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A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis

Luo, Yunyun; Samuels, Jonathan; Krasnokutsky, Svetlana; Byrjalsen, Inger; Kraus, Virginia B; He, Yi; Karsdal, Morten A; Abramson, Steven B; Attur, Mukundan; Bay-Jensen, Anne C
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.
PMID: 33687578
ISSN: 1590-9999
CID: 4809212

Colchicine Use and Incident Coronary Artery Disease in Male Patients with Gout

Shah, Binita; Toprover, Michael; Crittenden, Daria B; Jeurling, Susanna; Pike, V Courtney; Krasnokutsky, Svetlana; Xia, Yuhe; Fisher, Mark C; Slobodnick, Anastasia; Tenner, Craig T; Katz, Stuart D; Pillinger, Michael H
BACKGROUND:Inflammation is associated with coronary artery disease (CAD) and myocardial infarction (MI). Patients with gout are at increased risk of MI, and colchicine is associated with a reduced risk of MI. The objective of this study was to determine whether colchicine prevents incident development of CAD in patients with gout. METHODS:This retrospective study followed a cohort of male gout patients without known CAD at the time of gout diagnosis in the VA New York Harbor Healthcare System. The association between colchicine use and development of incident CAD, defined as evidence of ischemia or obstructive CAD on stress test or angiography, was determined using an inverse probability weighted (IPW) cox proportional hazard model. RESULTS:Among 178,877 patients, 1,638 met gout criteria, of whom 722 patients without known CAD at baseline (446 colchicine users and 276 non-users) were followed for a median of 96 months [57-117]. A trend toward association between colchicine use and reduced incident CAD was observed but not statistically significant (IPW HR 0.49 [0.23-1.05]). In patients without chronic kidney disease, colchicine use was associated with a lower rate of incident CAD (interaction p=0.005, IPW HR 0.31 [0.14-0.70]). Colchicine was also associated with a lower rate of the composite of incident CAD and MI (IPW HR 0.37 [0.16-0.83]). CONCLUSIONS:In male patients with gout and no known CAD, a trend of reduced incident CAD was observed with colchicine use that was not statistically significant. Larger, prospective studies will be required to definitively assess the primary prevention benefit of colchicine.
PMID: 32454073
ISSN: 1916-7075
CID: 4451692

The combination of an inflammatory peripheral blood gene expression and imaging biomarkers enhance prediction of radiographic progression in knee osteoarthritis

Attur, Mukundan; Krasnokutsky, Svetlana; Zhou, Hua; Samuels, Jonathan; Chang, Gregory; Bencardino, Jenny; Rosenthal, Pamela; Rybak, Leon; Huebner, Janet L; Kraus, Virginia B; Abramson, Steven B
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.
PMID: 32912331
ISSN: 1478-6362
CID: 4589512

Initiating guideline-concordant gout treatment improves arterial endothelial function and reduces intercritical inflammation: a prospective observational study

Toprover, Michael; Shah, Binita; Oh, Cheongeun; Igel, Talia F; Romero, Aaron Garza; Pike, Virginia C; Curovic, Fatmira; Bang, Daisy; Lazaro, Deana; Krasnokutsky, Svetlana; Katz, Stuart D; Pillinger, Michael H
BACKGROUND:Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. We conducted a prospective observational study to assess whether initiating guideline-concordant gout therapy with colchicine and a urate-lowering xanthine oxidase inhibitor (XOI) improves arterial function and reduces inflammation. METHODS:Thirty-eight untreated gout patients meeting American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for gout and ACR guidelines for initiating urate-lowering therapy (ULT) received colchicine (0.6 mg twice daily, or once daily for tolerance) and an XOI (allopurinol or febuxostat) titrated to ACR guideline-defined serum urate (sU) target. Treatment was begun during intercritical periods. The initiation of colchicine and XOI was staggered to permit assessment of a potential independent effect of colchicine. Brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent (smooth muscle) arterial responsiveness, respectively. High-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, myeloperoxidase (MPO) concentrations, and erythrocyte sedimentation rate (ESR) assessed systemic inflammation. RESULTS:Four weeks after achieving target sU concentration on colchicine plus an XOI, FMD was significantly improved (58% increase, p = 0.03). hsCRP, ESR, IL-1β, and IL-6 also all significantly improved (30%, 27%, 19.5%, and 18.8% decrease respectively; all p ≤ 0.03). Prior to addition of XOI, treatment with colchicine alone resulted in smaller numerical improvements in FMD, hsCRP, and ESR (20.7%, 8.9%, 13% reductions, respectively; all non-significant), but not IL-1β or IL-6. MPO and NMD did not change with therapy. We observed a moderate inverse correlation between hsCRP concentration and FMD responsiveness (R = - 0.41, p = 0.01). Subgroup analyses demonstrated improvement in FMD after achieving target sU concentration in patients without but not with established cardiovascular risk factors and comorbidities, particularly hypertension and hyperlipidemia. CONCLUSIONS:Initiating guideline-concordant gout treatment reduces intercritical systemic inflammation and improves endothelial-dependent arterial function, particularly in patients without established cardiovascular comorbidities.
PMCID:7353742
PMID: 32653044
ISSN: 1478-6362
CID: 4527612

