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Pain is the most common complication experienced by individuals living with sickle cell disease (SCD). While episodes of acute pain, also known as vaso-occlusive crises, are the hallmark of the disease, chronic pain is prevalent in SCD and is associated with many comorbidities. We review current understanding of pain in SCD across the lifespan, integrating definitions, mechanistic categories, and management within biologic, psychosocial, and environmental contexts. Acute vaso-occlusive pain, which emerges as early as infancy, evolves from intermittent nociceptive events driven by multicellular vaso-occlusion, hemolysis, inflammation, and ischemia-reperfusion injury. Chronic pain, which commonly emerges in adolescence and increases with age, reflects heterogeneous nociceptive, neuropathic, and nociplastic mechanisms shaped by SCD-related complications, psychological comorbidities, and social stressors. Chronic pain also contributes to the pathogenesis of acute pain through sensitization processes. Evaluation of mechanisms using tools such as quantitative sensory testing and functional neuroimaging supports hyperexcitability within the peripheral and central nervous system, which is likely important in the development and maintenance of chronic pain. Therapeutically, most guidelines to manage SCD pain are limited by low-certainty evidence; nonetheless, multimodal strategies emphasize timely individualized opioids with nonopioid and nonpharmacologic adjuncts, which are most effective when delivered within multidisciplinary, patient-centered care models. We propose that an individualized whole-person care approach guided by patient-report and biomarker-based framework is key in delineating mechanisms and advancing mechanistic interventions to address pain and related morbidities in SCD.

Harnessing biomass for bio-based industrial biotechnology is vital for addressing global energy needs and mitigating climate change. In this context, microorganisms are the cornerstone of biorefineries based on renewable materials, with applications in bioenergy, agriculture, biomedicine, and other sectors. By engineering metabolic pathways, microorganisms can be tailored to improve yields, tolerate industrial conditions, and selectively produce valuable compounds. Through advances in metabolic engineering and synthetic biology, engineered strains of the yeast Saccharomyces cerevisiae have been successfully developed to efficiently convert the pentose sugars D-xylose and L-arabinose. Despite this important breakthrough, the efficient transport of these sugars remains a major limitation. Sugar sensing and transport in yeast are regulated at both transcriptional and post-translational levels. D-xylose is not recognized as a fermentable carbon source, leading to downregulation of transporter expression, removal from the cytoplasmic membrane, and degradation via ubiquitination in the absence of extracellular glucose. Additionally, transporters exhibit lower affinity for C5 sugars compared to D-glucose, resulting in strong D-glucose repression. To address these challenges, cutting-edge strategies have been successfully employed, including rational protein engineering, directed evolution, and machine learning approaches, to expand the repertoire of C5 transporters available for engineering in S. cerevisiae. Specific D-xylose transporters have been redesigned, with key residues identified to reduce D-glucose affinity, while studies have demonstrated improvements in transporter stability and sugar uptake rates. This review summarizes the key bottlenecks in C5 sugar transport and highlights the major advances and progress made toward creating robust microbial platforms capable of sustainable and efficient bio-based production. This review highlights the progress in understanding and engineering sugar transport systems in Saccharomyces cerevisiae, focusing on transporters for C5 sugars derived from lignocellulosic biomass. It outlines the progression from discovering the first C5 sugar transporters to developing advanced, specialized transporters that improve sugar uptake and utilization. By integrating historical insights with modern strategies, this review showcases how this progress drives the development of yeast platforms optimized for efficient bio-renewable compound production, paving the way for a more sustainable bioeconomy and addressing critical global energy and environmental challenges.

