Faculty Bibliography

PURPOSE: To compare and assess subregional, compartmental, and whole T1rho values of menisci in patients with doubtful-minimal (Kellgren-Lawrence [KL] grade 1-2) as compared to moderate-severe (KL3-4) osteoarthritis (OA) and healthy controls at 3 Tesla (T). MATERIALS AND METHODS: Forty-six subjects were included in the study and subdivided into three subgroups: 16 healthy controls (4 females, 12 males; mean age = 34.4 +/- 10.2 years; age range, 24-63 years), 20 patients with doubtful-minimal (KL1-2) OA (9 females, 11 males; mean age = 61.9 +/- 10.8 years; age range, 40-80 years), and 10 patients with moderate-severe (KL3-4) OA (4 females, 6 males; mean age = 71.1 +/- 9.6 years; age range, 58-89 years). All subjects were evaluated on a 3T MR scanner using a spin-lock-based three-dimensional GRE sequence for T1rho mapping. Clinical proton density (PD)-weighted fast spin echoes (FSE) images in the sagittal (without fat saturation), axial, and coronal (fat-saturated) planes were acquired for cartilage Whole-Organ MR Imaging Score (WORMS) grading. Analysis of covariance was performed to determine whether there were any statistically significant differences between subregional, compartmental, and whole T1rho values of meniscus among healthy controls, OA patients with KL1-2 and with KL3-4. RESULTS: Lateral anterior (median +/- interquartile range: 26 +/- 3 ms) and medial posterior (29 +/- 6 ms) meniscus subregions in healthy controls had significantly lower T1rho values (P < 0.05) than the corresponding meniscus subregions in both KL1-2 (29 +/- 7 ms and 35 +/- 8 ms, respectively) and KL3-4 (30 +/- 12 ms and 40 +/- 13 ms, respectively) OA subjects. Significantly lower meniscus T1rho values (P < 0.05) were also identified in the medial compartment in healthy controls (28 +/- 5 ms) relative to both KL1-2 OA subjects and KL3-4 OA subjects (32 +/- 7 ms and 37 +/- 7 ms, respectively). The entire meniscus T1rho values in healthy controls (28 +/- 4 ms) were significantly lower than those of both KL1-2 and KL3-4 OA subjects (33 +/- 6 ms and 34 +/- 6 ms, respectively). CONCLUSION: Significant elevations of T1rho values in specific regions of menisci in both KL1-2 and KL3-4 OA patients indicate that T1rho mapping may be sensitive to meniscus degeneration. The preliminary results suggest that damage in the medial posterior subregion and medial compartment of menisci may possibly be associated with osteoarthritis. J. Magn. Reson. Imaging 2013. (c) 2013 Wiley Periodicals, Inc.

PURPOSE OF REVIEW: Since the early 1900s, the role of periodontal disease in the pathogenesis of rheumatoid arthritis has been a matter of intense research. The last decade has witnessed many advances supporting a link between periodontitis, the presence of specific bacterial species (i.e. Porphyromonas gingivalis) and their effects in immune response. This review will examine available evidence on the individuals. RECENT FINDINGS: Epidemiological studies have stressed the commonalities shared by periodontal disease and rheumatoid arthritis. Many groups have focused their attention toward understanding the periodontal microbiota and its alterations in states of health and disease. The presence of circulating antibodies against periodontopathic bacteria and associated inflammatory response has been found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. Most recently, the periodontal microbiota of smokers and patients with RA has been elucidated, revealing profound changes in the bacterial communities compared with those of healthy controls. This has led to several small clinical trials of progressive disease treatment as adjuvant for disease-modifying therapy in RA. SUMMARY: Smoking and periodontal disease are emerging risk factors for the development of RA. Epidemiological, clinical, and basic research has further strengthened this association, pointing toward changes in the oral microbiota as possible contributors to systemic inflammation and arthritis.

