ABSTRACT Introduction Adult secondary hemophagocytic lymphohistiocytosis (asHLH) is a fulminant hyperinflammatory condition triggered by cancers, infections, autoimmune conditions or drugs. The hallmark of its pathogenesis involves dysregulated immune effector cell activation and excessive cytokine release. Areas covered This narrative review updates the reader on modern treatment options for asHLH. The traditional one-size-fits-all strategy derived from the pediatric HLH-2004 protocol is increasingly viewed as outdated today. A significant shift toward a more individualized, trigger- directed treatment approach has occurred in the HLH literature of recent years. Expert opinion Apart from treating promptly the underlying trigger conditions, earlier incorporation of targeted anti-cytokine therapy such as anakinra is strongly favored these days. The cytotoxic etoposide shall be chiefly reserved for malignancy-associated HLH, including B-cell lymphomas, and refractory disease. Rituximab has led to superior outcomes when utilized to clear EBV-infected B-cell reservoirs. IVIG should be considered in infection-associated HLH. The anti-IFN-γ monoclonal antibody emapalumab has been approved for refractory HLH cases. The JAK 1/2 inhibitor ruxolitinib may prove useful in this space as well. The therapeutic arsenal is likely to evolve further in the direction of agents addressing specific pathophysiologic steps in asHLH. Targeting effector cytokines, their receptors, inflammasome pathways are promising future directions in asHLH therapeutics.

ABSTRACT Introduction Biologic therapies have transformed the management of moderate-to-severe psoriasis; however, long-term treatment requires optimization strategies to maintain efficacy, minimize adverse effects, and improve cost-effectiveness in real-world practice. Areas covered This narrative review summarizes current evidence on biologic optimization in psoriasis, including dose adjustment strategies (dose reduction and escalation), interval modification, switching between biologics, and treatment tapering. The role of therapeutic drug monitoring and immunogenicity in guiding treatment decisions is also discussed, along with emerging approaches such as combination biologic therapy. In addition, evolving biomarkers and computational tools, like machine learning, may enable the prediction of treatment response and guide personalized therapy. A structured literature review of published clinical trials, real-world studies, and review articles was undertaken to evaluate existing evidence and identify gaps in current practice. Expert opinion Biologic optimization should follow an individualized, mechanism-based approach integrating clinical response, pharmacokinetic variability, and patient-specific factors. While current evidence is heterogeneous, future research focusing on validated biomarkers, therapeutic drug monitoring, and artificial intelligence-driven models will be critical in advancing precision medicine and improving the optimization, durability and cost-effectiveness of biologic therapy.

ABSTRACT Introduction Biosimilar development is undergoing regulatory change, with growing emphasis on analytical comparability and targeted clinical pharmacology rather than routine comparative efficacy studies. A focused review is therefore needed to understand how global regulatory expectations are evolving, where they are converging, and what this means for future development. Areas covered This review examines biosimilar regulatory frameworks across agencies, including the FDA, EMA, PMDA, WHO, Health Canada, and ANVISA. It outlines the shift toward a stepwise, totality-of-evidence approach in which analytical similarity, functional characterization, pharmacokinetic/pharmacodynamic comparability, and immunogenicity assessment provide the basis for establishing biosimilarity. It also considers recent regulatory changes supporting a reduced role for comparative efficacy studies, broader use of foreign comparators and reliance pathways, and the emerging application of artificial intelligence in comparability assessment and model-informed development. Relevant regulatory documents and peer-reviewed literature were reviewed to summarize current trends, differences, and likely future directions. Expert opinion For many well-characterized biosimilars, particularly monoclonal antibodies, robust analytical and clinical pharmacology data can address most uncertainty, making routine comparative efficacy studies less necessary in many cases. Greater alignment in comparator policies, study expectations, and responsible use of artificial intelligence could help streamline development, reduce duplication, and improve patient access.

