INTRODUCTION:Switching from reference biologics to biosimilars usually occurs for non-medical reasons, such as cost-driven formulary changes. However, despite biosimilars having the same efficacy and similar safety profiles as their reference products, some patients discontinue treatment and 'switchback' to the reference product. AREAS COVERED:In this narrative review, the authors examine the frequency and causes of switchback reported in journal articles and congress abstracts published between 2016 and 2023, evaluating patients who switched from biosimilars back to the reference biologic. As almost all publications focused on tumor necrosis factor inhibitors, and so the authors restricted their analysis to this drug class. EXPERT OPINION:Evidence suggests that switchback rates are low, with most studies of at least 100 patients reporting rates of less than 20%. The main reasons for switchback are typically patient-reported loss of effectiveness (usually judged subjectively) and side effects. These findings support the view that the nocebo ('negative placebo') effect is a plausible and likely contributor to switchback. Healthcare professional and patient education on the effectiveness and safety of biosimilars is needed and will be vital to counter misinformation and minimize the nocebo effect, allowing biosimilars to continue contributing to sustainability in healthcare.
INTRODUCTION:Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by marked clinical and immunological heterogeneity. Recent advances indicate that SLE comprises multiple molecular endotypes driven by distinct immune pathways, underscoring the need for a precision medicine approach. AREAS COVERED:Literature was identified through searches of PubMed/MEDLINE using keywords including 'systemic lupus erythematosus,' 'precision medicine,' 'biomarkers,' 'multi-omics,' 'lupus nephritis,' 'CAR-T,' and related terms. Landmark clinical trials, translational studies, and recent high-impact publications published through May 2026 were preferentially included. This review summarizes advances in SLE stratification based on immune phenotyping and multi-omics approaches and outlines emerging therapies, including biologics, intracellular inhibitors, and cell-based treatments. It also discusses challenges in clinical trial design and treatment response assessment. EXPERT OPINION:Improving outcomes in SLE will require the integration of molecular stratification, mechanism-based therapy, and refined response assessment. However, the routine implementation of precision medicine remains limited by the lack of standardized biomarkers, accessible multi-omics platforms, and validated patient stratification algorithms. The development of standardized, clinically applicable stratification tools together with novel outcome measures will be essential for translating precision medicine into routine clinical practice.
BACKGROUND:CD (Castleman disease) is a rare and heterogeneous condition that poses a diagnostic and management challenge. Classification of CD has changed dramatically in recent years. This study aims to describe our experience with diagnosis and treatment of CD at a center in Canada. RESEARCH DESIGN AND METHODS:We conducted a retrospective study of our cohort of CD patients evaluated and treated at the University of British Columbia between 2016-2025. RESULTS:A total of 23 patients with biopsy-confirmed CD were included. 7/23 had unicentric CD (UCD), 1/23 had Oligocentric CD (OligoCD), and 15/23 had multicentric CD (MCD). All MCD cases were idiopathic (iMCD) and of these, 3/15 had iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis or renal dysfunction, and organomegaly), 4/15 had iMCD-idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and 8/15 had iMCD-not otherwise specified (iMCD-NOS). Median time to diagnosis was shortest for iMCD-TAFRO (1 month) and longest in iMCD-IPL (82 months). 100% of iMCD-TAFRO, 100% of iMCD-IPL, and 86% of iMCD-NOS cases treated with Siltuximab or Tocilizumab had at least a partial response. CONCLUSIONS:This study demonstrates the heterogeneous presentation, natural history, and response to treatment of CD in a North American center, and highlights the importance of awareness of the different subtypes of CD. Key limitations are its retrospective design and small sample size.
INTRODUCTION:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation that can occur secondary to medical interventions including immunomodulatory therapies such as immune checkpoint inhibitors and stem cell transplantation. However, lamotrigine and other anti-seizure medications (ASMs), which are not thought of as overtly immunogenic, are an important emerging cause and exploring the pathophysiology of lamotrigine-associated HLH may improve our understanding of secondary HLH. AREAS COVERED:We completed a literature search in EMBASE and MEDLINE for English language articles indexed between 1 January 1966, and 31 August 2025. We review the current understanding of the diagnosis and pathophysiology of known causes of immunomodulatory therapy-associated HLH including chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint inhibitors. We then discuss the clinical overlap between ASM-induced HLH & drug-induced hypersensitivity syndrome (DIHS) and explore underlying immune pathophysiology including mechanisms and potential contributors including host genetic factors and viral etiologies. EXPERT COMMENTARY:Lamotrigine-induced HLH has significant clinical overlap with DIHS, with common features of fever, diffuse skin rash, and multi-organ failure. Further advances in immune profiling of patients with ASM-associated HLH will improve our understanding of the pathogenesis and promote the development of novel immunotherapy agents for the treatment of the condition.