Cardiovascular disease (CVD) prediction models recommended by guidelines are developed using different populations, predictors, and outcome definitions. The implications of this heterogeneity for risk estimation are unclear, and direct comparisons remain limited. Head-to-head comparison of the performance and transportability of three guideline-endorsed CVD risk prediction models, focusing on their sex-specific performance. We evaluated models recommended by the American Heart Association (PREVENT), European Society of Cardiology (SCORE2), and the National Institute for Health and Care Excellence (QRISK3). Risk of bias was assessed using the PROBAST tool. External validation was performed using the UK Biobank (UKBB) in a primary analysis including all participants with complete data for all models, enabling direct comparison, and in a secondary analysis applying each model to participants meeting its original eligibility criteria. Model performance was assessed using Brier scores, Area Under the Receiver Operating Characteristic Curve (AUC), and calibration across original and alternative outcome definitions, stratified by sex. The PREVENT, SCORE2, and QRISK3 models varied substantially in terms of predictors, populations, and outcome definitions. We used data from 502,157 UKBB participants for the external validation in the primary analysis. Overall predictive performance (discrimination & calibration), as measured by Brier scores, was generally better in females. The AUC (95% CI) ranged from 0.7092 (0.7090-0.7094) to 0.7468 (0.7465-0.7471) for female and 0.6813 (0.6812-0.6814) to 0.6946 (0.6945-0.6946) for male populations. Calibration was suboptimal, particularly for older individuals, with systematic overestimation of risk. The models showed consistent performance when applied to different outcomes. All models were at high risk of bias. Despite heterogeneity in populations, predictors, and outcome definitions, PREVENT, SCORE2, and QRISK3 showed similar performance in the UKBB. Future studies should focus on prospective and standardized definitions and assessment of candidate predictors and outcomes.

Alkaline hydrogen evolution reaction (HER) is limited by slow water dissociation and by catalysts that degrade in saline electrolytes. Here we program vacancies to trigger selective Ni exsolution in multimetallic Prussian blue analogues (PBAs), creating cooperative defect-metal interfaces. Low-temperature annealing of FeMn@CoNi PBAs forms hollow nanocages (PBA-350) rich in cyanide vacancies and decorated with in situ exsolved Ni nanoparticles. Operando XRD/XAS, operando impedance, and theory reveal a dual-site mechanism: vacancy-stabilized Ni lowers the Volmer barrier, adjacent Co facilitates OH* removal, and the vacancy-modified lattice tunes H* binding toward thermoneutrality. PBA-350 delivers 28.4 mV at 10 mA cm-2 and a 56 mV dec-1 Tafel slope in 1.0 m KOH with negligible degradation over 100 h at -50 mA cm-2. An anion-exchange membrane electrolyzer reaches 1.76 V at 1.0 A cm-2, and PBA-350 remains stable in simulated seawater (1.0 m KOH + 0.5 m NaCl) by physically repelling chloride ions via hydration layers, establishing vacancy-assisted exsolution as a design rule for HER.

Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that lowers LDL-C and raises HDL-C. Although prior studies have demonstrated efficacy and general tolerability, a comprehensive evaluation of its safety profile across later-stage clinical trials is needed. Safety outcomes were assessed in a pooled analysis of two phase III trials comparing obicetrapib 10 mg daily with placebo in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD). Participants received treatment for 365 days. Safety endpoints included treatment-emergent adverse events (TEAEs) and prespecified events of special interest including hepatic, muscular, glycemic, renal and ocular parameters as well as overall rates of discontinuation. A total of 2,880 participants were included (mean age 64 years; 36 % female; 82 % with ASCVD; 35.8 % with diabetes). Overall TEAE rates were similar between obicetrapib and placebo (60.2 % vs 62.0 %). AEs leading to treatment discontinuation occurred in 4.1 % of obicetrapib-treated participants and 5.3 % on placebo, Risk Ratio (RR) 0.77 [0.54-1.08]. No clinically significant change in blood pressure was observed between groups and hypertension events were comparable. There was no difference between the groups in liver or muscle-related endpoints. Reduction in eGFR occurred less often with obicetrapib ( compared to placebo (6.7 % vs. 8.7 % RR 0.77 [0.59, 1.00])). Macular degeneration was reported once in the obicetrapib group (n= 1 [0.1 %]). Deaths were similar between treatment groups. No new safety signals were identified. Obicetrapib demonstrated a favorable safety profile over 12 months, with AE rates comparable to placebo. These findings extend our understanding of the safety and tolerability of obicetrapib.

