Faculty Bibliography

Background Estimates of global status by doctors (DOCGL) and patients (PATGL) are discordant in about 30-40% of patients with rheumatoid arthritis (RA).1,2 This discordance has been analyzed to date only in RA patients. Objectives To analyze levels of discordance between DOCGL and PATGL in all patients with any diagnosis seen in usual clinical care at a rheumatology setting. Methods Each patient seen at an academic rheumatology clinical setting since 2005 completes a self-report MDHAQ (multidimensional health assessment questionnaire) at each visit, with scales for physical function, pain, PATGL, fatigue, anxiety, depression and quality of sleep, and demographic data. DOCGL was completed by 2 rheumatologists. One random visit of patients seen between 2005 and 2011 was analyzed, patients were classified as PATGL=DOCGL (PATGL and DOCGL within 2 of 10 units), PATGL>DOCGL (PATGL >2 units than DOCGL), and DOCGL>PATGL (DOCGL >2 units than PATGL). Univariate odds ratios were computed to identify variables associated with discordance. Significant variables (p<0.05) were included in multivariate models, with selected variables when indicated. Results In a total of 980 patients studied, 509 (52%) had PATGL=DOCGL, 371 (38%) PATGL>DOCGL, and 100 (10%) DOCGL>PATGL. Patients with PATGL>DOCGL were more likely to be female, have less formal education and have higher MDHAQ scores (Table). In multivariate analysis, higher pain and fatigue scores were independent predictors of PATGL>DOCGL. If MDHAQ scores for pain and fatigue were not included in a second model, female gender, lower education and higher scores for depression and sleep problems were independent predictors of PATGL>DOCGL. In patients with DOCGL>PATGL, only lower fatigue was associated in multivariate analysis with lower odds of discordance (OR=0.88, 95% CI 0.79-0.98). Conclusions 38% of patients estimated their statusas worse than their physicians. These patients were more likely to score higher for pain and fatigue, be female and less educated tha!

PURPOSE OF REVIEW: Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. RECENT FINDINGS: The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. SUMMARY: Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs).

BACKGROUND: The purpose was to determine the relationship between the cartilage volumes in different regions of the femur and tibia, and the lengths of contacts between the meniscus and cartilage. The rationale was that less meniscal contact would make the cartilage more susceptible to loss of volume due to degeneration and wear. METHODS: Fifty MRI scans of osteoarthritic knees at varying degrees of severity were obtained. Computer models of the cartilage layers of the distal femur and proximal tibia were generated, from which cartilage volumes and thicknesses were calculated for different regions. The lengths of meniscal contact and heights were measured in frontal and sagittal views. RESULTS: Cartilage loss progressed initially on the central and inner regions of the distal femur, and on the tibia in the region uncovered by the meniscus. As the cartilage volume decreased further, the wear spread medially, and to a lesser extent anteriorly and posteriorly. There were inverse relations between the loss of volume on both the femur and tibia, and the meniscal contacts and heights. CONCLUSIONS: Cartilage loss initially occurred where there was direct contact between the cartilage of the femur and tibia. The meniscus did not prevent this, nor prevent the spread of the wear medially. This may have been due to the progressive reduction of cartilage-meniscal contact as the meniscus subluxed or lost substance, as the cartilage loss and deformity progressed. This suggested that the meniscus was not able to ameliorate the forces and pressures on the cartilage surfaces to prevent degeneration.

Chinese translation BACKGROUND: Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory cytokine in FMF. OBJECTIVE: To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF. DESIGN: Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907). SETTING: 6 U.S. sites. PATIENTS: Patients with FMF aged 4 years or older with 1 or more attacks per month. INTERVENTION: One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo. MEASUREMENTS: Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo. RESULTS: 8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept-placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, -1.74 [95% CI, -3.4 to -0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [-0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of -4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events. LIMITATION: Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations. CONCLUSION: Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF. PRIMARY FUNDING SOURCE: U.S. Food and Drug Administration, Office of Orphan Products Development.

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.