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Susceptibility of nucleotide-binding oligomerization domain 2 mutations to Whipple's disease

Williamson, Katrina A; Yun, Mark; Koster, Matthew J; Arment, Courtney; Patnaik, Asha; Chang, Tara W; Bledsoe, Adam C; Sae-Tia, Sutthichai; Shah, Aditya S; Samuels, Jonathan; Davis Iii, John M; Yao, Qingping
OBJECTIVES/OBJECTIVE:Whipple's disease (WD) results from infection of the bacteria Tropheryma whipplei (TW). This disease is characterized by macrophage infiltration of intestinal mucosa and primarily affects Caucasian males. Genetic studies of host susceptibility are scarce. Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is an innate immune sensor, resides mainly in monocytes/macrophages and contributes to defense against infection and inflammatory regulation. NOD2 mutations are associated with autoinflammatory diseases. We report the association of NOD2 mutations with TW and WD for the first time. METHODS:A multicenter, retrospective study of three patients with WD was conducted. Patients received extensive multidisciplinary evaluations and were cared for by the authors. NOD2 and its association with infection and inflammation were schematically represented. RESULTS:All patients were Caucasian men and presented with years of autoinflammatory phenotypes, including recurrent fever, rash, inflammatory arthritis, gastrointestinal symptoms, and elevated inflammatory markers. All patients underwent molecular testing using a gene panel for periodic fever syndromes and were identified to carry NOD2 mutations associated with NOD2-associated autoinflammatory disease. Despite initially negative gastrointestinal evaluations, repeat endoscopy with duodenal tissue biopsy ultimately confirmed WD. After initial ceftriaxone and maintenance with doxycycline and/or hydroxychloroquine, symptoms were largely controlled, though mild relapses occurred in follow up. CONCLUSION/CONCLUSIONS:Both NOD2 and TW/WD are intensively involved in monocytes/macrophages. WD is regarded as a macrophage disease. NOD2 leucin rich repeat-associated mutations in monocytes/macrophages cause functional impairment of these cells and consequently may make the host susceptible for TW infection and WD, especially in the setting of immunosuppression.
PMID: 37467078
ISSN: 1462-0332
CID: 5535812

Serum proteomic panel validated for prediction of knee osteoarthritis progression

Kraus, Virginia Byers; Reed, Alexander; Soderblom, Erik J; Moseley, M Arthur; Hsueh, Ming-Feng; Attur, Mukundun G; Samuels, Jonathan; Abramson, Steven B; Li, Yi-Ju
OBJECTIVE/UNASSIGNED:To further validate a serum proteomics panel for predicting radiographic (structural) knee OA progression. DESIGN/UNASSIGNED:Serum peptides were targeted by multiple-reaction-monitoring mass spectrometry in the New York University cohort (n ​= ​104). Knee OA progression was defined as joint space narrowing ≥1 in the tibiofemoral compartment of one knee per study participant over a 24-month follow-up. The discriminative ability of an 11-peptide panel was evaluated by multivariable logistic regression and area under the receiver operating characteristic curve (AUC), without and with demographic characteristics of age, sex, and body mass index. The association of each peptide with OA progression was assessed by odds ratios (OR) in multivariable logistic regression models adjusted for demographics. RESULTS/UNASSIGNED:The cohort included 46 (44%) knee OA progressors. The panel of 11 peptides alone yielded AUC ​= ​0.66 (95% CI [0.55, 0.77]) for discriminating progressors from non-progressors; demographic traits alone yielded AUC ​= ​0.66 (95% CI [0.55, 0.77]). Together the 11 peptides and demographics yielded AUC ​= ​0.72 (95% CI [0.62, 0.83]). CRAC1 had the highest odds for predicting OA progression (OR 2.014, 95% CI [0.996, 4.296], p ​= ​0.058). CONCLUSIONS/UNASSIGNED:We evaluated a parsimonious serum proteomic panel and found it to be a good discriminator of knee radiographic OA progression from non-progression. Since these biomarkers are quantifiable in serum, they could be deployed relatively easily to provide a simple, cost-effective strategy for identifying and monitoring individuals at high risk of knee OA progression.
PMID: 38116469
ISSN: 2665-9131
CID: 5612392