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Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of ≥200 subjects, and had ≥1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated. A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Blood pressure (BP)-lowering therapy reduces cardiovascular risk, but whether its proportional benefits increase with longer treatment duration remains unclear. We conducted an individual participant-level data meta-analysis of 51 randomized trials from the Blood Pressure Lowering Treatment Trialists' Collaboration (358,642 participants; median follow-up: 4.2 years). Using Cox proportional hazards models, we estimated time-stratified hazard ratios (HRs) for major cardiovascular events (MACE; fatal or non-fatal stroke, ischemic heart disease or heart failure) across annual follow-up intervals up to more than 5 years, standardized to a 5-mmHg systolic BP reduction. Network meta-analysis examined whether temporal patterns differed across antihypertensive drug classes. Annual MACE incidence was highest during year 1 (3.0% treatment versus 3.6% control), declined during years 1-5 and then rose at more than 5 years (3.1% versus 3.4%). BP lowering reduced MACE risk, with benefits established early and not progressively increasing over time. A 5-mmHg systolic BP reduction was associated with a 12% lower MACE risk in year 1 (HR = 0.88, 95% confidence interval (CI): 0.84-0.91), with modest attenuation thereafter: HRs were 0.88 (0.85-0.92) in years 1-2, 0.94 (0.90-0.98) in years 2-3, 0.87 (0.83-0.92) in years 3-4, 0.97 (0.91-1.03) in years 4-5 and 0.94 (0.87-1.01) at more than 5 years (P for trend = 0.006). Similar patterns occurred across five drug classes. These findings indicate that the relative cardiovascular benefits of BP lowering emerge within months and do not increase over time, suggesting that prioritizing higher-risk individuals for treatment yields greater clinical utility than prolonged treatment in low-risk individuals.

To study associations between prediabetes, type 2 diabetes (T2D) and insulin resistance with incident atrial fibrillation (AF) in patients with hypertension. Patients with hypertension but no AF between 2006 and 2010 were identified in the Swedish Primary Care Cardiovascular Database. Patients with type 1 diabetes or pre-existing cardiovascular disease were excluded. Patients were categorized into normoglycemia, prediabetes or T2D and followed until 2023 or incident AF. Insulin resistance was assessed using triglyceride-glucose (TyG) index and TyG-BMI index. Associations with incident AF and mortality were evaluated using multivariable models. Among 15 715 patients (64 ± 11 years, 55 % women), 60 % were normoglycemic, 17 % had prediabetes and 23 % T2D. During a median follow-up of 14.7 years, AF occurred in 18 %, 21 % and 20 %, respectively. Neither prediabetes (HR 0.99, 95 % CI 0.87-1.13) nor T2D (HR 1.00, 95 % CI 0.89-1.11) was associated with incident AF compared with normoglycemia. In contrast, the TyG index demonstrated a U-shaped association with incident AF, whereas the TyG-BMI index showed a positive association. Both prediabetes and T2D were associated with increased all-cause mortality (HR 1.17, 95 % CI 1.06-1.30 and HR 1.62, 95 % CI 1.50-1.75, respectively). Prediabetes and T2D were not independently associated with AF in hypertensive patients. Our findings suggest a potential role for BMI and insulin resistance in AF risk, independent of glycemic category, warranting further prospective investigation.

Saponins are natural products that consist of triterpene or sterol cores decorated with oxidations, glycosylations, and sometimes other modifications. Many saponins are utilized as nutraceutics (e.g., glycyrrhizin) or therapeutics (e.g., QS-21 and digitoxin/digoxin). The structure-activity relationships that govern saponin bioactivity can be identified by studying structurally related saponins; however, the production of varied sets of saponins remains challenging via either chemical (semi)synthesis or native/heterologous biosynthesis. This report describes the discovery that the GT1 family enzyme GuUGT73F15 (Glycyrrhiza uralensis) can be used to biosynthesize many different saponins via triterpene/sterol C3 β-O-glycosylation. GuUGT73F15 utilized 22 sugar acceptors (C3 hydroxyl-containing triterpenes/sterols) and 12 sugar donors (uridine diphosphate [UDP]-sugars) as substrates to produce 130 unique monoglycosylated saponins, of which more than 100 have not been reported as natural products to the best of our knowledge. GuUGT73F15 also accepted 13 cyclohexanol- and phenol-type molecules as minimized sugar acceptors. Based on Boltz-2x predictions, the broad substrate scope of GuUGT73F15 is hypothesized to arise from its varied sugar acceptor binding poses and consistent sugar donor binding poses. Applications of broad C3 β-O-glycosylation activity were exemplified via the production of antibody-saponin conjugates as well as the in vivo microbial biosynthesis and the in vitro biosynthesis of advanced QS-21 intermediates. Together, GuUGT73F15 is a versatile biocatalytic tool that can be utilized to produce libraries of high-value saponin natural products and new-to-nature saponins.