Colchicine for treatment of Osteoarthritis of the knee (CLOAK)-A phase 2, double-blind, placebo-controlled trial [Meeting Abstract]

Samuels, J; Bomfim, F; Toprover, M; Cohen, R; Davis, C; Krasnokutsky-Samuels, S; Pillinger, M H
Purpose: Current treatments for osteoarthritis (OA) remain inadequate. Accumulating evidence suggests that OA is an inflammatory disease, with a particular role for interleukin-1beta (IL-1beta) a product of the NLRP3 inflammasome. Additionally, both calcium and urate crystals have been suggested to play potential roles in OA and both are recognized to activate the NLRP3 inflammasome to produce IL-1beta. Colchicine is an ancient and well-tolerated anti-inflammatory agent and has recently been shown to inhibit inflammasome activation and IL-1beta generation. Several studies have examined the impact of colchicine on various aspects of OA, with varying Results. We are assessing the potential benefits of colchicine on several short-term features of knee OA.
Method(s): The CLOAK (CoLchicine for treatment of OsteoArthritis of the Knee) study is a randomized, double-blind, placebo-controlled trial of colchicine (0.8 mgs daily) for 90 days. (Figure 1). We are identifying patients as they are seen in the rheumatology clinics, as well as calling patients from our knee OA database of prior studies. The recruitment goal is to enroll 120 subjects at least 50 years of age who have symptomatic knee OA with radiographic confirmation (Kellgren-Lawrence grade 2 or 3), and who are willing to forego other anti-inflammatory therapy (i.e., topical or oral NSAID and/or intraarticular steroids or hyaluronic acid) during the trial. The primary clinical outcome is the difference between treatment and placebo groups in pain improvement by visual analog scale, along with changes in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and mean doses of analgesics used. Inflammatory outcomes between the two groups include changes in plasma inflammatory markers (such as hsCRP, PGE2, and IL-1Ra) and peripheral blood leukocyte genomic studies. All patients are scanned by knee ultrasound pre- and post-treatment, with assessment for synovitis and effusion. We also aspirate synovial fluid when appropriate, and will analyze all available samples together for inflammatory markers.
Result(s): To date, 78 patients have been contacted or approached, 18 screened, and 17 enrolled. Six have completed the study, with a mean BMI of 30.3. All 6 remain blinded as to study group; however, the mean VAS pain score among the group decreased by 1.7 in the index knee (which had greater pain at baseline), while the mean KOOS scores for symptoms, pain, activities of daily living, sports activity, quality of life and KOOS global all improved. Individually, 4 of the 6 completing subjects demonstrated VAS score improvement with 2 of 6 demonstrating worsening, a pattern that was duplicated in most of the KOOS scores.
Conclusion(s): The CLOAK trial is testing the potential benefit of colchicine on pain and inflammation in knee OA, specifically in patients with moderate radiographic disease who are not taking other anti-inflammatory agents. Supported by an investigator-initiated grant from Hikma Pharmaceuticals. [Formula presented]
Copyright
EMBASE:2005479217
ISSN: 1522-9653
CID: 4378232

Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease

Attur, Mukundan; Zhou, Hua; Samuels, Johathan; Krasnokutsky, Svetlana; Yau, Michelle; Scher, Jose U; Doherty, Michael; Wilson, Anthony G; Bencardino, Jenny; Hochberg, Marc; Jordan, Joanne M; Mitchell, Braxton; Kraus, Virginia B; Abramson, Steven B
OBJECTIVE:gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). METHODS:haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA. RESULTS:demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)). CONCLUSION/CONCLUSIONS:TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous 'anti-inflammatory' mechanisms.
PMID: 31852669
ISSN: 1468-2060
CID: 4242782

Colorectal Cancer Among Gout Patients Undergoing Colonoscopy

Slobodnick, Anastasia; Krasnokutsky, Svetlana; Lehmann, Robert A; Keenan, Robert T; Quach, Jonathan; Francois, Fritz; Pillinger, Michael H
BACKGROUND/OBJECTIVE/OBJECTIVE:The connection between gout and various cancers remains unclear. We assessed the relationship between gout and colorectal cancer in a population of veterans. METHODS:We reviewed the Computerized Patient Record System of the VA New York Harbor Health Care System to assess the 10-year occurrence of colorectal cancer in patients with gout undergoing colonoscopy, versus patients with osteoarthritis but no gout. RESULTS:Gout and osteoarthritis subjects were similar in age, ethnicity, body mass index, and smoking history. Among 581 gout and 598 osteoarthritis subjects with documented colonoscopies, the 10-year prevalence of colorectal cancer was significantly lower in gout (0.8%) versus osteoarthritis (3.7%) (p = 0.0008) patients. Differences in colorectal cancer rates remained significant after stratifying for nonsteroidal anti-inflammatory drug use. Among gout subjects, use of colchicine and/or allopurinol, as well as the presence/absence of concomitant osteoarthritis, did not influence colorectal cancer occurrence. On subanalysis, differences in colorectal cancer occurrence between gout and osteoarthritis subjects persisted among those who underwent diagnostic (0.5% in gout vs 4.6% in osteoarthritis subjects, p < 0.001) but not screening (0.9% in gout subjects vs 1% in osteoarthritis subjects, p = 1.0) colonoscopy. There was no significant difference in nonmalignant colorectal polyp occurrence between gout and osteoarthritis subjects. CONCLUSIONS:Subjects with gout had decreased colonoscopy-documented occurrence of colorectal cancer compared with osteoarthritis subjects, suggesting a possible protective effect.
PMID: 31764494
ISSN: 1536-7355
CID: 4215622

Urate and Osteoarthritis: Evidence For a Reciprocal Relationship

Neogi, Tuhina; Krasnokutsky, Svetlana; Pillinger, Michael H
Hyperuricemia is a common condition, and in a subset of patients leads to gout, the most common inflammatory arthritis. Osteoarthritis is the most common form of arthritis overall, and gout and osteoarthritis frequently coexist in the same patient. However, the relationship between the two remains poorly defined. More particularly, the impact of osteoarthritis on the development of gout, and the impact of gout on the development of osteoarthritis, remain to be determined. Additionally, whether hyperuricemia mediates osteoarthritis in the absence of gout is uncertain. Here, we review the evidence linking gout and osteoarthritis, with a special focus on the role of hyperuricemia in the presence or absence of gout. Since disease modifying agents are currently available for hyperuricemia and gout but not for osteoarthritis, a contributory role for urate in the pathogenesis of osteoarthritis could have important clinical implications.
PMID: 30471419
ISSN: 1778-7254
CID: 3480902

A low cartilage formation & repair endotype predicts radiographic progression in symptomatic knee osteoarthritis patients and identifies optimal responders to a potential OA treatment [Meeting Abstract]

