Faculty Bibliography

Purpose: To determine the safety and effectiveness of genicular artery embolization (GAE) in reducing knee pain in patients with mild to moderate knee osteoarthritis (OA), as measured by validated patient reported outcome measures, and to characterize pre/post-procedural trends in multiple OA-associated serum biomarkers
Material(s) and Method(s): In an ongoing, prospective, single-arm clinical trial, patients with mild to moderate (Kellgren-Lawrence grade 2-3) symptomatic knee OA, without prior surgery and who failed conservative therapy, were included. Pre-intervention imaging (plain radiographs and MRI), patient-reported outcome measures (KOOS, WOMAC, VAS), and serum biomarkers (IL-1Ra, CRP, Hyaluronan, COMP, VEGF, CCL2-MCP-1) were obtained. Each patient underwent transcatheter arterial embolization of one or more genicular arteries in the affected knee using 250-mum microspheres (Embozene, Varian). One- and three-month post-intervention patient-reported outcome measures and serum biomarkers were obtained. Baseline and follow-up outcomes were compared using paired Wilcoxon signed-rank tests.
Result(s): The first 7 patients (4 male, mean age 68 +/- 6y, mean BMI 30 +/- 2) recruited into this trial were included in this preliminary analysis. Technical success was 100%. There were no adverse events. By 3 months, VAS pain scores decreased from 56 to 21 (63% decrease); WOMAC pain scores decreased from 8 to 4 (50% decrease); and KOOS pain scores (for which higher scores indicate less pain) increased from 57 to 81 (42% increase), all P >0.05. Baseline and 3-month mean biomarker values were: IL-1Ra (471 +/- 276 vs 590 +/- 320 pg/mL), CRP (1.81 +/- 1.78 vs 3.24 +/- 4.25 mg/L), Hyaluronan (92 +/- 66 vs 166 +/- 102 ng/mL), COMP (942 +/- 336 vs 1057 +/- 462 ng/mL), VEGF (372 +/- 283 vs 303 +/- 101 pg/mL), and CCL2-MCP-1 (335 +/- 90 vs 323 +/- 69 pg/mL), all P >0.05.
Conclusion(s): Patient-reported pain scores demonstrated a trend in improvement 3 months after GAE at our interim analysis. There were no significant changes between baseline and 3-month follow-up in serum OA biomarkers in this small sample size. Full study analysis will further delineate trends in serum biomarkers after GAE.
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Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.

OBJECTIVES/OBJECTIVE:Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS:Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS:Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS:This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.

Background/Purpose: Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common alleles contribute to the genetic high IFN trait. In this study, we examine whether these common gain-of-function alleles in the type I IFN pathway are associated with protection from mortality in acute COVID-19.
Method(s): We studied IFN pathway SLE risk genes in patients with acute COVID-19 admitted to NYU Langone hospitals (751 European-American and 398 African-American ancestry). The samples were genotyped using low depth sequencing and imputation, and we analyzed data from the following SNPs: IRF5 (rs2004640, rs3807306, rs10488631, rs2280714), IRF7/PHRF (rs1131665, rs4963128), IRF8 (rs17445836, rs12444486), and PRKG1 (rs7897633). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome.
Result(s): We observed specific IRF5 haplotypes that are protective against SLE risk were associated with increased risk of mortality in acute COVID-19 patients in European-American ancestry (OR=3.74, p=0.015). Alleles of PRKG1 were also associated with mortality from COVID-19 in the European-American ancestry cohort (OR=1.80, p=0.0057), and this risk factor was particularly strong in younger patients (OR=29.2, p=0.01 in ages 45-54). IRF8 genotype at rs1244486 was associated with protection from mortality in COVID-19 in African-American subjects aged 65 and older (OR=0.34, p=0.04).
Conclusion(s): We find that a number of type I IFN pathway genes associated with risk of SLE also modulate risk of death during acute COVID-19. Similar to their associations with SLE, these alleles are variably associated with COVID-19 mortality across ancestral backgrounds, suggesting ancestral differences in the genetic regulation of the IFN pathway. These data confirm the critical role of the IFN pathway in our defense against viral infections, and support the idea that some common SLE risk alleles exert protective effects in anti-viral immunity

BACKGROUND:Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice. METHODS:(n = 3) and wt mice (n = 3) to discover genes and pathways altered by Postn knockout. RESULTS:mice, while those related to cell-cycle and DNA-repair were enriched in wt mice. CONCLUSIONS:Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations to better understand the mechanistic role of Postn and its potential as a therapeutic target in OA.

