Faculty Bibliography

OBJECTIVE: The study aimed determining whether assessment of cartilage oligomeric matrix protein (COMP) degradation products could serve as a serological disease course and therapeutic response predictor in arthritis. METHODS: We generated a panel of monoclonal antibodies against COMP fragments and developed a novel capture enzyme-linked immunosorbent assay (ELISA) for detecting COMP fragments in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). This test was also used to monitor COMP fragments in surgically-induced OA, collagen-induced arthritis (CIA), and tumor necrosis factor (TNF) transgenic animal models. RESULTS: Compared with a commercial COMP ELISA kit that detected no significant difference in COMP levels between OA and control groups, a significant increase of the COMP fragments were noted in the serum of OA patients assayed by this newly established ELISA. In addition, serum COMP fragment levels were well correlated with severity in OA patients and the progression of surgically-induced OA in murine models. Furthermore, the serum levels of COMP fragments in RA patients, mice with CIA, and TNF transgenic mice were significantly higher when compared with their controls. Interestingly, treatment with TNFalpha inhibitors and methotrexate led to a significant decrease of serum COMP fragments in RA patients. Additionally, administration of Atsttrin [Tang, et al., Science 2011;332(6028):478] also resulted in a significant reduction in COMP fragments in arthritis mice models. CONCLUSION: A novel sandwich ELISA is capable of reproducibly measuring serum COMP fragments in both arthritic patients and rodent arthritis models. This test also provides a valuable means to utilize serum COMP fragments for monitoring the effects of interventions in arthritis.

OBJECTIVE: To evaluate the relationships between both quantitative and semiquantitative assessments of the degree of knee synovitis on 3T magnetic resonance imaging (MRI) and the severity of knee osteoarthritis (OA) on radiography. METHODS: Fifty-eight patients with knee OA underwent nonfluoroscopic fixed-flexion knee radiography. In addition, dynamic contrast-enhanced 3T MRI of the knees was performed, before and after gadolinium administration, to quantify synovial membrane volume (SV) as a measure of synovial proliferation (expressed as the quantitative SV), and semiquantitative measures of synovitis were also applied using both contrast-enhanced and unenhanced images. Two radiologists scored the knee radiographs using the Osteoarthritis Research Society International atlas; interreader agreement was assessed using kappa statistics and concordance correlation coefficients. Multiple linear and logistic regression analyses were used to assess associations among variables, while controlling for the effects of age, body mass index, sex, and meniscal extrusion. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for measures of disease activity. RESULTS: The Kellgren/Lawrence (K/L) grade of radiographic knee OA severity (beta = 0.78), the diseased compartment joint space width (dcJSW) (beta = -0.22), and the diseased compartment joint space narrowing (dcJSN) score (beta = 0.53) were each significantly associated with the quantitative SV (P = 0.0001, P = 0.0003, and P = 0.0001, respectively). Furthermore, the quantitative SV strongly correlated with the total volume of subchondral bone marrow lesions (BMLs) (beta = 0.22, P = 0.0003). The K/L grade, dcJSW, and dcJSN score were each significantly associated with the semiquantitative Boston Leeds Osteoarthritis Knee Score (BLOKS) for the extent of infrapatellar synovitis (OR 9.05 [95% CI 1.94, 42.3] for K/L grade; OR 0.75 [95% CI 0.54, 1.03] for dcJSW; and OR 2.22 [95% CI 1.15, 4.31] for dcJSN score) and extent of joint effusion (OR 5.75 [95% CI 1.23, 26.8] for K/L grade; OR 0.70 [95% CI 0.50, 0.98] for dcJSW; and OR 1.96 [95% CI 1.02, 3.74] for dcJSN score). In addition, the semiquantitative synovitis grade on contrast-enhanced MRI was significantly associated with the K/L grade (beta = 0.036, P = 0.0040) and dcJSN score (beta = 0.015, P = 0.0266), and also significantly associated with the BLOKS synovitis score. CONCLUSION: Synovitis is a characteristic feature of advancing knee OA and is significantly associated with the K/L grade, JSW, JSN score, and total volume of BMLs on radiographs. Furthermore, BLOKS scoring of synovitis on unenhanced MRI is associated with measurements of synovitis on contrast-enhanced MRI

