Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation.

Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1ß. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1ß. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1ß was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1ß) known to be produced by uric acid-activated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.

Increased interleukin-1ß gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis.

OBJECTIVE: To evaluate whether gene expression profiles could serve as biomarkers of symptomatic knee osteoarthritis (OA) by examining gene expression profiles in peripheral blood leukocytes (PBLs) from patients with OA compared with those from non-OA controls, and to determine whether candidate genomic biomarkers (PBL expression of inflammatory genes) predict an increased risk of disease progression in patients with symptomatic radiographic knee OA. METHODS: Three independent cohorts of patients with knee OA and non-OA control subjects were studied. Two cohorts (a learning cohort and a validation cohort) were recruited at New York University Hospital for Joint Diseases (NYUHJD), and 1 cohort (a validation cohort) was recruited at Duke University Medical Center. PBL gene expression was assessed using Affymetrix microarray and was confirmed by quantitative polymerase chain reaction (qPCR). Radiographic progression at 2 years was assessed in 86 patients. RESULTS: We identified 173 genes that were significantly up-regulated or down-regulated (≥1.5-fold change) in OA PBLs, at a false discovery rate of 5%. Cluster analysis revealed 2 distinct subgroups among the patients with OA: those in whom the expression of interleukin-1ß (IL-1ß) was increased ≥2-fold compared with controls, and those in whom the expression of IL-1ß was comparable with that in controls. Overexpression of IL-1ß in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory "IL-1ß signature" had higher pain scores and decreased function and were at higher risk of radiographic progression of OA. CONCLUSION: PBLs from patients with symptomatic knee OA display a characteristic transcriptome profile. Moreover, increased expression of IL-1ß identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA.

Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations.

BACKGROUND: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs. OBJECTIVE: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease. METHODS: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients. RESULTS: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity. CONCLUSION: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials.

Pregnancy outcomes, fertility, and family planning in women with psoriatic arthritis.

OBJECTIVE: To quantify pregnancy outcomes and the frequency and cause of infertility among women with psoriatic arthritis. METHODS: Women with psoriatic arthritis aged 20-50 years completed a questionnaire about prior pregnancies, infertility, and family planning. Patient-reported pregnancy outcomes were validated by chart review. RESULTS: In 40 women with psoriatic arthritis, 67% of 70 pregnancies were live births. Patient-reported preterm birth and preeclampsia were more common after psoriatic arthritis diagnosis but were significantly over-reported. Most women reported no or mild joint pain during pregnancy and few took medications for psoriatic arthritis. Infertility was reported by 36% of women who were ever pregnant or ever tried to become pregnant, primarily due to polycystic ovary syndrome. CONCLUSION: The patient-reported pregnancy outcomes in this retrospective survey were not supported by chart review, making prospective studies essential to understand the interaction of psoriatic arthritis and pregnancy. Infertility, particularly due to polycystic ovary syndrome, appears to be an important issue in this population.

Fertility and Ovarian Reserve among Women with Rheumatoid Arthritis.

OBJECTIVE: We sought to identify causes for infertility in women with and without rheumatoid arthritis (RA). METHODS: Women with RA were matched to healthy controls. Differences in anti-Müllerian hormone (AMH) and anovulation were analyzed. RESULTS: Women with RA had lower AMH (ß -1.05, 95% CI -2.09 to -0.005), but no difference was observed when AMH was log-transformed. No difference in anovulation was observed. Infertility prevalence was similar between groups, primarily attributable to polycystic ovary syndrome in healthy controls but largely unexplained in women with RA. CONCLUSION: AMH was lower in women with RA, but reasons for infertility among women with RA remain unknown.

Contraception methods used by women with rheumatoid arthritis and psoriatic arthritis.

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are common in women of childbearing age and are often treated with teratogenic medications. In this study, we assessed contraceptive methods in young women with RA or PsA and correlated contraceptive method efficacy with use of concomitant rheumatic medications. We combined the data from several cross-sectional surveys of women under the age of 40 with RA or PsA. Two surveys recruited participants from a clinic setting (RA and PsA Clinic Surveys), and the third survey recruited participants from CreakyJoints.org , an online forum for patients with inflammatory arthritis (CreakyJoints Survey). Of the 164 women included, 138 had RA (67 in RA Clinic Survey, 71 in CreakyJoints Survey) and 26 had PsA (19 in PsA Clinic Survey, 7 in CreakyJoints Survey). Use of specific contraceptive and rheumatic medications were similar between the clinic and online surveys. In the pooled analysis of the Clinic and CreakyJoints survey data, women with RA and PsA reported similar utilization of highly effective contraception methods (31.9% RA, 34.6% PsA) and effective methods (31.2% RA, 30.8% PsA), but different utilization of ineffective methods (35.5% RA, 11.5% PsA) and no methods (1.5% RA, 23.1% PsA), p = 0.0002. These proportions remained similar across subgroups taking methotrexate, anti-TNF biologics, and novel medications. Approximately two thirds of women with RA and PsA reported using effective or highly effective methods of contraception, though women with PsA were more likely to report no methods of contraception.

