Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes

Abstract

Objective. Rheumatoid arthritis (RA) is characterized by inflammatory reactions in joints and adjacent tissues unaccompanied by clinically evident changes in lymphatics and lymph nodes draining the inflamed areas. The explanation for this phenomenon, which contrasts with infectious processes in joints and soft tissues that evoke major changes in the lymphatic system, is unclear. To determine which inflammatory factors produced in the joints of RA patients are transported in lymph to lymph nodes, we measured levels of immunoglobulins, cytokines, and chemokines in prenodal lymph from the foot joints of RA patients and quantified their rate of transport to regional lymph nodes.Methods. Lymph was collected from the cannulated lymphatics draining the foot joints, tendons, fascia, and skin of 20 RA patients. Lymph flow rate and concentrations of proteins and immunoglobulins were measured. Cytokine and chemokine levels were quantified by enzyme-linked immunosorbent assays. Results were compared with those obtained in 20 control subjects.Results. In the cannulated vessel, the mean ؎ SEM lymph flow rate in RA patients was almost 2-fold that in control subjects (22.6 ؎ 3.2 ml/24 hours versus 13.2 ؎ 1.1 ml/24 hours; P < 0.01). Lymph concentrations of total protein, IgG, and IgM were 1.80 ؎ 0.14 gm/dl, 384 ؎ 45 mg/dl, and 32.0 ؎ 1.5 mg/dl, respectively, in RA patients and 1.66 ؎ 0.14 gm/dl, 238 ؎ 32 mg/dl, and 15.0 ؎ Conclusion. High lymph concentrations of cyto-

Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling

“…24,44,46 The ratio of TMAbs concentration in tissue and plasma system was 0.057 (0.058 in Ref 23 ). The concentration of endogenous IgG in the interstitial space was 18% of that in plasma, which is consistent with the reported values from the experimental data (≥ 17% in Refs 24,47,48 ).…”

“…The simulated PK data from published adult/pediatric population PK analysis of two TMAbs were used in this study: bevacizumab for mPBPK model development and palivizumab for external validation of the developed mPBPK model. 10,46 Plasma concentration-time profiles of bevacizumab for adults and pediatric subjects with different weight were simulated using two-compartment linear PK model with the following covariate-parameter relationships for both pediatric and adult subjects; 46 Plasma drug concentrations of both bevacizumab and palivizumab were collected after a single intravenous bolus injection of 10 mg/kg of the antibodies at 1,2,6,8,12,24,48,96,168,336,504,672,840,1008, and 1176 h post injection. In adult subjects, body weights of 50, 60, 70, 80, 90 and 100 kg were used for simulation and fitting.…”

Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis

“…Synovial specimens from patients with rheumatoid arthritis (RA) and osteoarthritis have an increased number of lymphatic vessels and increased expression of the lymphatic growth factor vascular endothelial growth factor C (VEGF‐C) (8, 9). Furthermore, clinical reports have described larger lymph nodes (LNs) (10) and increased lymphatic flow rates in lymphatic vessels draining arthritic joints in RA patients (11). Similarly, recent studies of animal models of RA have demonstrated increased lymphatic vessel formation in inflamed joints and in draining popliteal LNs (12–14).…”

Lymphatic Muscle Cells Contribute to Dysfunction of the Synovial Lymphatic System in Inflammatory Arthritis in Mice

“…It is featured by synovitis with in ltration of in ammatory cells, predominance of catabolic factors including pro-in ammatory cytokines and pro-erosive mediators, and the progressive destruction of cartilage and bone. Clinical study reports that lymph drained from RA joints contains high levels of proin ammatory cytokines and chemokines [1], suggesting that removal of in ammatory factors via the lymphatic vessels (LVs) from synovial space and interstitial tissues may contribute to the pathogenesis of RA. The lymphatic vasculature is composed of capillaries and mature vessels that have different morphologies, structural compositions, and functions.…”