OBJECTIVE: Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. METHODS: Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] >/=6.9 mg/dl), and controls (no gout, serum UA </=6.8 mg/dl), and reader concordance within these 3 groups was assessed. RESULTS: We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, kappa = 1.000), 2) total joints (n = 200, 99% agreement, kappa = 0.942), 3) FAC (n = 100, 99% agreement, kappa = 0.942), and 4) first MTP joints (n = 100, 99% agreement, kappa = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. CONCLUSION: Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia

BACKGROUND:The use of intraoperative carbon dioxide (CO(2)) colonoscopy during a laparoscopic colon operation is becoming more common. Simultaneous intracolonic and intraabdominal CO(2) insufflation may result in significant physiologic changes, but in-depth physiologic effects have not been studied to date. This study aimed to evaluate the physiologic changes and the overall safety of simultaneous CO(2) laparoscopy and colonoscopy. METHODS:A prospective pilot study was performed with 26 subjects (17 men and 9 women) undergoing laparoscopic surgical treatment for colorectal conditions adjunctively managed with CO(2) intraoperative colonoscopy. Surgery proceeded with CO(2) insufflation to a maximum pressure of 12 mmHg by laparoscopy and with a maximum CO(2) flow of 5 l/min via colonoscopy. Serial intra- and postoperative arterial blood gases, end-tidal CO(2), and minute ventilation were recorded during predetermined periods: during initial laparoscopy, during simultaneous colonoscopy and laparoscopy, during laparoscopy after colonoscopy, and after desufflation. RESULTS:No significant morbidity resulted from simultaneous CO(2) insufflation. Three patients had a CO(2) partial pressure (PaCO(2)) greater than 50, and one patient with a body mass index (BMI) higher than 42 kg/m(2) had a PaCO(2) greater than 50 for more than 30 min and was compensated by increasing minute ventilation. The mean pH was 7.36 in the recovery room. Postoperatively, no patient had a pH lower than 7.3, prolonged intubation, or reintubation. CONCLUSION/CONCLUSIONS:Simultaneous CO(2) colonoscopy and laparoscopy lead only to transient alterations in respiratory parameters that can be compensated. Based on these findings, simultaneous insufflation of CO(2) into the peritoneal cavity and the large bowel lumen during complex endoscopic procedures may be considered safe for most patients.

Background: There is no current treatment alternative for patients with FMF whose disease is resistant to, or do not tolerate colchicine. Since pyrin has an important role in IL-1beta regulation we hypothesize that IL-1 inhibition will decrease the number of FMF attacks in these patients. Aim: To determine if rilonacept, a fusion protein that binds and neutralizes IL-1, decreases the number of FMF attacks compared to placebo. Methods: Subjects were FMF patients >=4 years of age recruited at 6 U.S. sites, who had at least 1 FMF attack per month despite receiving adequate doses of, or who were intolerant of colchicine. Subjects received two 3-month courses of rilonacept (Arm A) at 2.2 mg/kg (max 160 mg) by weekly SC injection and two 3-month courses of placebo (Arm B). Patients were randomized to 1 of 4 treatment sequences (ABAB, BABA, ABBA, BAAB). Escape visits were allowed to permit switching arms (blinding was maintained) for patients with at least 2 attacks within a course. The primary outcome was the difference of FMF attacks between rilonacept and placebo courses with responders defined as subjects with a >40% difference. Results were analyzed by paired t-and signed rank tests. Results: Fourteen subjects were randomized, 8 males and 6 females, mean (+/-SD) age 24.4+/-11.8 years (range 4.5-47.3; 4 patients <18 years), disease duration 17.5+/-12.6 yrs, with a baseline of 3.1+/-2.0 attacks per month. Eleven completed the full study and 3 dropped out (1 due to lack of efficacy, 1 due to distance from study site and 1 lost to follow-up). Among 12 patients who completed at least 2 treatment courses the mean number of attacks per month on rilonacept was 1.0+/-1.2 vs. 1.8+/-0.9 on placebo (P=0.021 by paired t-test and 0.027 by signed rank test). There were 8 responders; all 4 non-responders were adults. There were 2 respiratory infection SAEs, 1 on rilonacept and 1 on placebo. Injections site reactions were significantly more frequent with rilonacept but no differences were seen in other adverse events, including infections. Conclusions: Rilonacept significantly reduced the number of FMF attacks and had an acceptable safety profile. IL-1 inhibition is a treatment option for most (especially children) colchicine resistant FMF patients