ABSTRACT Background Clinical remission is an emerging goal in severe asthma (SA) management. While tezepelumab demonstrates broad efficacy, its real-world impact on remission—specifically in the context of small airway dysfunction (SAD)—remains incompletely defined. Methods This prospective, multicentre study enrolled 39 adults with SA treated with tezepelumab for 12 months. Clinical remission was defined by SANI criteria: complete oral corticosteroid (OCS) withdrawal, zero severe exacesrbations, Asthma Control Test score ≥20, and stable/improved FEV1. SAD remission required normalization of oscillometric parameters. Results At baseline, 44% of patients exhibited SAD. Tezepelumab eliminated severe exacerbations and achieved complete OCS withdrawal in 100% of evaluable patients. At 12 months, 77.4% of the overall evaluable cohort and 80.0% of those with baseline SAD achieved clinical remission. However, SAD remission was not observed; these patients maintained persistent oscillometric abnormalities despite reaching all clinical goals. Conclusion Tezepelumab enables high rates of clinical remission regardless of baseline small airway status. In the SAD phenotype, symptomatic and inflammatory recovery dissociates from physiological SAD remission. Persistent mechanical abnormalities highlight the necessity of oscillometry to identify hidden residual disease in patients who otherwise appear to be in remission.

ABSTRACT Background Psoriasis is an immune-mediated inflammatory skin disease with variable biologic therapy response. Current treatment selection lacks reliable predictive biomarkers for personalized decisions. Objectives To identify distinct immunological patient subgroups based on peripheral blood immune cells and evaluate their association with biologic therapy efficacy. Methods This retrospective cohort study included 329 plaque psoriasis patients initiating first-time biologic therapy and 169 healthy controls. Peripheral blood flow cytometry data were analyzed using hierarchical clustering. Kaplan-Meier analysis assessed time to PASI90 achievement among subgroups. Results Psoriasis patients showed significantly elevated lymphocyte populations. Three distinct immunological clusters were identified: Cluster 1 (57.8%) with moderate T cells and low NK cells; Cluster 2 (27.7%) with decreased T cells and increased NK cells; and Cluster 3 (14.6%) with increased total lymphocytes. Cluster 1 patients achieved PASI90 significantly faster with both IL-17 and IL-23 inhibitors (p < 0.001). Conclusion Peripheral blood flow cytometry identified distinct psoriasis immunophenotypes with significant differences in biologic therapy response, offering potential biomarkers for treatment selection and personalized medicine approaches.

ABSTRACT OBJECTIVES To assess prescription patterns and describe the long-term real-life effectiveness of different TNF inhibitors (TNFi) in juvenile idiopathic arthritis related uveitis (JIA-U). METHODS Patients with JIA-U treated with TNFi were retrospectively enrolled. RESULTS 96 JIA-U patients (77% female) with an age at diagnosis of 2.44 [interquartile range (IQR) 1.56–3.81] and a median follow-up of 19 years were included. Adalimumab was the most frequently prescribed TNFi (61%), followed by etanercept (19%), infliximab (15%) and golimumab (5%). Overall, adalimumab showed the lowest complications rate (51%; p < 0.001) and median number of uveitis relapse (1; IQR 0–2; p = 0.012). Conversely etanercept showed the highest median number of uveitis relapses (4; IQR 1–5). The cumulative incidences curves for ‘uveitis relapse’ were similar among TNFi. Conversely, when ‘treatment change’ was considered as the event, a significantly higher risk for patients treated with infliximab compared with those receiving adalimumab emerged (HR 3.06, 95% CI 1.41–6.63; p < 0.01). CONCLUSIONS All TNFi appear to be effective for long-term management of JIA-U. We observed some differences in number of uveitis relapses and ocular complication rates favoring adalimumab over infliximab and etanercept, findings to be further confirmed in prospective studies.