INTRODUCTION:Psoriatic arthritis (PsA) is an immune-mediated inflammatory disease in which the IL-23/Th17/IL-17 axis contributes to musculoskeletal and extra-musculoskeletal inflammation. Ocular manifestations, particularly dry eye disease (DED), uveitis, and less frequently episcleritis and scleritis, are increasingly recognized across psoriatic disease, although their pathobiology and relationship to systemic inflammatory pathways remain incompletely defined. AREAS COVERED:This narrative review examines evidence linking IL-17 to ocular disease in psoriatic disease, with emphasis on ocular surface inflammation. We summarize ocular involvement in PsA, review mechanistic and translational data across skin, enthesis, synovium, and the lacrimal-ocular surface unit, and appraise clinical data on IL-17-pathway inhibitors, including their established musculoskeletal and cutaneous efficacy and less consistent ocular effects. EXPERT OPINION:IL-17 may contribute to ocular surface inflammation in PsA, but this remains largely inferential because direct PsA-specific ocular data are scarce. IL-17A inhibitors are effective in musculoskeletal and cutaneous disease, yet ocular benefit cannot be assumed from systemic efficacy. Current evidence suggests limited impact on established DED and less consistent uveitis protection than monoclonal TNF inhibition. Prospective studies with adjudicated ocular endpoints and tear/conjunctival profiling are needed to define whether IL-17-responsive ocular phenotypes exist in PsA.
INTRODUCTION:Type 1 diabetes (T1D) has long been viewed as an immune-driven disease characterized by the destruction of otherwise healthy pancreatic beta cells. However, growing evidence indicates that beta cells may actively contribute to disease initiation. Intrinsic dysfunction - such as impaired protein processing, endoplasmic reticulum stress, neoantigen formation, and early upregulation of major histocompatibility complex (MHC) class I - could increase beta-cell immunogenicity and promote autoimmune recognition. This emerging paradigm has significant implications for prevention and therapeutic strategies. AREAS COVERED:This review synthesizes experimental, translational, and clinical evidence supporting beta cell stress and dysfunction as central components of T1D pathogenesis. It examines intrinsic beta cell pathways, mechanisms of immune recognition, and therapeutic approaches aimed at preserving beta-cell integrity. These findings challenge the traditional immune-centric model and support a more integrated view of disease progression, emphasizing the interplay between beta cell vulnerability and immune activation. EXPERT OPINION:Effective prevention will likely require combination strategies that address both beta cell stress and autoimmunity. Approaches integrating beta cell protective agents with antigen-specific tolerance therapies may delay or prevent progression when applied early. Stage-adapted interventions targeting both beta cell resilience and immune modulation may redefine T1D prevention and improve management of pre-symptomatic individuals.
INTRODUCTION:Ustekinumab has been an approved biologic therapy for moderate-to-severe psoriasis for over 16 years. With the emergence of newer IL-17 and IL-23 inhibitors, its use was largely supplanted by these more effective treatments. With the introduction of biosimilars, ustekinumab's potential role in the current treatment landscape warrants reassessment, as insurers may encourage first line use again. AREAS COVERED:This review summarizes the mechanism of action, clinical trial data, real-world evidence, and biosimilar development of ustekinumab in psoriasis. A literature search was conducted using PubMed and relevant clinical trial databases, focusing on studies published from 2008 to 2025. Key trials, including PHOENIX, ACCEPT, CLEAR, and UltIMMa, as well as registry data and recent observational studies, are discussed to evaluate efficacy, safety, and comparative effectiveness. EXPERT OPINION:While newer biologics are more effective, ustekinumab remains a good option due to its dosing convenience, established safety profile, efficacy for the common psoriatic arthritis comorbidity, and lower cost afforded by ustekinumab biosimilars. In health systems that prioritize exclusively efficacy and safety, ustekinumab may play little role in psoriasis management. However, in systems that prioritize lower cost treatment, biosimilar adalimumab and ustekinumab could be preferred first line treatments, and of these two, ustekinumab may be preferred over adalimumab because of greater efficacy, better safety, and fewer injections.