Alpha C-telopeptide of type I collagen is associated with subchondral bone turnover and predicts progression of joint space narrowing and osteophytes in osteoarthritis.

OBJECTIVE: To evaluate joint tissue remodeling using the urinary collagen biomarkers urinary α-C-telopeptide of type I collagen (α-CTX) and urinary C-telopeptide of type II collagen (CTX-II) and to determine the association of these biomarkers with osteoarthritis (OA) severity, progression, and localized knee bone turnover. METHODS: Participants (n = 149) with symptomatic and radiographic knee OA underwent fixed-flexion knee radiography at baseline and 3 years, and late-phase bone scintigraphy of both knees at baseline, which were scored semiquantitatively for osteophyte and joint space narrowing (JSN) severity and uptake intensity, with scores summed across knees. Urinary concentrations of α-CTX and CTX-II were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis of human OA knees was performed to localize the joint tissue origin of the biomarker epitopes. RESULTS: Urinary α-CTX concentrations correlated strongly with the intensity of bone scintigraphic uptake and with JSN progression (risk ratio 13.2) and osteophyte progression (risk ratio 3). Urinary CTX-II concentrations were strongly associated with intensity of bone scintigraphic uptake, with JSN and osteophyte severity, and with OA progression based on osteophyte score. Urinary α-CTX localized primarily to high bone turnover areas in subchondral bone. CTX-II localized to the bone-cartilage interface, the tidemark, and damaged articular cartilage. CONCLUSION: Baseline urinary α-CTX, which was localized to high turnover areas of subchondral bone, was associated with dynamic bone turnover of knees, as signified by scintigraphy, and progression of both osteophytes and JSN. Urinary CTX-II correlated with JSN and osteophyte severity and progression of osteophytes. To our knowledge, this represents the first report of serologic markers reflecting subchondral bone turnover. These collagen markers may be useful for noninvasive detection and quantification of active subchondral bone turnover and joint remodeling in knee OA.

Adipose depots, not disease-related factors, account for skeletal muscle insulin sensitivity in established and treated rheumatoid arthritis.

OBJECTIVE: In prior reports, individuals with rheumatoid arthritis (RA) exhibited increased insulin resistance. However, those studies were limited by either suboptimal assessment methods for insulin sensitivity or a failure to account for important determinants such as adiposity and lack of physical activity. Our objectives were to carefully assess, compare, and determine predictors of skeletal muscle insulin sensitivity in RA, accounting for adiposity and physical activity. METHODS: Thirty-nine individuals with established (seropositive or erosions) and treated RA and 39 controls matched for age, sex, race, body mass index, and physical activity underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity. Inflammation, body composition, and physical activity were assessed with systemic cytokine measurements, computed tomography scans, and accelerometry, respectively. Exclusions were diabetes, cardiovascular disease, medication changes within 3 months, and prednisone use over 5 mg/day. This investigation was powered to detect a clinically significant, moderate effect size for insulin sensitivity difference. RESULTS: Despite elevated systemic inflammation [interleukin (IL)-6, IL-18, tumor necrosis factor-α; p < 0.05 for all], persons with RA were not less insulin sensitive [SI geometric mean (SD): RA 4.0 (2.4) vs control 4.9 (2.1)*10(-5) min(-1)/(pmol/l); p = 0.39]. Except for visceral adiposity being slightly greater in controls (p = 0.03), there were no differences in body composition or physical activity. Lower insulin sensitivity was independently associated with increased abdominal and thigh adiposity, but not with cytokines, disease activity, duration, disability, or disease-modifying medication use. CONCLUSION: In established and treated RA, traditional risk factors, specifically excess adiposity, play more of a role in predicting skeletal muscle insulin sensitivity than do systemic inflammation or other disease-related factors.

Whole-body bone scintigraphy provides a measure of the total-body burden of osteoarthritis for the purpose of systemic biomarker validation.