OBJECTIVES: To investigate the value of diffusion tensor imaging (DTI) of articular cartilage to differentiate healthy from osteoarthritis (OA) subjects in all cartilage regions. METHODS: DTI was acquired sagittally at 7 T in ten healthy and five OA (Kellgren-Lawrence grade 2) subjects with a line scan diffusion tensor sequence (LSDTI). Three healthy volunteers and two OA subjects were examined twice to assess the test-retest reproducibility. Averaged mean diffusivity (MD) and fractional anisotropy (FA) were calculated in each cartilage region (femoral trochlea, lateral and medial femoral condyles, patella, and lateral and medial tibia). RESULTS: The test-retest reproducibility was 2.9 % for MD and 5.6 % for FA. Averaged MD was significantly increased (+20 %, p < 0.05) in the OA subjects in the lateral femoral condyle, lateral tibia and the femoral trochlea compartments. Averaged FA presented a trend of lower values in the OA subjects (-12 %), which was only significant for the lateral tibia. CONCLUSIONS: In vivo DTI of articular cartilage with coverage of all cartilage regions using an LSDTI sequence is feasible, shows excellent reproducibility for MD and FA, and holds potential for the diagnosis of OA. KEY POINTS: * DTI of articular cartilage is feasible at 7 T in all cartilage regions * DTI of articular cartilage can potentially differentiate healthy and OA subjects.

Targeting pro-inflammatory cytokines is a promising approach to the treatment of certain autoimmune diseases. However, the signaling mechanisms involved in the initiation and effector phases of auto-aggressive pathways are still an enigma. Rho-associated kinase 2 (ROCK2) regulates the secretion of inflammatory cytokines interleukin (IL)-21 and IL-17 and the development of autoimmunity in mice. Our data from a phase 1 clinical trial demonstrates that oral administration of KD025, a selective ROCK2 inhibitor, to healthy human subjects significantly down-regulates the ability of T cells to secrete IL-21 and IL-17, but not interferon (IFN)-g in response to TCR stimulation in vitro. Pharmacological inhibition with KD025 or siRNA-mediated inhibition of ROCK2, but not ROCK1, leads to down-regulation of STAT3 phosphorylation, interferon regulatory factor 4 (IRF4) and steroid receptor-type nuclear receptor RORgt protein levels in T cells derived from healthy subjects or rheumatoid arthritis (RA) patients. Simultaneously, ROCK2 inhibition induces phosphorylation of STAT5 and SMAD2/3, and subsequently increases the percentage of Foxp3+ T cells. Thus, ROCK2 signaling appears to be instrumental in regulating the balance between pro-inflammatory and regulatory T cell subsets in man. Targeted inhibition of ROCK2 may therefore have a role in the treatment of autoimmune disease with disturbed immune homeostasis

Osteoarthritis (OA) is the most common form of arthritic disease, and a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, affecting bone, cartilage and synovium that thereby presents multiple targets for treatment. This manuscript will summarise emerging observations from cell biology, preclinical and preliminary clinical trials that elucidate interactions between the bone and cartilage components in particular. Bone and cartilage health are tightly associated. Ample evidence has been found for bone changes during progression of OA including, but not limited to, increased turnover in the subchondral bone, undermineralisation of the trabecular structure, osteophyte formation, bone marrow lesions and sclerosis of the subchondral plate. Meanwhile, a range of investigations has shown positive effects on cartilage health when bone resorption is suppressed, or deterioration of the cartilage when resorption is increased. Known bone therapies, namely oestrogens, selective oestrogen receptor modifiers (SERMs), bisphosphonates, strontium ranelate, calcitonin and parathyroid hormone, might prove useful for treating two critical tissue components of the OA joint, the bone and the cartilage. An optimal treatment for OA likely targets at least these two tissue components. The patient subgroups for whom these therapies are most appropriate have yet to be fully defined but would likely include, at a minimum, those with high bone turnover.

