The PESTO trial's claim to provide Class I evidence that perispinal etanercept does not improve quality of life is precluded by the absence of publicly verifiable trial-wide inclusion/exclusion criteria and by its use of a novel primary responder definition that utilizes a non-accepted scoring pathway, of no established validity or reliability, that was first specified after data collection was completed. PESTO's Statistical Analysis Plan differs from the analysis its operative protocols and registration specify, and no amendment, registry update, or explanation discloses the change. PESTO's published primary quality-of-life measurement is unreliable, and its definitive negative conclusion cannot be relied upon as a statement of what the trial established. Whether the reported estimate would survive the prespecified analysis, the record cannot yet answer. Correction of PESTO's record and conclusions and reclassification of its Class I designation are due now. Further, independent multidisciplinary review, with separate statistical and research-ethics components, is required.

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by keratinocyte hyperproliferation and cytokine-driven immune activation, in which TNF-α plays a central pathogenic role. We developed a layered hydrated silk fibroin (SF) microneedle system (ETA@Hyd MN) with SF tips loaded with etanercept (ETA, a TNF-α inhibitor for psoriasis), for local cutaneous delivery to reduce systemic exposure and rapidly dissolving polyvinyl alcohol (PVA) bases that facilitate retention of the SF tips within the skin. Hydration markedly slowed ETA release, with approximately 80% released at 48 h compared with approximately 75% released within 1 h from microneedles without hydration. In HaCaT cell scratch assays, release media from ETA@Hyd MN attenuated the accelerated wound closure response, resulting in a greater remaining scratch width than that in the model group at 48 h. In an IMQ-induced psoriasis-like mouse model, ETA@Hyd MN improved clinical symptoms, reduced PASI scores, alleviated spleen enlargement, and suppressed epidermal hyperplasia and TNF-α/IL-6 expression. These results demonstrate that ETA@Hyd MN enables sustained ETA release and effectively suppresses inflammation, highlighting its potential for treating inflammatory skin diseases.

Sialylation is a critical quality attribute of therapeutic glycoproteins, yet strategies to specifically modulate O-glycan sialylation remain underdeveloped compared to N-glycosylation. While N-acetylmannosamine (ManNAc) is widely utilized as an established enhancer of N-glycan sialylation, its efficacy in modulating O-glycan structures has remained largely unexplored across different mammalian hosts. In this study, we investigated ManNAc supplementation as a practical approach for modulating O-glycan sialylation in recombinant Chinese hamster ovary (CHO) cells. Using etanercept and erythropoietin-Fc-fusion protein as models, we found that ManNAc supplementation resulted in a statistically significant, although modest, increase in the proportion of di-sialylated O-glycoforms and the overall content of O-linked sialic acid without compromising cell growth or protein productivity. This enhancement was accompanied by a substantial expansion of the intracellular CMP-sialic acid (CMP-SA) pool. Interestingly, despite increased CMP-SA levels following ManNAc supplementation in human embryonic kidney 293 (HEK293) cells, O-glycan sialylation remained largely unchanged, indicating that responsiveness to ManNAc supplementation differs among cell lines. Our results suggest that ManNAc supplementation can serve as a useful tool for adjusting O-glycan sialylation in CHO cell-based production systems, providing process-relevant insights for biosimilar quality control. Overall, this study provides fundamental mechanistic insights into the use of metabolic precursors to modify the sialylation profiles of O-glycosylated therapeutic glycoproteins.

Diabetic kidney disease involves hyperglycemia, inflammation, and epithelial cell dysfunction, but the relationship between these factors is not well understood. We demonstrate that human kidney organoids treated with elevated glucose exhibit a phenotype of epithelial detachment driven by tissue-intrinsic upregulation of proinflammatory cytokines, which can be targeted therapeutically. High glucose induces morphological deterioration of organoids featuring podocyte and tubular cell detachment without cytotoxicity. Cytokine addition sensitizes organoids to intermediate concentrations of elevated glucose. Transcriptomic analysis reveals that high glucose levels affect cytokine, inflammation, signaling, and cell adhesion pathways, resembling changes in human diabetic kidneys. Inhibitors of cytokines and signaling pathways rescue the high glucose phenotype, which is independent of osmotic effects. Thus, elevated glucose triggers a tissue-intrinsic inflammatory cascade to produce an organ-specific phenotype in epithelial cells. This paradigm is relevant for understanding and potentially treating diabetic complications in the kidneys and possibly other organs.

Ankylosing spondylitis (AS) is a prototypical axial spondyloarthritis (axSpA) defined by chronic inflammatory back pain, progressive spinal stiffness, and frequent extra-articular manifestations such as acute anterior uveitis (21%-33%), inflammatory bowel disease (5%-10%), and psoriasis (4%-13%). Management has shifted from non-steroidal anti-inflammatory drugs (NSAIDs) to highly targeted biologic and synthetic disease-modifying antirheumatic drugs (DMARDs). This comprehensive review focuses on the current evidence for biologic and targeted synthetic therapeutics in the management of AS, emphasizing mechanisms of action, regulatory approvals, dosing regimens, and clinical efficacy. Three major therapeutic classes are identified: two biologic DMARD classes, comprising tumor necrosis factor-alpha (TNF-α) inhibitors and interleukin-17 (IL-17) inhibitors, and the targeted synthetic DMARDs, namely, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors. TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, certolizumab pegol) typically achieve Assessment of Spondyloarthritis International Society 40% improvement (ASAS40) rates of 40%-58% at 12-24 weeks versus 13%-24% with placebo, and maintain clinical benefit in many patients over 5-8 years. IL-17 inhibitors (secukinumab, ixekizumab, bimekizumab, brodalumab, netakimab) yield broadly similar ASAS40 responses (30%-50% versus 10%-20% placebo) and are particularly useful in patients with concomitant psoriasis with substantially reduced risk of tuberculosis reactivation. JAK inhibitors (tofacitinib, upadacitinib) represent the newest class, offering oral administration with ASAS40 responses of 40%-52% versus 13%-26% for placebo in both biologic-naïve and biologic-experienced AS, though cardiovascular safety considerations necessitate careful patient selection. Therapeutic selection should consider comorbidities (uveitis favors TNF monoclonal antibodies; psoriasis favors IL-17 inhibitors), safety profile, route of administration, and sequencing after non-steroidal anti-inflammatory drug failure. Understanding these pharmacological distinctions enables personalized therapeutic decisions based on the specific molecular pathology and risk profile of the individual patient.