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

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.

Peri-Arthroscopic Management of Immunosuppressive Medications in Patients with Rheumatic Disease A Survey of Practice Trends Among Rheumatologists and Sports Medicine Orthopedic Surgeons.

PURPOSE: Rheumatologists and orthopedic surgeons frequently collaborate on difficult decisions regarding perioperative management of immunosuppression in rheumatic disease patients, balancing risk of postoperative infection with risk of disease flares. Current evidence-based guidelines pertain specifically to arthroplasty, thus we sought to understand the trends and common practices regarding peri-arthroscopic use of immunosuppression. METHODS: Rheumatologists and sports medicine surgeons, from a variety of New York hospitals and serving a broad range of demographics, were surveyed on immunosuppressive medication management in rheumatic disease patients undergoing arthroscopic surgeries. Physicians' preferences were elicited regarding the use of common anti-rheumatic medications with the lower risk meniscectomies and the higher risk anterior cruciate ligament (ACL) reconstructions and allografts. Physicians were asked specifically about peri-arthroscopic use of conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), biologics, and Janus kinase (JAK) inhibitors. RESULTS: During the survey period, 25 rheumatologists and 19 sports medicine fellowship-trained orthopedic surgeons completed the questionnaire. For lower-risk arthroscopies, rheumatologists favored continuing various csDMARDs (72% to 100%), biologics (50% to 64%) and JAK inhibitors (57%), while a majority of surgeons concurred for all three drug classes (csDMARDs 63%; biologics 53%; and JAK inhibitors 58%). For higher-risk arthroscopies, most rheumatologists preferred that patients continue csDMARDs (63% to 100%) but fewer supported the use of biologics (28% to 39%) or JAK inhibitors (22%). Surgeons were more hesitant to endorse any class of immunosuppressive antirheumatic medications (22% to 27%) around these higher risk surgeries. The rheumatologists were most concerned about surgeries taking place too soon after the last dose of rituximab, recommending these higher risk surgeries not take place for 7.7 ± 8.8 weeks following the last infusion. CONCLUSION: For lower-risk arthroscopies, most rheumatologists but only about half of orthopedic surgeons preferred patients continuing csDMARDs. Approximately half of both groups preferred patients hold biologics and JAK inhibitors. In more involved arthroscopies, most rheumatologists but few orthopedists supported the continued use of csDMARDs, and the consensus was to hold all other immunosuppression when possible. While the duration medications were held perioperatively were somewhat reflective of the current guidelines for arthroplasty, there is a need for evidencebased guidelines specifically regarding peri-arthroscopy immunosuppression in rheumatic disease patients.

Postoperative complications in rheumatic disease patients undergoing arthroscopy on immunosuppression.

BACKGROUND: There are currently no guidelines on peri-arthroscopic management of immunosuppressive (IS) treatment in rheumatic disease patients. PURPOSE: The purpose of this study is to characterize the rheumatic disease patient population undergoing arthroscopy, compare the incidence of postoperative complications among patients who either remained on IS perioperatively, held IS perioperatively or were not on IS at baseline, and compare the incidence of postoperative complications by rheumatic disease type, medication type, and procedure. METHODS: We conducted a retrospective review of all arthroscopic sports medicine surgeries in patients with a rheumatic disease diagnosis at our institution over an 11-year period. Patients on IS at baseline were grouped into those who remained on IS perioperatively or held all IS before the date of their surgery. These two groups were compared to patients who were not on IS at baseline. Incidence of postoperative complications was calculated for the three cohorts and by medication class, rheumatic disease type, and procedure risk. Analysis of variance (ANOVA), chi-squared, and Fisher's exact tests were used to determine the statistical significance of between-group differences in postoperative complication incidence. RESULTS: We identified 1,316 rheumatic disease patients undergoing arthroscopy, with 214 of them taking IS medications at baseline. In total, 8.4% (n = 110) remained on IS perioperatively, 7.9% (n = 104) held IS perioperatively, and 83.7% (n = 1102) were not on IS at baseline. In all cohorts, seven patients experienced postoperative complications; six of whom experienced infections. Two (1.82%) occurred in patients remaining on IS perioperatively, zero infections occured in patients who held all IS, and four (0.36%) occured in patients who were not on any IS at baseline. There was no statistically significant difference in postoperative infections or complication rates among the three cohorts or further subgroups. CONCLUSION: The risk of postoperative complications including infectious, major, and minor complications in patients on IS at the time of arthroscopy is low and acceptable.

Serum proteomic panel validated for prediction of knee osteoarthritis progression.

Objective: To further validate a serum proteomics panel for predicting radiographic (structural) knee OA progression. Design: Serum peptides were targeted by multiple-reaction-monitoring mass spectrometry in the New York University cohort (n â€‹= â€‹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: The cohort included 46 (44%) knee OA progressors. The panel of 11 peptides alone yielded AUC â€‹= â€‹0.66 (95% CI [0.55, 0.77]) for discriminating progressors from non-progressors; demographic traits alone yielded AUC â€‹= â€‹0.66 (95% CI [0.55, 0.77]). Together the 11 peptides and demographics yielded AUC â€‹= â€‹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 â€‹= â€‹0.058). Conclusions: 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.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee

To develop an evidence- based guideline for the comprehensive management of osteoarthritis (OA) as a collabora-tion between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommenda-tions for the management of hand, hip, and knee OA.Methods. We identied clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benets and harms of available educational, behavioral, psychosocial, physical, mind- body, and pharmacologic therapies for OA. Grading of Recommen-dations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, includ-ing rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations.Results. Based on the available evidence, either strong or conditional recommendations were made for or against the ap-proaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self- efcacy and self- management programs, tai chi, cane use, hand orthoses for rst carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exer-cises, yoga, cognitive behavioral therapy, kinesiotaping for rst CMC OA, orthoses for hand joints other than the rst CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, du-loxetine, and tramadol.Conclusion. This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision- making that accounts for patients' values, preferences, and comor-bidities. These recommendations should not be used to limit or deny access to therapies