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis

Fu, Wenyu; Vasylyev, Dmytro; Bi, Yufei; Zhang, Mingshuang; Sun, Guodong; Khleborodova, Asya; Huang, Guiwu; Zhao, Libo; Zhou, Renpeng; Li, Yonggang; Liu, Shujun; Cai, Xianyi; He, Wenjun; Cui, Min; Zhao, Xiangli; Hettinghouse, Aubryanna; Good, Julia; Kim, Ellen; Strauss, Eric; Leucht, Philipp; Schwarzkopf, Ran; Guo, Edward X; Samuels, Jonathan; Hu, Wenhuo; Attur, Mukundan; Waxman, Stephen G; Liu, Chuan-Ju
Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.
PMID: 38172636
ISSN: 1476-4687
CID: 5626502

Genicular Artery Embolization for Treatment of Knee Osteoarthritis: Interim Analysis of a Prospective Pilot Trial Including Effect on Serum Osteoarthritis-Associated Biomarkers

Taslakian, Bedros; Swilling, David; Attur, Mukundan; Alaia, Erin F; Kijowski, Richard; Samuels, Jonathan; Macaulay, William; Ramos, Danibel; Liu, Shu; Morris, Elizabeth M; Hickey, Ryan
PURPOSE/OBJECTIVE:To characterize the safety, efficacy, and potential role of genicular artery embolization (GAE) as a disease-modifying treatment for symptomatic knee osteoarthritis (OA). MATERIALS AND METHODS/METHODS:This is an interim analysis of a prospective, single-arm clinical trial of patients with symptomatic knee OA who failed conservative therapy for greater than 3 months. Sixteen patients who underwent GAE using 250-μm microspheres and had at least 1 month of follow-up were included. Six patients completed the 12-month follow-up, and 10 patients remain enrolled. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was evaluated at baseline and at 1, 3, and 12 months. Serum and plasma samples were collected for biomarker analysis. The primary end point was the percentage of patients who achieved the minimal clinically important difference (MCID) for WOMAC pain score at 12 months. Baseline and follow-up outcomes were analyzed using the Wilcoxon matched-pairs signed-rank test. RESULTS:Technical success of the procedure was 100%, with no major adverse events. The MCID was achieved in 5 of the 6 (83%) patients at 12 months. The mean WOMAC pain score decreased from 8.6 ± 2.7 at baseline to 4.9 ± 2.7 (P = .001), 4.4 ± 2.8 (P < .001), and 4.7 ± 2.7 (P = .094) at 1, 3, and 12 months, respectively. There was a statistically significant decrease in nerve growth factor (NGF) levels at 12 months. The remaining 8 biomarkers showed no significant change at 12 months. CONCLUSIONS:GAE is a safe and efficacious treatment for symptomatic knee OA. Decreased NGF levels after GAE may contribute to pain reduction and slowing of cartilage degeneration.
PMID: 37640104
ISSN: 1535-7732
CID: 5611392

Pathological tissue formation and degradation biomarkers correlate with patient reported pain outcomes: an explorative study

