Faculty Bibliography

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

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-1beta (IL-1beta) was increased >/=2-fold compared with controls, and those in whom the expression of IL-1beta was comparable with that in controls. Overexpression of IL-1beta in these OA subclasses was validated using qPCR in all 3 cohorts. Patients with the inflammatory 'IL-1beta 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-1beta identifies a subset of patients with OA who have increased pain and are at higher risk of radiographic progression of OA

OBJECTIVE: Rheumatoid arthritis (RA) patients who have never received treatment for RA have been found to have defective early B cell tolerance checkpoints, resulting in impaired removal of developing autoreactive B cells. However, it is unclear whether these defects in B cell tolerance checkpoints are a primary aspect of the disease or are the result of ongoing inflammatory processes in these patients. The aim of this study was to assess the impact of standard immunosuppressive treatments, methotrexate and anti-tumor necrosis factor alpha (anti-TNFalpha) agents, on early B cell tolerance checkpoints in RA patients. METHODS: Blood samples were obtained from RA patients before and after treatment with methotrexate and/or anti-TNFalpha agents. B cells were tested pre- and posttherapy for reactivity of recombinant antibodies cloned from single B cells, which allowed us to determine the evolution of the frequency of autoreactive clones in the mature naive B cell compartment in RA patients before and after treatment. B cells from healthy donors were used as controls. RESULTS: Posttreatment frequencies of autoreactive mature naive B cells were elevated in the blood of RA patients. Nevertheless, the frequencies after treatment remained similar to those observed in the same patients before treatment. CONCLUSION: Despite the achievement of clinical improvement in RA patients following treatment with methotrexate and/or anti-TNFalpha agents, these therapies did not correct the accumulation of peripheral autoreactive mature naive B cells in these patients, suggesting that inflammation is not responsible for the defective early B cell tolerance checkpoints in RA

OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1beta (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA

The use of musculoskeletal ultrasound (MSKUS) has increased in a variety of rheumatic conditions, particularly rheumatoid arthritis (RA). MSKUS complements the physical examination by allowing for superior visualization of synovitis and erosive changes compared to conventional radiography and provides detail comparable or supplementary to magnetic resonance imaging (MRI). This modality is also less expensive than MRI and CT scans, without claustrophobia or other contraindications, while uniquely providing dynamic, rather than static imaging. A growing body of literature for MSKUS in RA is contributing significantly to the understanding of diagnostic and prognostic utility, longitudinal assessment, and disease remission. Furthermore, scoring systems focusing on the patient level rather than individual joints have been developed, allowing for simplification of exams while still retaining accuracy and utility. The combination of these advances has led to increased use of MSKUS in RA in the realm of research as well as at the bedside and in the clinic