Muscular-based and patient-reported outcomes differentially associate with circulating superoxide dismutases and cytokines in knee osteoarthritis.

Muscular (i.e., quadriceps) weakness contributes to disease progression and precedes the appearance of patient-reported symptoms, such as pain and perceived physical dysfunction, in knee osteoarthritis (OA). It is unknown, however, if muscular-based and patient-reported outcomes differentially associate with systemic biomarkers reflective of the local mediators in knee OA. The purpose of this study was to identify if muscular-based and patient-reported outcomes differentially associate with circulating superoxide dismutase (SOD) and cytokines in knee OA. Subjects (n = 29) with pain, muscular weakness, and radiographic evidence (Kellgren-Lawrence grade ≥2) of knee OA in the involved (INV) leg were included in this study. Serum Cu/Zn and Mn SOD and cytokine concentrations were measured in fasting blood samples. Pain and physical dysfunction were subjectively assessed and muscle strength (i.e., peak isometric force and torque, and peak isokinetic-concentric knee-extension and -flexion torques) was determined unilaterally in the INV and non-involved (NI) legs. Peak isometric and peak isokinetic-concentric knee-flexion torques in the INV leg correlated with serum Cu/Zn SOD (both p < 0.05). Peak isometric force and torque and peak isokinetic-concentric knee-extension and -flexion torques in the INV leg correlated with serum Mn SOD (all p < 0.05). Pain and dysfunction inversely associated with serum IL-1ß, IL-4, IL-5, IL-12, IL-13, and/or IFN-γ (p < 0.05). Neither SOD associated with pain or dysfunction, and none of the cytokines associated with muscular-based outcomes. We conclude that common outcome measures used in the clinical evaluation of OA differentially associate with circulating SOD and cytokines.

Tourniquet use during total knee arthroplasty does not modulate the neutrophil-to-lymphocyte ratio, pain, or activity.

The purpose of our study was to identify the influence of tourniquet use during total knee arthroplasty (TKA) on the neutrophil-to-lymphocyte ratio (NLR) shortly after surgery and patient-reported outcomes (pain and physical activity) from outpatient physical therapy. This retrospective study consisted of 104 subjects who underwent primary unilateral TKA (51 subjects with and 53 subjects without tourniquet assistance) between 2010 and 2012. The NLR was calculated from the absolute neutrophil and lymphocyte counts obtained immediately before and after (1 and 2 days) knee arthroplasty. The Knee Outcome Survey (KOS) of Activities of Daily Living and numeric pain scores collected at the first [33.0 (34.2) days after surgery] and last [85.5 (40.7) days after surgery] outpatient physical therapy visits were extracted from an electronic database. The NLR, pain, and KOS score were not significantly (all p > 0.05) different with tourniquet use. Based on these findings, we conclude that tourniquet use during TKA neither increases systemic inflammation shortly after surgery nor impairs patient-reported outcomes obtained during outpatient physical therapy. LEVEL OF EVIDENCE: IV.

Circulating interleukin-6 is not altered while γ-tocopherol is increased in subjects scheduled for knee surgery with low vitamin D.

The purpose of this study was to identify if circulating interleukin (IL)-6 and γ-tocopherol (γT) fluctuate with vitamin D status in subjects with an underlying knee joint injury or disease. We hypothesized that low vitamin D associates with an increase in plasma γT while serum IL-6 remains unchanged in subjects with an underlying knee joint trauma or disease. Fifty-four subjects scheduled to undergo primary, unilateral anterior cruciate ligament reconstructive surgery (ACL; n=27) or total knee arthroplasty (TKA; n=27) were studied. Circulating γT, α-tocopherol (αT), lipids (cholesterol and triglycerides), IL-6, and 25-hydroxyvitamin D (25(OH)D) were measured in fasting blood samples obtained prior to surgery. Subjects were classified as vitamin D deficient, insufficient, or sufficient if they had a serum 25(OH)D concentration <50, 50-75, or >75nM, respectively. The majority (57%) of the subjects possessed a serum 25(OH)D less than 50nM. Circulating cholesterol, triglycerides, and IL-6 were not significantly (all p>0.05) different between vitamin D status groups. However, lipid corrected αT was significantly (p<0.05) decreased and both lipid- and non-lipid-corrected plasma γT concentrations were significantly (both p<0.05) increased with low serum 25(OH)D (i.e., <50nM). A significant (p<0.05) multi-variate analysis revealed that an increase in plasma γT per lipids was significantly (p<0.05) predicted by a decrease in serum 25(OH)D but not by a decrease in plasma αT per lipids. We conclude that low vitamin D associates with an increase in plasma γT but not IL-6 in subjects with an underlying joint injury or disease.

Serum cytokines are increased and circulating micronutrients are not altered in subjects with early compared to advanced knee osteoarthritis.

Knee osteoarthritis (OA) is a leading cause of physical disability. At the early stage of knee OA, the increase in synovial fluid cytokine concentrations could contribute to the pathogenesis of OA by degrading articular cartilage. It is unknown, however, if inflammatory cytokines increase systemically at the early or advanced stage of knee OA. The systemic increase of inflammatory cytokines could be detrimental to the endogenous status of micronutrients that protect against excessive inflammation and cytokine-mediated events. The purpose of this study was to test the hypothesis that an increase in serum cytokines associate with a decrease in circulating micronutrients in subjects with early compared to advanced knee OA. Advanced knee OA subjects (n=14) displayed radiographic, pain, and muscular weakness symptoms of knee OA. Early knee OA subjects (n=14) were matched (age, gender, and body mass index) to the advanced OA group and displayed one or two of the aforementioned symptoms of knee OA. Inflammatory cytokines, vitamins C (ascorbic acid), D (25-hydroxyvitamin D), and E (α- and γ-tocopherols), and ß-carotene were measured in fasting blood samples. In the early OA group, serum tumor necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-12, and IL-13 concentrations were significantly (all p<0.05) increased. Circulating ascorbic acid, 25-hydroxyvitamin D, α- and γ-tocopherol's, and ß-carotene concentrations were not significantly different between groups. Based on these preliminary results, we conclude that the systemic increase of inflammatory cytokines is not associated with a decrease in circulating micronutrients in subjects with early compared to advanced knee OA.

