Faculty Bibliography

Background/Purpose: Psoriatic Arthritis (PsA) affects up to 30% patients with psoriasis and is characterized by wide spread synovio-entheseal inflammation. Physiologically, the human gut microbiota metabolizes dietary fiber into shortchain fatty acids (FA)- which exert anti-inflammatory effects by increasing activity of regulatory T cells (Tregs).Moreover, we have previously shown decreased abundance of Akkermansia and Ruminococcus and concomitant decrease in mediumchain FA (MCFA) levels in stool of PsA patients. We therefore hypothesized that FA supplementation may have favorable effects on gut microbiome and lead to increase in tolerance, potentially serving as therapeutic target in psoriatic disease.
Method(s): Wild type (WT)animals were fed SCFA-rich diet for 14 days followed by 16S rRNA sequencing and microbiota analysis of pellet specimens.We then evaluated effects ofMCFA-rich diet in healthy subjects. Peripheral blood and stool samples were collected at days 0, 7 and 14 for 16s rRNA sequencing and FACS. Finally, we conducted a small, prospective, proof-ofprinciple study in new-onset, drug-naive psoriatic disease patients (with or without PsA). Each participant received MCFA (1 gm 4 times a day for 6 weeks). Clinical history was obtained at baseline. Skin and joint exam were performed at baseline and follow up. Serum and stool samples were collected at baseline, weeks 3, and 6 for 16S rRNA sequencing and FACS, respectively. Wilcoxon signed-rank test was used to compare differences in Tregs before and after MCFA-rich administration.
Result(s): SCFA rich diet in WT mice led to statistically significant perturbations in gut bacterial composition 14 days into intervention, with a dramatic increase in commensals (Fig 1A; p<0.001), most notably in Akkermansia(Fig 1B). MCFA administration to healthy subjects (n=7) also led to significant changes in community structure (Fig 2A; p=0.03) and associated increases in circulating Treg cells (Fig 2B; p<0.001). These findings were also observed in psoriatic disease patients (n=4) showing a significant alteration in specific taxa, including Actinobacteria (Fig 2 C; p<0.05) and Mollicutes (p=0.09) and concomitant increase in circulatory Treg cells (Fig 2D)
Conclusion(s): In both health and psoriatic disease, MCFA supplementation is associated with distinct changes in human gut microbiota composition and peripheral Treg cells. These findings rationalize the need for a larger placebo controlled, prospective trial to study the effects of MCFA in patients with psoriasis and PsA as a potential therapy alone or in combination with DMARDs. (Figure Presented)

Background/Purpose: To investigate the expression of vascular adhesion protein -1 (VAP-1) in joint tissues and serum in knee osteoarthritis (OA) patients and examine whether VAP-1 levels predict increased risk of disease severity or progression of knee OA.
Method(s): Baseline serum and synovial fluid VAP-1/semicarbazide-sensitive amine oxidase (SSAO) levels were assessed in cohorts of patients with tibiofemoral medial knee OA and healthy subjects. Standardized fixed-flexion posteroanterior knee radiographs were scored for Kellgren Lawrence (KL) grade (0-4) and medial joint space width (JSW) at the mid-portion of the joint space. Radiographic severity was defined by KL2/3 vs. KL4. Biochemical markers assessed comprised VAP-1/ SSAO, IL-1Ra, IL-6, sRAGE, CCL2, CCL4, CD163, hsCRP and MMPs-1,-3,-9. Associations between biomarkers and radiographic severity (logistic regression controlling for covariates) and pain (Spearman correlation) were evaluated.
Result(s): VAP-1 was locally overexpressed at least 2 fold in the OA synovium based on immunohistochemical, microarray and qRT-PCR analyses compared to controls. Synovial fluid SSAO levels was also significantly higher in OA (107.94+41.42) compared to normals (38.12 + 22.98 ng/ml; p=0.0001) and inversely associated with radiographic severity. We observed a positive correlation with the levels of SSAO in the synovial fluid and serum of OA patients (r=0.47; p=0.014). However, serum SSAO levels in OA patients were lower than in controls, and inversely correlated with pain and inflammation markers (CRP and soluble RAGE). Serum SSAO levels were also lower in radiographically severe (KL4) OA patients compared to KL2/3. Serum SSAO did not correlate with other markers of inflammation or radiographic joint space narrowing (JSN) over 24 months.
Conclusion(s): Synovial fluid VAP-1/SSAO levels were elevated in OA and correlate with radiographic severity. However, serum or circulating SSAO levels are lower in OA patients and inversely correlate with pain and inflammation. Serum VAP-1 levels could identify patients at increased risk for knee radiographic severity

OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABT-981, a human dual variable domain immunoglobulin simultaneously targeting interleukin (IL)-1alpha and IL-1beta, in patients with knee osteoarthritis. METHOD: This was a randomized, double-blind, placebo-controlled, single-center study of multiple subcutaneous (SC) injections of ABT-981 in patients with mild-to-moderate osteoarthritis of the knee (NCT01668511). Three cohorts received ABT-981 (0.3, 1, or 3 mg/kg) or placebo every other week for a total of 4 SC injections, and one cohort received ABT-981 (3 mg/kg) or placebo every 4 weeks for a total of 3 SC injections. Assessment of safety and tolerability were the primary objectives. A panel of serum and urine biomarkers of inflammation and joint degradation were evaluated. RESULTS: A total of 36 patients were randomized (ABT-981, n=28; placebo, n=8); 31 (86%) completed the study. Adverse event (AE) rates were comparable between ABT-981 and placebo (54% vs 63%). The most common AE reported with ABT-981 versus placebo was injection site erythema (14% vs 0%). ABT-981 significantly reduced absolute neutrophil count and serum concentrations of IL-1alpha/IL-1beta, high-sensitivity C-reactive protein, and matrix metalloproteinase (MMP)-derived type 1 collagen. Serum concentrations of MMP-derived type 3 collagen and MMP-degraded C-reactive protein demonstrated decreasing trends with ABT-981. Antidrug antibodies were found in 37% of patients but were not associated with the incidence or severity of AEs. CONCLUSION: ABT-981 was generally well tolerated in patients with knee osteoarthritis and engaged relevant tissue targets, eliciting an anti-inflammatory response. Consequently, ABT-981 may provide clinical benefit to patients with inflammation-driven osteoarthritis.

OBJECTIVE: Arthroscopy with lavage and synovectomy can remove tissue debris from the joint space and the synovial lining to provide pain relief to patients with osteoarthritis (OA). Here, we developed an in vitro model to study the interaction of cartilage wear particles with fibroblast-like synoviocytes (FLS) to better understand the interplay of cartilage particulates with cytokines on cells of the synovium. METHOD: In this study sub-10mum cartilage particles or 1mum latex particles were co-cultured with FLS +/- 10 ng/mL interleukin-1alpha (IL-1 alpha) or tumor necrosis factor- alpha (TNF-alpha). Samples were analyzed for DNA, glycosaminoglycan (GAG), and collagen and media samples were analyzed for media GAG, nitric oxide (NO) and prostaglandin-E2 (PGE2). The nature of the physical interaction between the particles and FLS was determined by microscopy. RESULTS: Both latex and cartilage particles could be phagocytosed by FLS. Cartilage particles were internalized and attached to the surface of both dense monolayers and individual cells. Co-culture of FLS with cartilage particulates resulted in a significant increase in cell sheet DNA and collagen content as well as NO and PGE2 synthesis compared to control and latex treated groups. CONCLUSION: The proliferative response of FLS to cartilage wear particles resulted in an overall increase in ECM content, analogous to the thickening of the synovial lining observed in OA patients. Understanding how cartilage particles interface with the synovium may provide insight into how this interaction contributes to OA progression and may guide the role of lavage and synovectomy for degenerative disease.

OBJECTIVE: OA pathogenesis includes both mechanical and inflammatory features. Studies have implicated synovial fluid urate (UA) as a potential OA biomarker, possibly reflecting chondrocyte damage. Whether serum urate (sUA) levels reflect/contribute to OA is unknown. We investigated whether sUA predicts OA progression in a non-gout knee OA population. METHODS: Eighty-eight subjects with medial knee OA (BMI <33) but without gout were included. Baseline sUA was measured in previously banked serum. At 0 and 24 months, subjects underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs to determine joint space width (JSW) and Kellgren-Lawrence (KL) grades. Joint space narrowing (JSN) was determined as JSW change from 0 to 24 months. Twenty-seven subjects underwent baseline contrast-enhanced 3T knee MRI for synovial volume (SV) assessment. RESULTS: sUA correlated with JSN in both univariate (r=0.40, p/=6.8; JSN of 0.31 mm for sUA<6.8, p<0.01). Baseline sUA distinguished progressors (JSN>0.2mm) and fast progressors (JSN>0.5mm) from nonprogressors (JSN