INTRODUCTION:The link between the risk of developing Multiple Sclerosis (MS) and Epstein-Barr virus (EBV) infection has been confirmed. However, the mechanisms by which EBV influences MS remain unclear, likely due to the complex interplay among the EBV subtype, the host's immune response, and viral and environmental exposures. AREAS COVERED:In this review, we explore some of those complexities and the evidence on how EBV may contribute, at the molecular level, to MS pathogenesis across the spectrum of MS disease, both relapsing-remitting and progressive. For this review, we searched PubMed and Medline entries using a combination of terms related to 'Epstein-Barr Virus,' 'Multiple Sclerosis,' 'disease-modifying therapies,' and 'EBV activity.' Those search results were then used to address how EBV relates to MS pathophysiology and how the effects of MS risk factors and the efficacy of disease-modifying therapies may be explained by their effects on EBV. EXPERT OPINION:We posit that addressing EBV infection and viral replication is vital to the discovery of a cure for MS. Given that multiple genetic factors are involved, targeting EBV within cellular reservoirs and suppressing EBV protein expression is likely to provide the greatest benefit in preventing MS disease activity, progression, and immune-mediated neurodegeneration.
INTRODUCTION:Alopecia areata is a prevalent autoimmune non-scarring alopecia with high post-treatment relapse and refractory rates, which severely impairs patients' physical and mental health. While CD8+ T cells are well-established as the primary effector cells in AA, emerging evidence indicates that dendritic cells (DCs) play important upstream regulatory roles in disease initiation and progression. AREAS COVERED:This narrative review systematically synthesizes relevant studies from the PubMed database published up to May 2026, dissecting the dual roles of distinct DC subsets in maintaining hair follicle immune privilege and driving autoimmune cascade, along with core molecular pathways. It also analyses DC-related mechanisms of standard therapies and emerging DC-targeted therapeutic strategies. EXPERT OPINION:DCs play important roles in the complex immunopathological network of AA. DC-targeted precision therapies hold substantial potential to overcome the limitations of broad immunosuppression and restore long-term follicular immune homeostasis, with single-cell multi-omics technologies enabling further mechanistic and translational advances.
INTRODUCTION:Respiratory syncytial virus (RSV) is an important respiratory pathogen among older adults and those with chronic conditions. METHODS:Two systematic literature reviews identified the impacts of chronic conditions on RSV infection outcomes in adults, and how immunological changes alter RSV infection susceptibility in older individuals. Searches using MEDLINE/Embase identified relevant papers published between 1 January 1990, and 2 August 2023. RESULTS:Of 4,699 records, 212 were selected. Inclusion criteria were based on relevant comorbidities, outcomes, and study methodologies. The prevalence of severe RSV-associated disease, hospitalization risk, and mortality increased with age. Contributing factors for increased RSV infection susceptibility and morbidity in adults included immunosenescence, age-related physiological function decay, and presence of certain chronic conditions. Mechanisms underlying increased RSV susceptibility in those with chronic conditions included epithelial damage, inflammation, and direct or indirect myocardial damage. Vaccines for the prevention of RSV-associated lower respiratory disease in older adults have potential to prevent substantial morbidity and mortality. CONCLUSIONS:Immunosenescence and chronic medical conditions increase susceptibility of adults to RSV, yet knowledge gaps remain regarding RSV pathogenesis in chronic conditions. Recently approved RSV vaccines support preventive strategies for these individuals.The protocol for this study is PROSPERO registered (identifier: CRD42021293292).
INTRODUCTION:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare, life-threatening autoimmune conditions requiring complex pharmacological management. Contemporary strategies have transitioned from empirical cytotoxic therapy toward mechanistically targeted approaches, reflecting a deeper understanding of B-cell immunity and the alternative complement pathway. This review synthesizes current guidance and presents recent evidence on treatment modalities and emerging options. AREAS COVERED:This paper reviews and synthesizes current international guidance from the European League Against Rheumatism (EULAR), the British Society for Rheumatology (BSR), and the American College of Rheumatology (ACR) on remission induction and maintenance for granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Key shifts discussed include the established role of rituximab as a primary induction agent, the implementation of reduced-dose glucocorticoid tapering, and the integration of anti-IL-5 therapies for eosinophilic phenotypes. EXPERT OPINION:In our opinion, the management of AAV has entered a precision era defined by targeted, steroid-sparing regimens. The most significant progress lies in standardizing B‑cell depletion and the emergence of complement inhibition. Despite the evolution of steroid-sparing protocols, mitigation of treatment-related morbidity remains a primary challenge. Ultimately, AAV management must transition toward biomarker-driven precision medicine to individualize therapy and improve long-term outcomes.