BACKGROUND:Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. MATERIALS AND METHODS/METHODS:The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. RESULTS:In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011). CONCLUSION/CONCLUSIONS:Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. LEVEL OF EVIDENCE/METHODS:Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.

Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane proteinase with a short cytoplasmic tail, is a major effector of extracellular matrix remodeling. Genetic silencing of MT1-MMP in mouse (Mmp14

Background/Purpose: Symptomatic knee osteoarthritis (SKOA) patients with obesity who undergo bariatric surgery experience knee pain relief, though the reduced mechanical load explains only part of the improvement. A reduction in inflammatory biomarkers from adipose tissue may also impact pain. We previously identified an IL1RN haplotype (TTG; rs419598, rs315952, and rs9005) that associates with OA severity and inflammatory markers. We aimed to determine whether TTG distinguishes patients who lose more weight and have more significant decreases in inflammation with greater knee OA pain relief.
Method(s): From 2013-2019 we enrolled patients >=30 years old with BMI >=30 kg/m 2 and painful knee OA who planned surgical (sleeve gastrectomy, gastric bypass, or laparoscopic band) or medical weight loss (MWL) at Bellevue Hospital or NYU Langone Health. Patients with lupus, rheumatoid arthritis, or psoriatic arthritis were excluded. Weight-bearing knee x-rays assessed OA severity to confirm a Kellgren-Lawrence grade of at least 1 (scale 0-4). Participants completed the Knee Injury and Osteoarthritis Outcomes (KOOS) questionnaire and provided blood at baseline and 1, 3, 6, and 12 months. Patients were genotyped to determine whether they carried 1 or 2 copies of the TTG haplotype (TTG-1/2) or none (TTG-0). Sleeve was the most common weight loss intervention, therefore our analysis is focused on this surgical subset to minimize variable effects on weight and biomarkers.
Result(s): We enrolled 113 patients (95 F, 18 M) with painful knee OA prior to their weight loss intervention. The mean age, BMI, and KOOS pain at baseline were 50.3 +/- 12.0 years, 44.8 +/- 8.9 kg/m 2, and 48.4 +/- 18.2 (0-100, with 100 = no pain). Of 113 patients, 48 underwent sleeve, 20 bypass, 9 laparoscopic banding, 12 did not have the surgery, and 24 pursued medical weight loss. The 77 who completed surgery had a mean % excess weight loss (%EWL) of 51.7 after 6 months, with significant decreases in hsCRP (4.4 mg/L) and leptin (32.8 ng/dL), and mean KOOS pain improvement of 22.4 (MCID= 16.7). The corresponding changes for patients who tried various MWL regimens were modest at best. We obtained the IL1RN haplotype for 45 of the 48 sleeve patients, and found 34 (70.8%) carried the TTG-1 or TTG 2 haplotype while 11 were TTG-0 (with similar baseline age, BMI, and KOOS for the two groups). At each follow-up time point through 6 months (Figure 1), TTG-1/2 patients had more difficulty losing weight than the TTG-0 group (p< 0.005 by ANOVA), with corresponding smaller reductions in hs CRP (p=0.36) and leptin (p=0.006). TTG-1/2 carriers also reported less KOOS pain relief relative to the TTG-0 group (p=0.021), markedly at 1 and 3 months with some improvement later (Table 1). All of these findings held true when only plotting data only from the 23 patients (18 TTG-1/2, 5 TTG-0) who completed each of the followup visits.
Conclusion(s): SKOA patients with obesity achieve marked excess weight loss, reductions in inflammatory mediators, and knee pain relief with bariatric surgery. The subset of patients with the TTG-0 IL1RN haplotype demonstrated more significant and/or rapid improvement in each of these outcomes, suggesting a potential predictor of which OA patients will have a more successful response to bariatric surgery

OBJECTIVE:Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone. METHODS:PBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). RESULTS:We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p < 0.0001) and the odds ratio from 6.31 to 19.10 (p < 0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL inflammatory gene expression further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL inflammatory gene expression and BML independently influenced mJSN. CONCLUSION/CONCLUSIONS:The use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.