OBJECTIVE: To establish whether there is an association between TSG-6 activity and osteoarthritis progression. DESIGN: TSG-6 activity was determined in 132 synovial fluids from patients with OA of the knee, using a novel quantitative TSG-6 activity assay. The association between TSG-6 activities at baseline and four distinct disease progression states, determined at 3-year follow-up, was analyzed using logistic regression. RESULTS: There was a statistically significant relationship between TSG-6 activity at baseline and all OA progression states over a 3-year period. Patient knees with TSG-6 activities in the top tenth percentile, compared to the median activity, had an odds ratio (OR) of at least 7.86 (confidence interval (CI) [3.2, 20.5]) for total knee arthroplasty (TKA) within 3 years, and of at least 5.20 (CI [1.8, 13.9]) after adjustment for confounding factors. Receiver operating characteristic (ROC) analysis for knee arthroplasty yielded a cut-off point of 13.3 TSG-6 activity units/ml with the following parameters: area under the curve 0.90 (CI [0.804, 0.996]), sensitivity 0.91 (CI [0.59, 0.99]), specificity 0.82 (CI [0.74, 0.88]) and a negative predictive value (NPV) of 0.99 (CI [0.934, 0.994]). CONCLUSION: The TSG-6 activity is a promising independent biomarker for OA progression. Given the high NPV, this assay may be particularly suitable for identifying patients at low risk of rapid disease progression and to assist in the timing of arthroplasty.

BACKGROUND: Age, gender and genetic predisposition are major intrinsic risk factors for osteoarthritis (OA). Iron increases are associated with age and gene mutation. In the present study, we examined whether serum ferritin, an indicator of total body iron stores, correlates with clinical features in patients with OA, and whether the hemochromatosis Fe (HFE) gene mutation plays a role. METHODS: In a 2-year longitudinal observational study, 127 patients with knee OA and 20 healthy individuals (controls) were enrolled. All patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiographs. Peripheral blood samples were analyzed for serum ferritin, and genotyped for HFE using allelic discrimination methods. RESULTS: Higher levels of serum ferritin were found in patients older than 56 years (P =0.0186) and males (P =0.0006), with a trend toward higher ferritin in patients with OA. HFE gene mutation carriers were more prevalent among patients with OA than among healthy controls. When stratified further by gender, we found that male patients with OA had higher levels of serum ferritin than male control subjects [odds ratio = 4.18 (limits of 95% confidence interval: 0.86-27.69, P = 0.048)]. Analyses of radiographic data indicated that higher ferritin was associated with narrower joint space width at baseline (P = 0.032) in male patients. Additionally, among men, risk prediction of radiographic severity [Kellgren-Lawrence (KL) grade >2)] in the higher ferritin group was almost five times that of the lower ferritin group (odds ratio = 4.74, P = 0.023). CONCLUSION: Our data suggest that increased ferritin levels are associated with symptomatic knee OA in males. This finding needs to be validated in a larger cohort of patients.

PURPOSE OF REVIEW: Despite the progress toward understanding the molecular pathogenesis of rheumatoid arthritis (RA), its cause remains elusive. Genes are important but rather insufficient to explain the majority of RA cases. This review describes the novel data supporting the microbiome and its interactions with the human host as potential en('in')vironmental factors in RA pathogenesis. RECENT FINDINGS: Animal models of inflammatory arthritis have shown that the presence of bacteria in mucosal surfaces is sufficient to alter local and systemic host immune responses and elicit joint inflammation. Human RA studies have focused on three mucosal sites: the gut, the gingiva, and the respiratory tree. The oral microbiome, and specifically Porphyromonas gingivalis, has long been implicated. Novel sequencing technologies have allowed investigations into the role of the gut microbiome in the development of autoimmune arthritis. Most recently, the pulmonary parenchyma has also been described as yet another possible mucosal site of initiation of autoimmunity in RA. SUMMARY: Emerging data implicate the microbiome in RA pathogenesis. Mucosal sites exposed to a high load of bacterial antigens - such as the periodontium, lung, and gut - may represent the initial site of autoimmune generation. If validated, these findings could lead to the discovery of potential biomarkers and therapeutic approaches in the preclinical and clinical phases of RA.