INTRODUCTION:Infectious disease screening is now a routine component in the management of patients with rheumatological conditions and is mandatory in some settings before initiating biologic or conventional immunosuppressive therapies. AREAS COVERED:In this narrative review, we summarize the current literature to assist clinicians in interpreting screening results and risk stratification, and to guide subsequent clinical management, including prophylaxis, monitoring, and treatment strategies. The review of the literature was performed using MEDLINE and Embase, complemented by manual searches of reference lists and gray literature, to identify evidence on infectious disease screening in patients with rheumatologic conditions undergoing immunosuppressive therapy. EXPERT OPINION:Available evidence supports the importance of effective pre-treatment screening and risk assessment in patients requiring immunosuppression. However, significant knowledge gaps remain, particularly regarding infectious risks linked to certain drug classes and the optimal implementation of screening strategies.
INTRODUCTION:The antigen uptake receptor DEC205 has been extensively studied in dendritic cells (DCs). By mediating antigen delivery to major histocompatibility complex (MHC) class II processing compartments, DEC205 facilitates efficient antigen presentation, a property that has been widely exploited for targeted antigen delivery to DCs. AREAS COVERED:This review summarizes studies investigating various molecular strategies employing anti-DEC205 conjugates, as well as conjugates targeting other DC-specific receptors, to induce either immune activation or immune tolerance in animal models and clinical trials. EXPERT OPINION:Clinical studies have demonstrated the therapeutic potential of in vivo DC-targeted antibody conjugates. In this context, anti-DEC205 conjugates have served as a paradigm for DC-specific antigen targeting. Beyond DEC205, recent research has identified additional DC-specific receptors that may broaden the scope of targeted immunotherapies. Furthermore, antibody-based approaches that do not rely on antibody conjugates have attracted increasing attention. We anticipate that future research will focus on (i) optimizing antigen-antibody conjugation strategies, (ii) combining DEC205-mediated antigen targeting with immune checkpoint blockade, and (iii) evaluating the efficacy of co-stimulatory adjuvants in vaccination protocols.
INTRODUCTION:The ocular surface is a frontline mucosal immune barrier that protects the eye from pathogens while preserving immune tolerance essential for vision. Breakdown of this innate immune homeostasis can trigger chronic ocular surface inflammation, exemplified by Stevens-Johnson syndrome/toxic epidermal necrolysis with severe ocular complications (SJS/TEN with SOC) and atopic keratoconjunctivitis (AKC). AREAS COVERED:The review summarizes current knowledge of ocular surface innate immunity, focusing on pattern-recognition receptors (TLR3, RIG-I, MDA5) and downstream interferon-stimulated genes (e.g. IFI44L, CXCL10, IFIT2) and their regulation. The influence of host genetic predispositions and microRNA regulatory networks on these pathways is highlighted, and innate immune profiles are compared among SJS/TEN with SOC, AKC, and healthy ocular surfaces. EXPERT OPINION:Dysregulation of mucosal innate immunity - shaped by host genetic factors, abnormal epithelial responses, and microRNA-mediated feedback loops - underlies the persistence and severity of chronic ocular surface disorders such as SJS/TEN with SOC and AKC. A deeper understanding of these mechanisms may inform the development of novel diagnostic biomarkers (e.g. microRNA signatures) and immune-modulating therapies to restore immune homeostasis and prevent vision-threatening inflammation. PubMed was used as the literature search methodology.
INTRODUCTION:Assessment of disease activity in juvenile systemic sclerosis (jSSc) is essential for clinical care and trial readiness, yet no validated pediatric activity measures exist. Adult systemic sclerosis activity tools, including the Scleroderma Clinical Trials Consortium Activity Index, revised CRISS, and revised EUSTAR, provide conceptual frameworks but require adaptation for developmental, physiologic, and feasibility considerations for children. At the 17th Hamburg Symposium on JSSc, an international multidisciplinary panel reviewed adult indices, evaluated corresponding variables in the jSSc Inception Cohort and the NRCOS registry, and conducted a structured Delphi process to define organ-specific indicators of clinically meaningful activity in jSSc. AREAS COVERED:Across skin, pulmonary, cardiac, vascular, musculoskeletal, gastrointestinal, renal, and global domains, the panel reached broad and often unanimous consensus on variables reflecting active, potentially reversible disease. Key endorsed measures included mRSS progression, new ILD on HRCT, ≥10% declines in FVC or DLCO, new cardiac abnormalities, active digital ulcers, synovitis, myositis, nutritional decline, and physician global assessment. Patient-reported outcomes were strongly supported across domains. EXPERT OPINION:These consensus-derived indicators provide the first comprehensive pediatric-specific foundation for defining disease activity in jSSc and represent a critical step toward developing and validating a unified pediatric activity index suitable for future clinical trials.