ABSTRACT INTRODUCTION Over the past two decades, targeted biological therapies have profoundly transformed the management of type 2 (T2) inflammatory diseases, including severe asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, chronic spontaneous urticaria, and eosinophilic granulomatosis with polyangiitis. This paper reviews the key milestones of this twenty-year journey, focusing on the evolving therapeutic goals, from disease control to clinical remission. AREAS COVERED This paper synthesizes evidence from pivotal clinical trials, real-world registries, extension studies, and systematic reviews on biologics in T2 inflammatory diseases. A targeted literature search was conducted across PubMed and major respiratory, allergy, and dermatology journals, prioritizing publications from 2020 to 2026, with inclusion of landmark earlier studies. EXPERT OPINION Clinical remission in biologic-treated T2 inflammatory diseases is achievable but not yet reliably predictable; the field urgently requires globally standardized, validated composite remission indices for each major T2 condition that integrate symptom scores, organ function measures, and biomarker profiles. The defining challenge of the next decade is determining whether early biologic intervention can genuinely modify the disease trajectory and achieve sustained off-treatment remission.

ABSTRACT INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently affects children and is associated with significant morbidity and impaired quality of life. Recent advances in our understanding of AD immunopathogenesis have led to the development of targeted biological and small-molecule therapies. AREAS COVERED This review focuses on the available and emerged targeted therapies for pediatric AD, linking mechanistic rationale to currently available and emerging biologics and JAK inhibitors and highlighting the limits of pediatric evidence, real-world data, and treatment selection. The literature was reviewed by searching PubMed and other relevant clinical trial databases, focusing on studies that evaluated targeted systemic treatments in children and adolescents with AD. EXPERT OPINION Targeted therapies are reshaping the management of pediatric AD and improving disease control and quality of life. However, long-term safety data, validated biomarker-guided treatment strategies, and equitable access to these therapies remain key challenges.

ABSTRACT INTRODUCTION Childhood-onset systemic lupus erythematosus (cSLE) accounts for 15–20% of all forms of SLE. It is associated with greater disease severity and requires more aggressive treatment than adult-onset SLE. Despite therapeutic advances, many patients do not achieve sustained remission, highlighting the need for more effective treatment strategies. AREAS COVERED This review summarizes the literature published in the past two decades on the use of biologic medications for the treatment of cSLE. It is based on the narrative analysis of recent clinical trials, observational studies and patient series or individual clinical cases. We discuss the rationale, indications, effectiveness and safety of the biologic agents utilized thus far in patients with cSLE, with a primary focus on rituximab and belimumab. In addition, we address the future perspectives of the management of cSLE. EXPERT OPINION The improved understanding of the mechanisms involved in immunopathogenesis of SLE has led to the development of increasing numbers of biologic agents that target specific cells or pathways. This advance has increased the therapeutic options available for the management of cSLE and holds great promise for transforming the landscape of cSLE care through the implementation of precision medicine and personalized therapeutic approaches, with the ultimate goal of reaching sustained, glucocorticoid-free disease remission.

ABSTRACT Introduction The concept of difficult-to-treat (D2T)/difficult-to-manage (DTM) disease was first defined in rheumatoid arthritis (RA). Recent definitions for axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) combine non-response to treatment including targeted and biologic treatment, inflammatory disease activity, and patient symptoms. This concept could apply to other chronic inflammatory diseases such as psoriasis (PsO) and inflammatory bowel disease (IBD). A consensus definition of D2T IBD is available but is yet to be fully articulated in PsO. Areas covered This article aims to provide an expert overview of the shared elements and potential differences between the definitions and concepts of D2T/D2M in these diseases. Expert opinion D2T/D2M definitions should allow better evaluation of refractory diseases, accurate determination of disease severity, and effective treatment of the D2T areas or domains. Definitions should consider response to previous lines of treatment, control of inflammation, and global disease improvement, and consider the impact of D2T disease on patient status/quality of life. Proof-of-concept studies need to assess the current and future definitions of D2T/D2M populations in axSpA, PsA, PsO, and IBD, to accurately determine the prevalence of patients meeting each of those D2T criteria sets, and to identify risk factors, disease burden, and appropriate management strategies.