Liver disease causes substantial global morbidity and mortality, with a growing burden from steatotic liver disease driven by alcohol use and metabolic dysfunction, alongside persisting challenges from chronic viral hepatitis. Liver disease burden is unequal between and within countries, with high rates in people with low socioeconomic status and marginalised groups due to increased exposure to risk factors and compounded by reduced access to prevention, diagnosis, and treatment. Liver disease frequently coexists with multimorbidity-including diabetes, cancer, and mental illness-with bidirectional relationships that demand integrated, person-centred pathways of care. Primary care, as the cornerstone of first-contact, comprehensive health care, is uniquely positioned to deliver population-level prevention, early detection, and management of liver disease while reducing health disparities. However, despite increasing emphasis on prevention and long-term condition management globally, liver disease has received scarce attention within primary care policy, training, and system design. This Commission brings together multidisciplinary global expertise to review current evidence and provide recommendations to strengthen primary care-led liver health care. Central themes include reducing inequalities in liver care, defining a minimum package of primary care services, embedding liver health within non-communicable disease strategies, leveraging digital innovation, enhancing multidisciplinary collaboration, and advancing a coordinated research and implementation agenda focused on real-world care pathways and stigma reduction.

Externally controlled single-arm trials are critical to assess treatment efficacy across therapeutic indications for which randomized controlled trials are not feasible. A closely-related research design, the unanchored indirect treatment comparison, is often required for disconnected treatment networks in health technology assessment. We present a unified causal inference framework for both research designs. We develop an estimator that augments a popular weighting approach based on entropy balancing-matching-adjusted indirect comparison (MAIC)-by fitting a model for the conditional outcome expectation. The predictions of the outcome model are combined with the entropy balancing MAIC weights. While the standard MAIC estimator is singly robust where the outcome model is non-linear, our augmented MAIC approach is doubly robust (DR), providing increased robustness against model misspecification. This is demonstrated in a simulation study with binary outcomes and a logistic outcome model, where the augmented estimator demonstrates its DR property, while exhibiting higher precision than all non-augmented weighting estimators and near-identical precision to G-computation. We describe the extension of our estimator to the setting with unavailable individual participant data for the external control, illustrating it through an applied example. Our findings reinforce the understanding that entropy balancing-based approaches have desirable properties compared to standard "modeling" approaches to weighting, but should be augmented to improve protection against bias and guarantee double robustness.

Recent approvals of disease-modifying therapies by the European Medicines Agency mark a historic shift in the treatment landscape of Alzheimer's disease (AD) within the European Union that will challenge national health-care systems and require major adaptations and modernization. This Perspective article provides an overview of the major obstacles in Europe concerning successful implementation of amyloid-targeting treatments and offers potential solutions to overcome them. Major hurdles include a lack of recognition regarding the critical importance of an early, biomarker-based AD diagnosis; low acceptance of blood tests and digital cognitive screening tools; insufficient investment in magnetic resonance imaging capacities; and a fragmented infrastructure for clinical registries. We call on European clinicians, research institutions, and policy makers for a bold and coordinated action to urgently modernize diagnostic pathways and monitoring infrastructure to deliver novel AD treatments in a timely, safe, and equitable manner to all patients who may benefit.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide and is tightly linked to cardiometabolic comorbidities. A major clinical focus on MASLD is the detection of hepatic fibrosis, which most strongly predicts liver-related events, hepatocellular carcinoma risk and mortality. While lifestyle modification and sustained weight loss remain foundational, therapeutic innovation has rapidly expanded, shifting the metabolic dysfunction-associated steatohepatitis (MASH) treatment landscape towards targeted pharmacotherapies that address metabolic stress, inflammation and fibrogenesis, particularly for moderate/advanced fibrosis (i.e., F2/F3 fibrosis and cirrhosis). This review summarises the burden and systemic complications of MASLD, highlights endocrine influences that modulate hepatic steatosis and disease severity and emphasises the central role of fibrosis staging and non-invasive risk stratification in clinical decision-making. We then synthesise emerging pharmacotherapies across key mechanistic axes, including incretin-based agents (GLP-1 receptor agonists and dual/triple agonists), hepatocyte-directed metabolic modulators (thyroid hormone receptor-β agonists, fatty acid synthase inhibitors, acetyl-CoA carboxylase and other de novo lipogenesis inhibitors), bile acid pathway therapies (FXR agonists) and pleiotropic metabolic-fibrotic regulators (fibroblast growth factor 21 [FGF21] analogues and peroxisome proliferator-activated receptor [PPAR] agonists). We also discuss combination strategies, candidate agents with potential direct antifibrotic activity and the growing role of genetic risk stratification and hepatocyte-targeted oligonucleotide therapeutics. Finally, we outline current surrogate endpoints used in clinical trials and propose future directions towards stage-specific, mechanism-informed and combination regimens to achieve persistent MASH resolution and meaningful fibrosis regression.