OBJECTIVE: To evaluate the association of serum and synovial fluid cartilage oligomeric matrix protein (COMP) with systemic and local measures of osteoarthritis (OA) activity by bone scintigraphy. METHODS: Samples of serum and knee joint synovial fluid (275 knees) were obtained from 159 patients with symptomatic OA of at least 1 knee. Bone scintigraphy using (99m)Tc-labeled methylene diphosphonate was performed, and early-phase knee scans and late-phase whole-body bone scans of 15 additional joint sites were scored semiquantitatively. To control for within-subject correlations of knee data, generalized linear modeling was used in the correlation of the bone scan scores with the COMP levels. Principal components analysis was used to explore the contribution of each joint site to the variance in serum COMP levels. RESULTS: The correlation between synovial fluid and serum COMP levels was significant (r = 0.206, P = 0.006). Synovial fluid COMP levels correlated most strongly with the early-phase knee bone scan scores (P = 0.0003), even after adjustment for OA severity according to the late-phase bone scan scores (P = 0.015), as well as synovial fluid volumes (P < 0.0001). Serum COMP levels correlated with the total-body bone scan scores (r = 0.188, P = 0.018) and with a factor composed of the bone scan scores in the shoulders, spine, lateral knees, and sacroiliac joints (P = 0.0004). CONCLUSION: Synovial fluid COMP levels correlated strongly with 2 indicators of knee joint inflammation: early-phase bone scintigraphic findings and synovial fluid volume. Serum COMP levels correlated with total-body joint disease severity as determined by late-phase bone scintigraphy, supporting the hypothesis that whole-body bone scintigraphy is a means of quantifying the total-body burden of OA for systemic biomarker validation.

Dehydroascorbate transport in human chondrocytes is regulated by hypoxia and is a physiologically relevant source of ascorbic acid in the joint.

OBJECTIVE: To evaluate the dehydroascorbate (DHA) transport mechanisms in human chondrocytes. METHODS: The transport of L-(14)C-DHA in human chondrocytes was analyzed under various conditions, including the use of RNA interference (RNAi), to determine the role of glucose transporter 1 (GLUT-1) and GLUT-3 in L-14C-DHA transport and to evaluate the effects of physiologically relevant oxygen tensions on L-14C-DHA transport. In order to estimate the contributions of reduced ascorbic acid (AA) and DHA to intracellular ascorbic acid (Asc), the quantities of AA and DHA were measured in synovial fluid samples from osteoarthritis (OA) patients and compared with the reported levels in rheumatoid arthritis (RA) patients. RESULTS: DHA transport in human chondrocytes was glucose-sensitive, temperature-dependent, cytochalasin B-inhibitable, modestly stereoselective for L-DHA, and up-regulated by low oxygen tension. Based on the RNAi results, GLUT-1 mediated, at least in part, the uptake of DHA, whereas GLUT-3 had a minimal effect on DHA transport. DHA constituted a mean 8% of the total Asc in the synovial fluid of OA joints, in contrast to 80% of the reported total Asc in RA joints. CONCLUSION: We provide the first evidence that chondrocytes transport DHA via the GLUTs and that this transport mechanism is modestly selective for L-DHA. In the setting of up-regulated DHA transport at low oxygen tensions, DHA would contribute 26% of the total intracellular Asc in OA chondrocytes and 94% of that in RA chondrocytes. These results demonstrate that DHA is a physiologically relevant source of Asc for chondrocytes, particularly in the setting of an inflammatory arthritis, such as RA.

A comparative assessment of alignment angle of the knee by radiographic and physical examination methods.

OBJECTIVE: To compare the knee-alignment angle from a full-limb radiograph (mechanical axis) with the anatomic-axis angle as measured by physical examination using a goniometer and by 2 other radiographic methods. METHODS: The knee-alignment angle was measured in 114 knees of 57 subjects who had radiographic osteoarthritis (OA), with a Kellgren/Lawrence grade of >/=1 in at least one knee. The mechanical axis was defined as the angle formed by the intersection of 2 lines, one from the center of the head of the femur to the center of the tibial spines, and a second from the center of the talus to the center of the tibial spines. The anatomic axis was defined as the angle formed by 2 lines, each originating from a point bisecting the femur and tibia and converging at the center of the tibial spine tips. The anatomic-axis angle was measured by 3 methods: 1) physical examination using a goniometer, 2) a posteroanterior (PA) fixed-flexion knee radiograph (anatomic(PA) axis), and 3) an anteroposterior (AP) full-limb radiograph (anatomic(AP) axis). RESULTS: Significant correlations were found between the mechanical-axis angle and the anatomic-axis angle measured by each of the 3 methods: by goniometer (r = 0.70, P < 0.0001), by anatomic(PA) axis (r = 0.75, P < 0.0001), and by anatomic(AP) axis (r = 0.65, P < 0.0001). The anatomic axis was offset a mean 4.21 degrees valgus from the mechanical axis (3.5 degrees in women, 6.4 degrees in men), which was consistent across all methods. CONCLUSION: Knee alignment assessed clinically by goniometer or measured on a knee radiograph is correlated with the angle measured on the more cumbersome and costly full-limb radiograph. These alternative measures have the potential to provide useful information regarding the risk of progression of knee OA when a full-limb radiograph is not available.