Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Hand osteoarthritis (hand OA), the most common peripheral arthritis in the world, is less studied than osteoarthritis (OA) of the knee and hip. However, it is uniquely situated to offer novel insight into OA as a disease process by removing weight-bearing as a confounder of systemic disease mechanisms. Here we review the epidemiology of hand OA and key risk factors for its development. RECENT FINDINGS/RESULTS:Mounting evidence points to obesity as an important risk factor for hand OA development, with new evidence implicating a role for leptin and serum fatty acids. Disease progression in hand OA and specifically the erosive OA subtype may be associated with diabetes. New evidence supports an association between cardiovascular disease progression and symptomatic hand OA. Alcohol use may be associated with increased synovitis and erosive hand OA. Differences in ethnical distributions of hand OA have become more apparent, with a lower prevalence in Black patients compared to White patients. Novel genetic insights implicating the WNT gene pathway and IL-1β have led to novel potential targets in hand OA pathogenesis. Hand OA is a heterogeneous disease with many modifiable and non-modifiable risk factors that can determine disease severity and shed light on disease pathogenesis.

Objective/UNASSIGNED:To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. Methods/UNASSIGNED:Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. Results/UNASSIGNED:Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. Conclusions/UNASSIGNED:In two independent cohorts of IMID patients, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines. KEY MESSAGES/UNASSIGNED:These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.

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.

OBJECTIVE:Intra-articular (IA) injections of glucocorticoids (GCs) have been shown to decrease pain, increase mobility, and improve quality of life in patients with osteoarthritis (OA) of the knee. Concerns about cartilage loss with IA GCs have prompted reconsideration of their use in knee OA. This review has three objectives: 1) critically review the clinical, molecular, and structural effects of IA GCs in knee OA; 2) provide a design for a clinical trial aimed at improving our understanding of the long-term consequences of IA GCs; and 3) provide practical guidance on the use of IA GCs in patients with knee OA based on current information. DESIGN:A narrative review of current literature on the use of IA GCs for OA of the knee. RESULTS:Important questions remain to be fully answered with respect to IA GCs, including long-term effects on all aspects of the structural and molecular environment of the knee, and identification of factors that can reliably predict a positive or negative response to IA GCs. CONCLUSIONS:While awaiting results from an appropriately designed study, several provisional statements regarding IA GCs can be put forward: 1) IA GCs appear to be a relatively safe option that is effective in specific patients with symptomatic knee OA; 2) there is no definitive evidence that IA GCs accelerate joint deterioration to an important extent or hastens the requirement for knee replacement; and 3) there are few contraindications to IA GCs and injection-associated complications are rare when IA GCs are delivered with proper technique.

Background/Purpose: Hand osteoarthritis (HOA) data is often obtained from large knee OA cohorts. Targeted HOA cohorts in Europe have shed light on this disease, but the etiologies and pathophysiology remain less defined than other sites of OA. Some studies suggest a metabolic role of adiposity in OA (beyond mechanical load), as evidenced by prevalent HOA in obese patients, while other reports link hormonal status to HOA pain. Our dedicated cohort of HOA patients aims to study factors that contribute to its prevalence and severity.
Method(s): From 2016 to 2020, we enrolled patients with interphalangeal (IP) OA, regardless of 1 st carpometacarpal (CMC) involvement. Patients with rheumatoid arthritis, psoriatic arthritis or lupus were excluded. Demographic and relevant history data were collected. Participants completed adapted versions of the Michigan Hand Outcomes (MHQ) and QuickDASH Outcome questionnaires to assess pain, stiffness, and function. The semi-quantitative scores were aggregated and normalized to a 0-100 scale. Hand x-rays, if available, were scored in binary fashion for joint narrowing, osteophytes, and central erosions in all 20 joints (18 IPs, 2 1st CMCs). Blood and urine were banked for future assays.
Result(s): We screened 337 patients and found 170 to be eligible and willing to enroll. The present cohort is 80.0% Caucasian and 78.8% female with an average age of 66.3+/-9.5 years (range 42-90) and BMI of 26.2+/-5.0 kg/m 2 (range 16.4-42.1). Bilateral hand x-rays, available for 149 patients, involved 10.5+/-5.1 joints with OA on average, with 102 (68.4%) having concurrent IP and CMC OA. Radiographs revealed central erosive changes in >=1 joint in 36.5% of patients, with this subset also reporting a higher number of affected joints (12.5 vs. 9.1, p=< 0.001). Patients with BMI > 30 kg/m 2 had significantly more hand pain (p=0.022) and stiffness (p=0.047) by the adapted MHQ, and more disability (p=0.025) by the QuickDASH, compared to those with BMI < 25 despite similar ages and joint burden by x-ray (Table 1). Patients reporting OA in additional sites also reported more hand pain (p=0.018) and more disability (p=0.003), though this signal could be confounded by this subgroup's advanced age (67.7 vs. 62.3 years, p=0.01). Women reported significantly more pain (p=0.035), disability (p=0.004), and a higher average number of joints affected (p=0.02) than men with similar ages and BMI. A small subgroup of likely perimenopausal women (ages 48-54) reported more pain and disability than their older counterparts, despite a lower mean BMI and fewer hand joints affected by OA. (Figure. 1). Our analyses did not reveal any association between hand symptoms and tobacco use, comorbidities, or prior hand trauma.
Conclusion(s): We have established the only registry and biorepository in North America focused on hand OA, which could enhance progress made by existing cohorts. HOA pain and disability independently associated with adiposity, and was more severe in women. We postulate that hormonal influences during the perimenopausal state may increase HOA symptoms during those years. As we run assays on stored biospecimens, we anticipate the HONEY cohort will further our understanding of HOA etiologies and pathophysiology while facilitating future clinical trials