The most common hereditary transthyretin (ATTRv) amyloidosis variant in the United States, Val122Ile (p.Val142Ile), is predominantly detected in populations of African ancestry. In this narrative review, we highlight the current challenges and discuss priority focus areas to improve the timely diagnosis and treatment of p.Val142Ile ATTRv amyloidosis across populations. Studies suggest geographic, economic, and socio-economic discordance in timely diagnosis, treatment access, and outcomes in regions with a high proportion of at‑risk individuals. Many ATTR amyloidosis symptoms overlap with other diseases due to their nonspecific and heterogenous nature. Consequently, optimized screening tools for biomarker identification and specialty care services/networks are required to determine at-risk individuals and improve clinical outcomes. However, access to genetic screening can be limited and diagnosis is complicated by variable p.Val142Ile ATTRv amyloidosis penetrance coupled with phenotypic evolution. To enhance existing treatment guidelines, regular monitoring of "at-risk" patients, multidisciplinary management, and purposeful clinical trial recruitment of minority populations are recommended.

Objectives Patient portal use has steadily increased across most populations. Prior, now dated, studies indicated lower adoption rates among Spanish- vs. English- speaking patients. This study compared patient portal activation and use patterns between Spanish- and English-speaking patients. Methods This retrospective cohort study was conducted at three North Texas health systems using the MyChart patient portal (Epic Systems Co.) and included patients ≥18 years with ≥1 completed clinician encounter between 4/5/2021 and 4/4/2022. The primary activation outcome was the baseline MyChart account activation rate. The secondary activation outcome was the MyChart account activation rate within the following year among patients without an account at baseline. The primary use outcome was the rate of patients logging in. Secondary use outcomes included rates of results review, notes review, and message initiation in the following year. We also evaluated the rates of proxy account use and mobile app use. We fit multivariable logistic regression models adjusting for health system, age, sex, comorbidity count, and the number of prior-year encounters. Results Spanish speakers represented 128,338 of 1,550,220 (8.3%) patients. Spanish speakers had lower odds of having an activated account at baseline (aOR 0.39 [0.39 - 0.40]) or activating one in the next year (aOR 0.68 [0.65 - 0.71]). Spanish speakers also had lower odds of logging in (aOR 0.62 [0.61 - 0.63]), reviewing results (aOR 0.79 [0.76 - 0.81]), reviewing notes (aOR 0.87 [0.84 - 0.89]), or sending messages (aOR 0.41 [0.40 - 0.42]). More Spanish than English speakers used the mobile app (59% vs 50%). There were inter-site differences in the rate of proxy account use. Conclusions Given lower levels of portal activation and use among Spanish-speaking patients, strategies are needed to identify and address barriers to activation and use. Qualitative studies could delineate these barriers and potential mitigating strategies.