Bay-Jensen, Anne C; Attur, Mukundan; Samuels, Jonathan; Thudium, Christian S; Abramson, Steven B; Karsdal, Morten A
BACKGROUND/UNASSIGNED:The lack of disease modifying drugs in Osteoarthritis (OA) may be attributed to the difficulty in robust response based on patient-reported outcomes (PROs) linked to drug mechanism of action. Joint tissue turnover biomarkers are associated with disease progression. A subset of patients has elevated serum levels of CRP metabolite (CRPM). This explorative study investigates the associations between PROs and joint tissue turnover markers in patients with high or low CRPM. METHODS/UNASSIGNED:Serum of 146 knee OA patients of the New York Inflammation cohort and 21 healthy donors were assessed for biomarkers of collagen degradation (C1M, C2M, C3M, C4M), formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4), and CRPM. Mean (SD) age was 62.5 (10.1); BMI, 26.6 (3.6); 62% women; and, 67.6% had symptomatic OA. WOMAC pain, stiffness, function, and total were recorded at baseline and at two-year follow-up. Associations were adjusted for race, sex, age, BMI, and NSAID. RESULTS/UNASSIGNED:group. The best predictive models for improvement were found for function and total with AUCs of 0.74 (p ​< ​0.01) and 0.78 (p ​< ​0.01). The best predictive models for worsening were found for function and total with AUCs of 0.84 (p ​< ​0.01) and 0.80 (p ​< ​0.05). CONCLUSION/UNASSIGNED:We hypothesize that collagen markers are prognostic tools for segregating patient populations in clinical trials.
PMID: 37342785
ISSN: 2665-9131
CID: 5542742

Genicular artery embolization for treatment of knee osteoarthritis pain: Systematic review and meta-analysis

Taslakian, Bedros; Miller, Larry E.; Mabud, Tarub S.; Macaulay, William; Samuels, Jonathan; Attur, Mukundan; Alaia, Erin F.; Kijowski, Richard; Hickey, Ryan; Sista, Akhilesh K.
Objective: Genicular artery embolization (GAE) is a novel, minimally invasive procedure for treatment of knee osteoarthritis (OA). This meta-analysis investigated the safety and effectiveness of this procedure. Design: Outcomes of this systematic review with meta-analysis were technical success, knee pain visual analog scale (VAS; 0"“100 scale), WOMAC Total Score (0"“100 scale), retreatment rate, and adverse events. Continuous outcomes were calculated as the weighted mean difference (WMD) versus baseline. Minimal clinically important difference (MCID) and substantial clinical benefit (SCB) rates were estimated in Monte Carlo simulations. Rates of total knee replacement and repeat GAE were calculated using life-table methods. Results: In 10 groups (9 studies; 270 patients; 339 knees), GAE technical success was 99.7%. Over 12 months, the WMD ranged from −34 to −39 at each follow-up for VAS score and −28 to −34 for WOMAC Total score (all p "‹< "‹0.001). At 12 months, 78% met the MCID for VAS score; 92% met the MCID for WOMAC Total score, and 78% met the SCB for WOMAC Total score. Higher baseline knee pain severity was associated with greater improvements in knee pain. Over 2 years, 5.2% of patients underwent total knee replacement and 8.3% received repeat GAE. Adverse events were minor, with transient skin discoloration as the most common (11.6%). Conclusions: Limited evidence suggests that GAE is a safe procedure that confers improvement in knee OA symptoms at established MCID thresholds. Patients with greater knee pain severity may be more responsive to GAE.
ISSN: 2665-9131
CID: 5549022

Assessing the impact of bariatrics on osteoarthritis progression [Editorial]

Samuels, Jonathan; Attur, Mukundan
PMID: 36775136
ISSN: 1522-9653
CID: 5421162

Efficacy and safety of colchicine for the treatment of osteoarthritis: a systematic review and meta-analysis of intervention trials