INTRODUCTION:Sarcoid-like reactions (SLR) are granulomatous conditions characterized by non-caseating epithelioid cell granulomas that mimic sarcoidosis but arise in patients who do not fulfill diagnostic criteria for systemic sarcoidosis. The overlap with sarcoidosis poses a significant challenge, as misdiagnosis can lead to inappropriate treatment. AREAS COVERED:We performed a comprehensive review of the available literature summarizing SLRs associated with malignancies, infections, and most relevant drugs involved, discussing the timing of onset, patterns of organ involvement, and prognostic implications. Management strategies are discussed according to the underlying trigger, ranging from simple observation to corticosteroids or targeted immunosuppression, and from pathogen-directed therapy to careful continuation or modification of anticancer treatment. EXPERT OPINION:SLRs represent a diagnostic and pathogenetic challenge due to the plasticity of the granulomatous immune response, which can be triggered by drugs, malignancy, or other stimuli, often mimicking systemic sarcoidosis. Dedicated studies are needed to develop standardized diagnostic criteria and algorithms that integrate clinical, histological, and immunological features to accurately distinguish SLRs from sarcoidosis and guide management.
BACKGROUND:Circannual variation in immune function may influence the efficacy of immune checkpoint inhibitors (ICIs), yet clinical evidence regarding seasonal effects remains limited. METHODS:We retrospectively analyzed adults with metastatic solid tumors treated with anti-PD-1 monotherapy at a single center between 2015 and 2024. Seasons were defined by regional daylight patterns: summer (April-October) and winter (November-March). Primary endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier estimates, log-rank tests, multivariable Cox regression, propensity score matching (PSM), and a 3-month landmark analysis were performed. RESULTS:Among 430 patients, 245 (57.0%) initiated ICIs in summer and 185 (43.0%) in winter. In the unmatched cohort, summer initiation was associated with longer PFS and OS. After PSM, 181 patients remained in each group, and the survival advantage persisted: median PFS was 6.2 versus 3.6 months (HR 0.72, 95% CI 0.56-0.91) and median OS was 21.5 versus 12.4 months (HR 0.74, 95% CI 0.58-0.94) for summer versus winter, respectively. Landmark and multivariable analyses confirmed these findings. CONCLUSIONS:Initiation of anti-PD-1 therapy during summer was associated with significantly improved survival, suggesting that seasonal modulation of host immunity may influence ICI outcomes.
BACKGROUND:Ocular mucous membrane pemphigoid (OcMMP) is a chronic autoimmune scarring disease that may lead to progressive visual impairment. Evidence regarding the use of leflunomide (LFN) in OcMMP is limited. RESEARCH DESIGN AND METHODS:We conducted a retrospective, observational multicenter study including adult patients with OcMMP treated with LFN between May 2006 and June 2025 at rheumatology centers in Argentina. Clinical characteristics, treatment regimens, and outcomes were collected from medical records. Disease severity and progression were assessed using Foster staging. LFN was used as second-line therapy after methotrexate failure, as monotherapy or in combination. Treatment effectiveness at 6 months was defined as suppression of ocular inflammation and achievement of a glucocorticoid-sparing effect. Treatment failure included persistent inflammation, discontinuation due to adverse events, lack of steroid-sparing effect, or need for additional immunomodulatory therapy. RESULTS:Thirty-six patients (mean age 67.1 years) were included. At 6 months, 61.1% achieved inflammatory control with glucocorticoid reduction or discontinuation; overall effectiveness during follow-up was 55.5%. Foster stage progression occurred in 8.5%. Adverse events leading to discontinuation were infrequent. CONCLUSIONS:LFN may be a safe and effective option for selected OcMMP patients, although the retrospective design and limited sample size warrant prospective studies.