Myasthenia gravis (MG) is a rare autoimmune disease characterised by fluctuating and fatigable muscle weakness. In the randomised, double-blind phase III MycarinG study, one 6-week rozanolixizumab cycle significantly improved MG-specific outcomes versus placebo and was generally well tolerated in patients with generalised MG (gMG). To assess the efficacy and safety of cyclic rozanolixizumab treatment. A pooled analysis of the MycarinG, MG0004 and MG0007 studies. Following MycarinG, eligible patients could enrol in the open-label extension studies MG0004 or MG0007 to receive rozanolixizumab 7 or 10 mg/kg. In MG0004, patients received chronic weekly treatment for ⩽52 weeks. In MG0007, after an initial 6-week treatment cycle, subsequent cycles were based on symptom worsening (investigator's discretion). Final efficacy data were pooled across MycarinG, MG0004 (first 6 weeks) and MG0007 for patients receiving ⩾2 symptom-driven cycles. Efficacy endpoints included change from baseline (CFB) in MG Activities of Daily Living (MG-ADL), MG Composite (MGC) and Quantitative MG (QMG) scores. Safety outcomes were assessed in patients who received ⩾1 cycle with a ⩽8-week follow-up period across MycarinG and MG0007. Overall, 188 patients received ⩾1 cycle and 129 received ⩾2 symptom-driven cycles. Across Cycles 1-13, mean (standard deviation) CFB to Day 43 in MG-ADL score ranged from -3.2 (3.3 (n = 113; Cycle 3)) to -6.0 (3.9 (n = 24; Cycle 12)). Consistent improvements in MGC and QMG scores were also observed across repeated cycles. Treatment-emergent adverse events (TEAEs) were experienced by 175/188 (93.1%) patients; most mild or moderate. Incidence remained stable with repeated cyclic treatment among patients who remained in the study at each cycle. The most common TEAE was headache (n = 94/188 (50.0%)). Repeated rozanolixizumab treatment cycles demonstrated consistent, clinically meaningful improvements in MG-specific outcomes as early as 1 week after the first infusion. Rozanolixizumab was generally well tolerated with an acceptable safety profile, supporting its long-term use as a treatment option for adults with gMG. ClinicalTrials.gov: NCT03971422; NCT04124965; NCT04650854. Long-term treatment with cycles of rozanolixizumab improved symptoms in patients with generalised myasthenia gravis in a combined analysis of final data from the MycarinG study and its two extension studies Generalised myasthenia gravis (gMG) is an autoimmune disease that damages the connections between nerves and muscles, causing muscle weakness. In the MycarinG study, treatment with rozanolixizumab once a week for 6 weeks was better at improving gMG symptoms than placebo in adults with gMG. After MycarinG, patients could enter the extension studies MG0004 and MG0007. These studies assessed the side effects of long-term rozanolixizumab treatment and measured patients’ symptoms to see whether rozanolixizumab remained effective. In MG0004, patients received rozanolixizumab once a week for up to 52 weeks. In MG0007, patients received rozanolixizumab once a week for 6 weeks, termed a treatment cycle. After the first treatment cycle, patients only received more cycles if their symptoms worsened. We looked at data from patients who received repeated rozanolixizumab treatment cycles across MycarinG, MG0004 (first 6 weeks only) and MG0007. Treatment side effects and gMG symptoms were assessed. Overall, 129 patients received two or more rozanolixizumab cycles due to worsening symptoms. We saw consistent improvements in gMG symptoms across multiple measures; improvements were maintained over repeated treatment cycles. Altogether, we assessed 188 patients for side effects; 175 (93.1%) reported a side effect, most of which were mild or moderate in severity. The most common side effect was headache. The number of reported side effects and how bad they were did not change much across treatment cycles among patients who stayed in the study at each cycle. In the first year of treatment, patients had an average of four treatment cycles. Based on this, rozanolixizumab treatment would be expected to follow a repeated pattern of 6 weeks on treatment and 6–8 weeks off in the first year. Together, these data suggest that repeated rozanolixizumab cycles can be used for long-term treatment in patients with gMG.

Hidradenitis suppurativa (HS) is a painful inflammatory skin disease within the pilosebaceous unit associated with numerous comorbidities, including obesity type-2-diabetes (T2DM), and a general meta-inflammatory state. This narrative review explores the therapeutic potential of GLP-1-receptor-agonists (GLP-1RAs) in treating HS by analyzing mechanisms of action and clinical outcomes. Based on a literature search, encompassing 12 cohorts and 4 case-based reports, current evidence demonstrates significant improvements in both clinical and patient-reported outcomes in patients with HS treated with GLP-1RAs. Treatment consistently resulted in reduced body mass index (BMI) and disease activity, measured by Hurley-staging and the number of nodules and abscesses. Patients across studies experienced fewer flares and less pain, supporting improvements in dermatology quality of life (DLQI) scores. Studies observed reductions in systemic inflammatory markers and improved glycemic control. The beneficial effects of GLP-1RAs in HS are attributed to the reduction in mechanical friction and metabolic improvements from weight loss. Suggestively, concurrent and direct anti-inflammatory mechanisms, including inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and modulation of cytokines, occur independently of weight-reduction. Results from cohorts and cases supported this theory, showing significant improvements in HS and metabolic markers independent of weight-related outcomes. Four supplementary cohorts found GLP-1RAs beneficial for cardiovascular comorbidities in patients with HS. Additionally, studies suggest that GLP-1RAs enhance the efficacy of biologic therapies used for HS and reduce the need for adjunctive treatment. In conclusion, GLP-1RAs represent a promising pleiotropic treatment within a multimodal therapy strategy for HS and comorbidities.