Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Utility of Serum IgG4 Levels in a Multiethnic Population.

BACKGROUND: IgG4-related disease (IgG4-RD) is a recently recognized condition defined by characteristic histopathologic findings in affected organs. Serum IgG4 concentration is often but not always elevated. The sensitivity and specificity of serum IgG4 vary greatly across studies and has been anecdotally associated to ethnicity. Our study was conducted to investigate the difference in serum IgG4 levels between Asian and non-Asian patients with IgG4-RD. METHODS: This is a single-center retrospective study of 26 Asian and 10 non-Asian patients with histologically confirmed IgG4-RD. Serum IgG4 levels, clinical features and other laboratory findings were compared between the 2 groups, 31 Asian and 11 non-Asian patients with non-IgG4-RD rheumatic diseases were randomly identified to evaluate test characteristics of serum IgG4 measurement. RESULTS: Median serum IgG4 at time of diagnosis was significantly higher in Asian (median = 11.2g/L, interquartile range: 4.6-19.7) than non-Asian patients (median = 2.9g/L, interquartile range: 0.7-5.4, P = 0.0094), as well as the median serum IgG and total protein. Asian patients had more eosinophilia and polyclonal hypergammaglobulinemia than non-Asian patients (P = 0.016 and 0.001, respectively). Test sensitivity was higher in Asian (96%) than non-Asian patients (67%), whereas test specificity was higher in non-Asian patients (91% versus 71%). CONCLUSION: Asian patients with IgG4-RD have more exuberant serum IgG4, IgG and polyclonal hypergammaglobulinemia than non-Asian patients; the mechanism of this difference requires further study. These findings have significant clinical importance and must be accounted for in the diagnostic workup of patients in multiethnic settings.

Effectiveness and safety of infliximab in rheumatoid arthritis: analysis from a Canadian multicenter prospective observational registry.

OBJECTIVE: To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab in Canadian routine care and to assess the real-world effectiveness and safety of infliximab. METHODS: Biologics-naive RA patients from the Biologic Treatment Registry Across Canada were stratified based on their enrollment year. Effectiveness was assessed with the changes in clinical/laboratory parameters and patient-reported outcomes and the achievement of minimal disease activity and remission. Safety was assessed with the incidence of treatment-emergent adverse events (AEs). RESULTS: Among 628 patients, 45.9%, 34.6%, and 19.6% were enrolled between 2002-2005, 2005-2008, and 2008-2011, respectively. Patients recruited in more recent years had significantly lower Disease Activity Score with a 28-joint count using the C-reactive protein level (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), swollen joint count in 28 joints, tender joint count in 28 joints, physician's global assessment of disease activity, patient's global assessment of disease activity, Health Assessment Questionnaire disability index, pain, erythrocyte sedimentation rate, and CRP level (P < 0.01 for all). Patient management also changed with a trend to initiate infliximab after failure of fewer disease-modifying antirheumatic drugs (DMARDs). Six-month treatment with infliximab resulted in statistically significant and clinically important improvements in all disease parameters examined, which were sustained over 36 months. The cumulative probability of achieving remission by 36 months, as defined by the DAS28, SDAI, and CDAI, was 56.2 (95% confidence interval [95% CI] 47.8-64.8), 31.0 (95% CI 23.8-39.8), and 36.2 (95% CI 28.5-45.3), respectively, which was significantly greater in patients with lower baseline disease activity. The profile and incidence of AEs were comparable to data previously reported for tumor necrosis factor α inhibitors. CONCLUSION: RA patient characteristics at infliximab initiation changed over time toward lower disease activity. Furthermore, a trend to treat patients with fewer DMARDs before initiation of infliximab was observed. However, treatment with infliximab was effective in significantly reducing disease activity independent of the treatment initiation year.