Pro-inflammatory cytokines mediate the decrease in serum 25(OH)D concentrations after total knee arthroplasty?

Vitamin D is a fat-soluble micronutrient that regulates inflammation and skeletal muscle size and function. Inflammation and skeletal muscle dysfunction (i.e., atrophy and weakness) are predominant impairments that continue to challenge the rehabilitation from total knee arthroplasty (TKA). Data suggest a decrease in serum 25-hydroxyvitamin D (25(OH)D) concentrations after TKA. Despite the decrease being attributed to a systemic inflammatory response, it is unclear what inflammatory mediator(s) is contributing to the decrease in serum 25(OH)D concentrations after TKA. In immune cells, pro-inflammatory cytokines mediate the enzymatic conversion of 25(OH)D to 1,25-dihydroxyvitamin D, implying that pro-inflammatory cytokines contribute to the decrease in substrate availability (i.e., 25(OH)D). We propose the hypothesis that pro-inflammatory cytokines mediate the decrease in serum 25(OH)D concentrations after TKA. To complement the supporting literature for the proposed hypothesis, we analyzed serum 25(OH)D and pro-inflammatory cytokine concentrations prior to and serially after TKA in a case subject (female; age, 62 year; height, 160 cm; body mass, 63 kg; body mass index, 26.5 kg/m(2)). The subtle decrease (12%) from pre-surgery to 2-d post-surgery and the more pronounced decrease (74%) from 3-week to 8-week post-surgery in serum 25(OH)D concentrations corresponded with the increase in serum pro-inflammatory cytokine (i.e., TNF-α, IFN-γ, IL-1ß, GM-CSF, and IL-6) concentrations. This observation lends credence to the proposed hypothesis that pro-inflammatory cytokines could contribute to the decrease in serum 25(OH)D concentrations after TKA. Clearly, future research is needed to confirm the proposed hypothesis and to identify if attenuating the decrease in serum 25(OH)D concentrations improves patient outcomes after TKA.

Etoricoxib provides analgesic efficacy to patients after knee or hip replacement surgery: a randomized, double-blind, placebo-controlled study.

UNLABELLED: In this randomized, double-blind, placebo-controlled, multicenter study we assessed the analgesic effect of etoricoxib (a new cyclooxygenase-2 inhibitor) in patients having had knee or hip replacement surgery. A total of 228 patients with moderate or severe pain were randomly allocated within 72 h after surgery to receive etoricoxib 120 mg, controlled-release naproxen sodium 1100 mg, or placebo (1:1:1) on day 1 followed by etoricoxib and placebo (1:2) on days 2 to 7. Patients reported pain scores, rescue (opioid-combination) medication use, and the response to study drug. On day 1, etoricoxib provided an analgesic effect superior to placebo and similar to controlled-release naproxen sodium as demonstrated by the total pain relief score over 8 h, the primary end-point; least-squares mean scores were 11.0, 11.5, and 5.6, respectively (P < 0.001 versus placebo). Similarly, a larger percentage of patients receiving etoricoxib and naproxen sodium than those receiving placebo reported good to excellent responses to study drug: 53%, 60%, and 26% respectively. On days 2-7, etoricoxib demonstrated a significant reduction of rescue medication use, 35% (P < 0.001 versus placebo). The clinical relevance of the decrease was confirmed by Patient's Global Evaluation (P < 0.05 versus placebo). Patients receiving etoricoxib also experienced significantly less "worst" and "average" pain than did those on placebo. Etoricoxib was generally well tolerated in this study; the incidence of adverse experiences was infrequent and similar across treatment groups. In summary, etoricoxib provided analgesia that was similar to controlled-release naproxen sodium on day 1 and superior to placebo with reduced supplemental opioid use over 7 days. IMPLICATIONS: In a postsurgery setting (knee and hip replacements), etoricoxib 120 mg provided analgesia superior to placebo and similar to controlled-release naproxen sodium 1100 mg. Patients receiving etoricoxib suffered less pain and took less opioid rescue medication compared with patients on placebo.

Intravenous parecoxib sodium foracute pain after orthopedic knee surgery.

Our objective in a randomized, multicenter, double-blind, parallel-group, placebo- and active-controlled study was to evaluate and compare the analgesic effectiveness of single intravenous (IV) doses of parecoxib sodium 20 and 40 mg, morphine 4 mg, and ketorolac 30 mg in the postsurgical orthopedic pain model. After undergoing unilateral total knee replacement surgery, 208 healthy adult patients were randomized to receive placebo or a study drug within 6 hours of discontinuation of patient-controlled analgesia on postoperative day 1. Onset of analgesia was similarly rapid with IV parecoxib sodium 40 mg, morphine, and ketorolac. Level and duration of analgesia were significantly superior with parecoxib sodium than with morphine and were similar for parecoxib sodium and ketorolac. Parecoxib sodium was safe and well tolerated. In conclusion, IV parecoxib sodium 40 mg is as effective as ketorolac 30 mg and is more effective than morphine 4 mg and therefore has potential widespread utility in acute postoperative pain management.