9%, from 17.7 (15.7–19.9; n = 283) to 25.3 (22.5–28.4; n = 288). Overall age-standardised incidence declined non-significantly until 2015 (Annual Percentage Change (APC) −0.69%, 95% CI −7.61 to 0.90) followed by a significant increase thereafter (APC +2.84%, 95% CI 0.94–11.58). Incidence increased steadily in males (APC +1.54%, 95% CI 0.47–2.61), and, among females, rose significantly from 2013 onward (APC +2.30%, 95% CI 0.89–8.83). Over the study period, the female-to-male incidence rate ratio decreased from 2.4 (95% CI, 2.0–2.8) to 1.7 (1.5–1.9), whereas the corresponding prevalence ratio changed from 2.1 (95% CI, 2.0–2.2) to 1.9 (1.9–2.1). Mean age at death increased by about 6–10 years linearly since 2005, reaching 69.6 years (median 71.0, IQR 61.0–78.0, SD 11.7) among males and 73.8 years (75.0, 66.5–81.0, 10.7) among females in 2024. Interpretation MS incidence and prevalence increased over two decades, particularly among younger adults alongside older age at death. These findings may reflect changing disease risk, improved diagnostic sensitivity, and advances in treatment. Continuous surveillance using linked administrative data is essential for healthcare planning and resource allocation. Funding None.
The 16th Acromegaly Consensus Conference in September 2024 updated recommendations on diagnosis and treatment of acromegaly comorbidities. Since the 2020 acromegaly comorbidity management guideline was published, new evidence has emerged on novel and known comorbidities and new treatment approaches. Forty-three experts in the management of acromegaly reviewed the current literature and assessed changes in clinical practice standards and management. Current outcome goals were considered and updated, with a focus on the impact of current and emerging treatments of these comorbidities. Participants assessed factors that determine pharmacological choices, as well as use of specific agents in the management of the most relevant acromegaly comorbidities. We present consensus recommendations highlighting optimization of evidence-based acromegaly comorbidities management.
Disease progression in multiple sclerosis (MS) remains a major unmet clinical challenge, as it is driven by pathogenic mechanisms that are poorly targeted by currently available disease-modifying treatments. Whereas acute focal inflammation characterizes the relapsing–remitting phase, converging neuropathological, imaging and experimental evidence identifies a chronic low-grade compartmentalized inflammatory process, the so-called “smoldering” inflammation, as a central driver of disease progression in MS. Recent findings suggest that both tissue hypoxia (primarily resulting from vascular dysfunction) and virtual hypoxia (a state of metabolic supply–demand mismatch culminating in bioenergetic failure) may critically contribute to the onset, persistence and compartmentalization of smoldering inflammation. In this review, we first delineate the pathological mechanisms underlying smoldering inflammation, distinguishing between lesional and extra-lesional features. We then examine the processes leading to tissue and virtual hypoxia in MS. As a key link between smoldering inflammation and hypoxia, we focused on the Hypoxia-Inducible Factor (HIF) signaling, the master regulator of cellular responses to hypoxia. Particularly, we reviewed recent evidence supporting its role as a central immunometabolic hub shaping immune and glial cell function within the hypoxic microenvironment of smoldering inflammation in MS. Finally, we critically evaluate the potential of the HIF signaling as a therapeutic target to hamper smoldering inflammation and disease progression in MS.
The approval of ibrutinib over a decade ago introduced Bruton tyrosine kinase (BTK) inhibition as a foundational, chemotherapy-free treatment approach for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). A continuous single-agent BTK inhibitor (BTKi) or a time-limited B cell lymphoma 2 inhibitor (BCL2i)-based regimen plus an anti-CD20 monoclonal antibody or BTKi is now standard of care for CLL/SLL. Although ibrutinib offers durable remission for many patients, its use is limited by side effects associated with inhibition of kinases other than BTK (off-target effects). The second-generation BTKi zanubrutinib was developed to provide sustained BTK inhibition with greater selectivity for BTK in order to improve clinical efficacy and tolerability with minimized off-target effects. The head-to-head ALPINE study of patients with relapsed/refractory (R/R) CLL/SLL demonstrated superior efficacy with zanubrutinib versus ibrutinib, with superior overall response rates and prolonged progression-free survival (PFS), while acalabrutinib demonstrated non-inferior PFS outcomes versus ibrutinib in patients with high-risk R/R CLL/SLL. Data also showed improved safety outcomes with zanubrutinib versus ibrutinib with significantly lower rates of atrial fibrillation/flutter, and infection, and a trend toward lower rates of other adverse events associated with ibrutinib, with the exception of neutropenia. This is reflected in treatment guidelines for CLL, where zanubrutinib and the other approved second-generation BTKi, acalabrutinib, are recommended over ibrutinib owing to their superior safety profiles (particularly reduced cardiotoxicity). In this review, we consider the pharmacologic properties of zanubrutinib that differentiate it from ibrutinib and acalabrutinib, and provide a comprehensive overview of the efficacy and safety data that led to zanubrutinib monotherapy becoming a preferred therapy for a significant subgroup of patients with CLL/SLL. We also highlight trials in CLL/SLL and Richter’s transformation with zanubrutinib in targeted therapy combinations that offer the potential for time-limited treatment courses.
Neurofibromatosis type 1 (NF1) is a genetic disorder with recognized ocular involvement, primarily optic pathway gliomas (OPGs). However, retinal structural changes in NF1 patients without gliomas remain poorly defined. This study aimed to evaluate optical coherence tomography (OCT) findings in glioma-free NF1 patients. A systematic search of PubMed, Embase, Scopus, and Web of Science through January 2025 identified studies comparing OCT parameters in NF1 patients without OPGs versus healthy controls. A total of eight studies comprising 129 patients with NF1 and 243 healthy controls were included in the analysis. Among pediatric participants, no significant differences were detected in peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell–inner plexiform layer (GC-IPL) thickness, or macular volume. In contrast, adult NF1 patients exhibited a significant reduction in GC-IPL (p < 0.001) and outer nuclear layer (ONL) thickness (p = 0.03), whereas macular RNFL thickness remained comparable to healthy controls. Retinal structure appears preserved in pediatric NF1 patients without gliomas. However, significant thinning of inner and outer retinal layers in adults suggests progressive, glioma-independent retinal neurodegeneration. OCT may serve as a valuable tool for detecting subclinical changes in adult NF1 patients.