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

Background/Purpose: High body mass index (BMI, kg/m2) is a modifiable risk factor that has been associated with the development and progression of osteoarthritis (OA) and knee pain. While total knee arthroplasty (TKA) is the gold standard for the treatment of end stage OA, morbidly obese patients (BMI>=40kg/m2) are often required to lose weight prior to TKA due to increased surgical risk and a higher rate of complications. While conservative weight-loss often fails to help these patients, bariatric surgery can be an alternative option. Here we present interim data from the trial entitled "Surgical Weight-loss to Improve Functional Status Trajectories following arthroplasty for painful knee osteoarthritis". This current multi-center, prospective study compares pain and functional outcomes in patients receiving bariatric surgery prior to TKA versus obese patients who go straight to TKA.
Method(s): Patients with BMI >=40 kg/m2 and painful knee osteoarthritis who met the indications for TKA were recruited at four hospital centers. Patients with a BMI >35 kg/m2 were also recruited if they had a qualifying comorbid condition including obstructive sleep apnea, diabetes, hypertension or hyperlipidemia. Patients were assigned to either the bariatric (BAR) or TKA arm based on surgical choice (goal n=150 for each arm), with all bariatric patients having anatomy-altering sleeve gastrectomy or gastric bypass. At baseline and several time points after surgery (Figure 1), we documented height, weight, the Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog pain (VAS) scales, and the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and had patients perform functional assessments (Timed-Up and Go, 30-second Chair Stand and 40-meter fast paced walk test). We targeted minimum detectable change (MDC) in outcomes for the VAS for knee pain (33% reduction), Timed Up and Go (decrease by 2 seconds), 30-second Chair Stand (increase by 2 reps), 40-meter fast paced walk (increase by 0.16 m/s), WOMAC score (16% reduction), and the KOOS pain score (10-point improvement). Using a logistic regression to adjust for age and baseline BMI, we compared the percentage of patients in the two arms who achieved an MDC for the various outcomes.
Result(s): To date, 25 BAR and 28 TKA patients have completed their follow-up visits through at least 6 months. Although there was a similar sex distribution, the bariatric group was younger (52 vs 60 years old, p=0.0023) with a higher baseline BMI (47.0 vs 41.6 p=0.0006). Most bariatric patients achieved comparable improvement to the TKA cohort with regards to the benchmarks of the 30-second Chair Stand (TKA 54% vs BAR 33%, p=0.156), KOOS pain score (TKA 91% vs BAR 67%, p=0.130), the Visual Analog Pain Scale (TKA 50% vs BAR 39%, p=0.466), Timed Up and Go test (TKA 43% vs BAR 22%, p=0.141) and the 40-meter fast paced walk (TKA 61% vs BAR 35%, p=0.073). The TKA cohort had a greater percent with a MDC for the WOMAC (TKA 88% vs BAR 54%, p=0.030).
Conclusion(s): In morbidly obese patients who are eligible for TKA, bariatric surgery may result in modest improvements in knee outcomes and may eventually delay the need for a TKA

Multiple disease-modifying osteoarthritis drug (DMOAD) trials were done in the last two decades, but no pharmacological agent has yet been approved by regulatory agencies as an effective therapy to date. Given the fact that we have seen the recent discontinuation of several late-stage drug development trials, a careful strategy is needed in formulating a plan for a successful DMOAD trial - including the various roles of imaging. This narrative review article will summarize how imaging is utilized in osteoarthritis from the perspective of disease modification to clinical utility. We will describe how semi-quantitative and quantitative magnetic resonance imaging approaches have been deployed in DMOAD trials. We will then review the utility of musculoskeletal ultrasound in research and clinical settings. Finally, novel hybrid positron emission tomography/MRI techniques and current research using artificial intelligence will be discussed, focusing on original research. Older publications are included for the discussion of the previous DMOAD trials and other relevant topics where deemed appropriate.

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.