Luo, Y; Samuels, J; Krasnokutsky, S; Byrjalsen, I; Andersen, J; Bihlet, A; He, Y; Karsdal, M; Abramson, S; Attur, M; Bay-Jensen, A
Background/Purpose : Osteoarthritis (OA) is a highly heterogeneous disease, which suggest that multiple endotypes exist. Identification and characterization of such endotypes may assist in precision medicine for identification of faster progressors whom may benefit from a given type of intervention. Recent published data have shown that SNPs in growth factors such as TGFbeta and GDF are associated with OA, which indicate that cartilage formation and repair play an important role in progression of OA. The aim was to determine whether a biomarker of type II collagen formation measured in serum, as a potential surrogate measure of cartilage formation, could predict radiographic progression in knee OA population. Subsequently, we investigated if such a proposed low cartilage formation/repair endotype was more responsive to a potential treatment of OA. Methods : hsPRO-C2, a measurement of the type II collagen pro-peptide, was measured in blood samples of two independent knee OA cohorts: 106 recruited at New York University (NYU cohort) and 147 from the phase III OA trial SMC021-2301 (clinicaltrial.gov: NCT00486434) evaluating the efficacy and safety of oral salmon calcitonin. Patients were dichotomized based on their baseline level of hsPRO-C2 and the mean difference in two-year radiographic progression (joint space narrowing (JSN)) was analyzed using ANCOVA adjusting for baseline demographics and clinical characteristics. Results : In the NYU cohort, baseline plasma hsPRO-C2 levels were negatively correlated with the progression of radiographic JSN (r = -0.26, p = 0.009). Quartile analysis demonstrated a significant difference in mean JSN from quartile 1 to 4 (0.51 mm versus -0.07 mm, p = 0.036, fig. 1). Knee OA patients with low hsPRO-C2 levels (<= 1.48 ng/mL) revealed significantly larger JSN compared to the individuals with high hsPRO-C2 levels ( > 1.48 ng/ mL) at 24 months (0.37 mm vs 0.02 mm, p = 0.042). In the SMC cohort, there was no significant treatment effect on the medial JSN over 2 years before stratification by hsPRO-C2; however, as observed in the NYU cohort, JSN was on average higher in the low hsPRO-C2 (<= 1.96 ng/mL) group compared to the high group ( > 1.96 ng/ mL). Furthermore, in the low baseline hsPRO-C2 subgroup, sCT-treated patients on average had a lower JSN compared to placebo patients (p < 0.05, fig. 2). The opposite trend was observed in patients with high baseline hsPRO-C2. Conclusion : Here we show that low levels of cartilage formation, measured by PRO-C2, were associated with radiographic progression and greater likelihood of response to a salmon calcitonin. Low PRO-C2 may provide a measure of an OA endotype with low background cartilage formation (at baseline) and higher capacity for repair when treated with a potential cartilage anabolic drug
EMBASE:633059507
ISSN: 2326-5205
CID: 4633502

The association between asymptomatic hyperuricemia and knee osteoarthritis: data from the third National Health and Nutrition Examination Survey

Wang, S; Pillinger, M H; Krasnokutsky, S; Barbour, K E
OBJECTIVE:In vitro and clinical studies suggest that urate may contribute to osteoarthritis (OA) risk. We tested the associations between hyperuricemia and knee OA, and examined the role of obesity, using a cross-sectional, nationally representative dataset. METHOD/METHODS:National Health and Nutrition Examination Survey (NHANES) III used a multistage, stratified probability cluster design to select USA civilians from 1988 to 1994. Using NHANES III we studied adults >60 years, with or without hyperuricemia (serum urate > 6.8 mg/dL), excluding individuals with gout (i.e., limiting to asymptomatic hyperuricemia (AH)). Radiographic knee OA (RKOA) was defined as Kellgren-Lawrence grade ≥ 2 in any knee, and symptomatic radiographic knee osteoarthritis (RKOA) (sRKOA) was defined as RKOA plus knee pain (most days for 6 weeks) in the same knee. RESULTS:AH prevalence was 17.9% (confidence interval (CI) 15.3-20.5). RKOA prevalence was 37.7% overall (CI 35.0-40.3), and was 44.0% for AH vs 36.3% for normouricemic adults (p = 0.056). symptomatic radiographic knee osteoarthritis (sRKOA) was more prevalent in AH vs normouricemic adults (17.4% vs 10.9%, p = 0.046). In multivariate models adjusting for obesity, model-based associations between AH and knee OA were attenuated (for RKOA, prevalence ratio (PR) = 1.14, 95% CI 0.95, 1.36; for sRKOA, PR = 1.40, 95% CI 0.98, 2.01). In stratified multivariate analyses, AH was associated with sRKOA in adults without obesity (PR = 1.66, 95% CI 1.02, 2.71) but not adults with obesity (PR = 1.21, 95% CI 0.66, 2.23). CONCLUSIONS:Among adults aged 60 or older, AH is associated with knee OA risk that is more apparent in adults without obesity.
PMCID:6702067
PMID: 31158484
ISSN: 1522-9653
CID: 4112222