Radjesh J. Bisoendial

Dendritic cell (DC) migration via afferent lymphatics to draining LNs (dLNs) occurs in distinct steps that require the chemokine C–C motif ligand 21 (CCL21). In addition to full-length CCL21, which forms an immobilized perilymphatic gradient, a truncated soluble variant with enhanced gradient-forming capacity (CCL21-ΔC) was recently identified in tissues. We show that in skin, plasmin is continuously activated in a urokinase plasminogen activator (uPA)-dependent manner on lymphatic endothelial cells (LECs) and cleaves full-length CCL21, generating CCL21-ΔC. Inflammatory conditions, while promoting overall DC migration, markedly enhance this process, reducing immobilized perilymphatic CCL21 and increasing dermal CCL21-ΔC levels. Inhibition of uPA-mediated CCL21 cleavage causes full-length CCL21 to accumulate around dermal lymphatics, while CCL21-ΔC levels decline in the skin and dLN subcapsular sinus. Consequently, DC entry into afferent lymphatics is diminished, whereas DC egress from the subcapsular sinus into the LN parenchyma is enhanced. These findings reveal uPA/plasmin-dependent regulation of lymphatic CCL21 gradients and identify CCL21-ΔC as critical for DC migration.

Recent studies show that obesity significantly increases disease severity and progression in several forms of inflammatory arthritis, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and gout. Obesity increases the risk for developing inflammatory arthritis. Similarly, obesity negatively impacts disease severity and treatment outcomes. The underlying mechanisms driving these relationships are not fully understood. One emerging area of investigation is the role of the lymphatic vasculature. Obesity profoundly impacts lymphatic function. Excess adipose tissue can compress and disrupt lymphatic vessels, leading to impaired flow and drainage. Additionally, obesity-associated inflammation and metabolic dysregulation have been linked to lymphatic endothelial cell dysfunction, further compromising transport and immunoregulatory capacities. This impairment fosters an environment for the accumulation of inflammatory cells and mediators, sustaining chronic inflammation. In this review, we will provide new perspectives on the detrimental triangle of obesity, lymphatic dysfunction, and inflammation in chronic inflammatory arthritis and find new starting points for therapeutics.

Introduction Disease-Modifying Anti-Rheumatic Drug (DMARD) treatment fails to achieve clinical remission in a substantial proportion of patients with rheumatoid arthritis (RA). Patient-derived synovial tissue (ST)-signatures, thought to determine this heterogeneity of treatment responses, can be studied by single-cell RNA sequencing (scRNA-seq). Study aims The first aim was to obtain viable ST from RA patients using wrist arthroscopy. The second aim was to identify patient-specific transcriptome signatures from the ST omics data that relate to clinical course and treatment responses in RA. Methods Radiocarpal and midcarpal synovectomy was performed using a standard set-up wrist arthroscopy. Single-cell suspensions of ST from affected wrists of two RA patients and a control subject were processed on the 10X Genomics Chromium Platform. Seurat was used for downstream analysis. Results In two RA patients and one non-inflammatory control, ST was successfully removed during wrist arthroscopy. No surgical complications occurred. For the RA patients and control, 17,176 and 7,884 high-quality cells were analyzed, respectively. Apart from enrichment of cell compartments in RA, including those of B- and plasma cells, T cell populations, NK cells, and macrophages, we observed interpatient variability that may influence the relationship between RA synovial signature and clinical phenotype, potentially also affecting treatment response and outcome. In-depth analysis of the prevailing cell-type abundance phenotype (CTAP) in the RA patients, as described previously, provided insights into the extent to which these CTAPs may be used to predict treatment responses. Conclusion In this feasibility study, we demonstrated that wrist arthroscopy successfully retrieves ST with good tissue viability, which may provide informative and high-quality transcriptomic data for predicting therapy response at an individual level.

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disease characterized by thrombosis, pregnancy morbidity, and the presence of antiphospholipid antibodies (aPL). Anticoagulants form the mainstay of treatment in PAPS. A growing number of studies suggest a previously underappreciated role of the immune system in the pathophysiology of PAPS. Although B-cells are strongly implicated in the pathophysiology of other autoimmune diseases such as systemic lupus erythematosus (SLE), little is known about the role of B-cells in PAPS. Shifts in B-cell subsets including increases in plasmablasts and higher levels of BAFF are present in patients with PAPS. However, while treatment with rituximab and belimumab may ameliorate thrombotic and non-thrombotic manifestations of PAPS, these treatments do not reduce aPL serum levels, suggesting that B-cells contribute to the pathophysiology of APS beyond the production of autoantibodies.

Objective: We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations.Methods: A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings.Results: The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain.Conclusion: Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations.