Singh, Ambrish; Molina-Garcia, Pablo; Hussain, Salman; Paul, Alok; Das, Siddharth Kumar; Leung, Ying-Ying; Hill, Catherine L; Danda, Debashish; Samuels, Jonathan; Antony, Benny
OBJECTIVE:Colchicine, an approved treatment for gout, has been trialed in many diseases including osteoarthritis (OA) due to its anti-inflammatory effects. However, its efficacy and safety remain unclear in OA. This systematic review and meta-analysis evaluated the efficacy and safety of colchicine for the treatment of OA. METHODS:PubMed, Web of Science, Scopus, and Cochrane Central were searched from inception through September 2022. Two reviewers independently screened for randomized controlled trials (RCTs) comparing colchicine with placebo or other active comparators for the treatment of OA (knee, hand, or hip OA), extracted data, and performed Cochrane risk of bias assessments. RESULT/RESULTS:Nine RCTs for the knee OA and one for the hand OA were identified, consisting of 847 patients (429 in colchicine arms, 409 in control arms). The studies were conducted between 2002 and 2021 with follow-up periods ranging from 2 to 12 months, in India, Iran, Turkey, Australia, Singapore, and Iraq. Moderate-quality evidence showed no clinically important pain reduction with colchicine compared to control (standardized mean difference [SMD], 0.17; 95% confidence interval [CI], - 0.55, 0.22). Moderate-quality evidence showed no improvement in function with colchicine compared to control in knee OA patients (SMD, - 0.37; 95% CI, - 0.87, 0.13). Colchicine showed an acceptable safety profile with AEs/SAEs comparable to control. CONCLUSION/CONCLUSIONS:Current evidence does not suggest a benefit of colchicine in reducing pain and improving physical function in the overall cohort of hand/knee OA patients. Future trials should focus on the subgroups of OA patients with local or systemic inflammation and/or mineralization who might benefit from colchicine.
PMID: 36224305
ISSN: 1434-9949
CID: 5361012

Postoperative flares and peri-arthroscopic management of immunosuppressive medications in patients with rheumatic disease

Vasavada, Kinjal; Shankar, Dhruv S; Avila, Amanda; Lin, Charles C; Marulanda, David; Jazrawi, Laith M; Samuels, Jonathan
PURPOSE/OBJECTIVE:To determine the rate and characteristics of postoperative flares in rheumatic disease patients undergoing arthroscopic surgery, and the role of perioperative immunosuppression (IS) management in preventing or provoking these exacerbations. METHODS:We conducted a retrospective review of arthroscopic surgeries in patients with rheumatologic disease over 11 years. Patients taking IS at baseline and those without were matched 1:1 using propensity scores on age, sex, rheumatic disease type, and procedure complexity. Patients taking IS at baseline were sub-divided into those remaining on IS perioperatively versus those who held IS before surgery. Multivariable logistic regression identified risk factors for postoperative flares for the three IS groups, and survival analysis was used to compare the probability of remaining flare-free up to 12 weeks postoperatively. RESULTS:After matching, 428 patients (214 on various types of baseline IS, 214 not on baseline IS) were included, with 110 on baseline IS remaining on it perioperatively. Rates of postoperative flares were similar for those staying on vs holding their baseline IS (9.1% vs 9.6%) but flares were less frequent in patients not on baseline IS (1.9%). Patients who remained on perioperative IS did not have significantly less flares compared to patients taken off perioperative IS (OR 0.764 [0.267, 2.181]; p = 0.61). Patients not on baseline IS had a significantly higher probability ofremaining flare-free up to 12 weeks (p = 0.004). CONCLUSION/CONCLUSIONS:Rheumatic disease patients who hold IS medication before undergoing arthroscopy, out of concern for potential infection or complications, do not significantly increase their risk of flaring their autoimmune disease whether they had been taking csDMARDs or biologic agents. Those not taking any IS at baseline have a much lower risk of post-arthroscopic flaring, though as a group they likely harbor less of an autoimmune burden.
PMID: 36702051
ISSN: 1873-5800
CID: 5419682

Low incidence and transient elevation of autoantibodies post mRNA COVID-19 vaccination in inflammatory arthritis

Blank, Rebecca B; Haberman, Rebecca H; Qian, Kun; Samanovic, Marie; Castillo, Rochelle; Jimenez Hernandez, Anthony; Vasudevapillai Girija, Parvathy; Catron, Sydney; Uddin, Zakwan; Rackoff, Paula; Solomon, Gary; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya; Mulligan, Mark J; Hu, Jiyuan; Scher, Jose U
OBJECTIVES/OBJECTIVE:Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls. METHODS:Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization. RESULTS:Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, p= 0.014). Incidence of de novo anti-cyclic citrullinated protein (CCP) seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titer, transient, and not associated with increase in IA flares. CONCLUSIONS:In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population.
PMID: 35640110
ISSN: 1462-0332
CID: 5235902