Interleukin 17A (IL-17A) has been put forward as a strong ally in our fight against invading pathogens across exposed epithelial surfaces by serving an antimicrobial immunosurveillance role in these tissues to protect the barrier integrity. Amongst other mechanisms that prevent tissue injury mediated by potential microbial threats and promote restoration of epithelial homeostasis, IL-17A attracts effector cells to the site of inflammation and support the host response by driving the development of ectopic lymphoid structures. Accumulating evidence now underscores an integral role of IL-17A in driving the pathophysiology and clinical manifestations in three potentially life-threatening autoimmune diseases, namely, systemic lupus erythematosus, Sjögren’s syndrome, and systemic sclerosis. Available studies provide convincing evidence that the abundance of IL-17A in target tissues and its prime source, which is T helper 17 cells (Th17) and double negative T cells (DNT), is not an innocent bystander but in fact seems to be prerequisite for organ pathology. In this regard, IL-17A has been directly implicated in critical steps of autoimmunity. This review reports on the synergistic interactions of IL-17A with other critical determinants such as B cells, neutrophils, stromal cells, and the vasculature that promote the characteristic immunopathology of these autoimmune diseases. The summary of observations provided by this review may have empowering implications for IL-17A-based strategies to prevent clinical manifestations in a broad spectrum of autoimmune conditions.

High-quality three-dimensional (3D) microscopy allows detailed, unrestricted and non-destructive imaging of entire volumetric tissue specimens and can therefore increase the diagnostic accuracy of histopathological tissue analysis. However, commonly used IgG antibodies are oftentimes not applicable to 3D imaging, due to their relatively large size and consequently inadequate tissue penetration and penetration speed. The lack of suitable reagents for 3D histopathology can be overcome by an emerging class of single-domain antibodies, referred to as nanobodies (Nbs), which can facilitate rapid and superior 2D and 3D histological stainings. Here, we report the generation and experimental validation of Nbs directed against the human endothelial cell-selective adhesion molecule (hESAM), which enables spatial visualization of blood vascular networks in whole-mount 3D imaging. After analysis of Nb binding properties and quality, selected Nb clones were validated in 2D and 3D imaging approaches, demonstrating comparable staining qualities to commercially available hESAM antibodies in 2D, as well as rapid and complete staining of entire specimens in 3D. We propose that the presented hESAM-Nbs can serve as novel blood vessel markers in academic research and can potentially improve 3D histopathological diagnostics of entire human tissue specimens, leading to improved treatment and superior patient outcomes.

Background: Rheumatoid arthritis (RA) of the wrist can lead to loss of wrist function and progressive joint destruction if inadequately treated. Arthroscopic synovectomy of the wrist may prove a valuable treatment for local inflammation. Objective: The aim of this study was to perform a systematic review evaluating functional outcomes and pain following arthroscopic synovectomy of the wrist in RA patients. Methods: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines. MEDLINE, EMBASE, The Cochrane Library, Web of Science, and Google Scholar were searched for studies describing pain or functional outcomes following arthroscopic synovectomy of the wrist in RA patients (CRD42021270846). Risk of bias was assessed using the Methodological Index for Non-Randomized Studies. Data collection included patient characteristics, pain scores, wrist function questionnaires, secondary surgery, and complications. Results: Six noncomparative cohort studies were included, with a total of 153 arthroscopic synovectomies. Disease duration of RA ranged from 32 to 89 months, and radiographic progression was mild to moderate. The Methodological Index for Non-Randomized Studies scores ranged from 8 to 10 out of 16. Mean follow-up ranged from 21 to 95 months. Improvements were seen in pooled mean visual analog scale pain score (from 7.7 to 2.2, p < 0.05), pooled mean Modified Mayo Wrist Score (from 43.3 to 70.4, p < 0.05), and the Disability of the Arm, Shoulder, and Hand (from 67.5 to 36.5, p < 0.05). Two complications occurred, and 5 patients required secondary surgery. Conclusions: There is limited evidence suggesting that arthroscopic synovectomy of the wrist improves wrist function and pain in patients with RA, with few complications. In centers with arthroscopic expertise, it can be considered as a treatment option.

Lymphatic endothelial cells (LECs) line the lymphatic vasculature and play a central role in the immune response. LECs have abilities to regulate immune transport, to promote immune cell survival, and to cross present antigens to dendritic cells. Single-cell RNA sequencing (scRNA) technology has accelerated new discoveries in the field of lymphatic vascular biology. This review will summarize these new findings in regard to embryonic development, LEC heterogeneity with associated functional diversity, and interactions with other cells. Depending on the organ, location in the lymphatic vascular tree, and micro-environmental conditions, LECs feature unique properties and tasks. Furthermore, adjacent stromal cells need the support of LECs for fulfilling their tasks in the immune response, such as immune cell transport and antigen presentation. Although aberrant lymphatic vasculature has been observed in a number of chronic inflammatory diseases, the knowledge on LEC heterogeneity and functional diversity in these diseases is limited. Combining scRNA sequencing data with imaging and more in-depth functional experiments will advance our knowledge of LECs in health and disease. Building the case, the LEC could be put forward as a new therapeutic target in chronic inflammatory diseases, counterweighting the current immune-cell focused therapies.