Structural Changes over a Short Period Are Associated with Functional Assessments in Rheumatoid Arthritis.

OBJECTIVE: To investigate the correlation between changes in radiological quantitative assessment with changes in clinical and functional assessment from baseline to 3 months in patients with rheumatoid arthritis (RA). METHODS: Twenty-eight patients with RA [methotrexate (MTX) and anti-tumor necrosis factor-α (TNF-α) group with high disease activity (n = 18); and MTX group with low disease activity (n = 10)] underwent assessments at baseline and 3 months: clinical [28-joint count Disease Activity Score (DAS28)], functional [Health Assessment Questionnaire (HAQ) and Michigan Hand Outcome Questionnaire (MHQ)], and imaging-based [3 Tesla magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT)]. MR images were evaluated semiquantitatively [RA MRI scoring (RAMRIS)] and quantitatively for the volume of synovitis and bone marrow edema (BME) lesions. Erosion volumes were measured using HR-pQCT. RESULTS: After 3 months, the anti-TNF-α group demonstrated an improvement in disease activity through DAS28, HAQ, and MHQ. MRI showed significant decreases in synovitis and BME volume for the anti-TNF-α group, and significant increases in the MTX group. HR-pQCT showed significant decreases in bone erosion volume for the anti-TNF-α group, and significant increases in the MTX group. No significance was observed using RAMRIS. Changes in synovitis, BME, and erosion volumes, but not RAMRIS, were significantly correlated with changes in DAS28, HAQ, and MHQ. CONCLUSION: Quantitative measures were more sensitive than semiquantitative grading when evaluating structural and inflammatory changes with treatment, and were associated with patient clinical and functional outcomes. Multimodality imaging with 3T MRI and HR-pQCT may provide promising biomarkers that help determine disease progression and therapy response.

Baseline knee joint effusion and medial femoral bone marrow edema, in addition to MRI-based T2 relaxation time and texture measurements of knee cartilage, can help predict incident total knee arthroplasty 4-7 years later: data from the Osteoarthritis Initiative.

OBJECTIVE: To evaluate if baseline pathological knee conditions as assessed via single features of the MR-based Whole-Organ Magnetic Resonance Imaging Scoring (WORMS), standard T2, and T2 gray-level co-occurrence matrix (GLCM) texture parameters of knee cartilage can serve as potential long-term radiological predictors of incident total knee arthroplasty (TKA) 4-7 years later. MATERIALS AND METHODS: Baseline 3-T knee MRIs of 309 subjects from the Osteoarthritis Initiative (n = 81 TKA cases, with right-knee TKA 4-7 years after enrolment, and n = 228 TKA-free matched controls) were evaluated for the presence and severity of pathological knee conditions via modified WORMS. Knee cartilage was segmented and standard T2 cartilage and T2 GLCM texture measures (contrast, variance) were computed. Statistical analysis employed conditional logistic regression. RESULTS: We found that a one-point increase on the joint effusion scale, the bone marrow edema scale or on the cartilage lesion scale at baseline predicted incident TKA (ORs: 2.45, 1.65, and 1.37 respectively (p ≤ 0.003)). For T2 cartilage measurements, we observed that in the lateral femur, a 1-SD increase in T2 relaxation time yielded a 28% increase in the odds of TKA (1.28 [1.09-1.643], p = 0.046). When looking at cartilage texture, we similarly noted that a 1-SD increase in the cartilage texture parameter "contrast" was associated with a 33-40% increased risk of incident TKA in the lateral femur and tibia (0.003 ≤ p ≤ 0.021), as was a 1-SD increase in the texture parameter "variance" in the lateral femur (p = 0.002). CONCLUSION: Radiological evaluation of standard knee MR images via single WORMS features and T2 standard and texture analysis at baseline can help predict the patient's individual risk for an incident TKA 4-7 years later.

Conservatively treated knee injury is associated with knee cartilage matrix degeneration measured with MRI-based T2 relaxation times: data from the osteoarthritis initiative.

OBJECTIVE: To investigate the association of cartilage degeneration with previous knee injuries not undergoing surgery, determined by morphologic and quantitative 3-T magnetic resonance imaging (MRI). MATERIALS AND METHODS: We performed a nested cross-sectional study of right knee MRIs from participants in the Osteoarthritis Initiative (OAI) aged 45-79 with baseline Kellgren-Lawrence score of 0-2. Cases were 142 right knees of patients with self-reported history of injury limiting the ability to walk for at least 2 days. Controls were 426 right knees without history of injury, frequency-matched to cases on age, BMI, gender, KL scores and race (1:3 ratio). Cases and controls were compared using covariate-adjusted linear regression analysis, with the outcomes of region-specific T2 mean, laminar analysis and heterogeneity measured by texture analysis to investigate early cartilage matrix abnormalities and the Whole-Organ Magnetic Resonance Imaging Score (WORMS) to investigate morphologic knee lesions. RESULTS: Compared to control subjects, we found significantly higher mean T2 values in the injury [lateral tibia (28.10 ms vs. 29.11 ms, p = 0.001), medial tibia (29.70 ms vs. 30.40 ms, p = 0.014) and global knee cartilage (32.73 ms vs. 33.29 ms, p = 0.005)]. Injury subjects also had more heterogeneous cartilage as measured by GLCM texture contrast, variance and entropy (p < 0.05 in 14 out of 18 texture parameters). WORMS gradings were not significantly different between the two groups (p > 0.05). CONCLUSION: A history of knee injury not treated surgically is associated with higher and more heterogeneous T2 values, but not with morphologic knee abnormalities. Our findings suggest that significant, conservatively treated knee injuries are associated with permanent cartilage matrix abnormalities.

Association of diabetes mellitus and biochemical knee cartilage composition assessed by T2 relaxation time measurements: Data from the osteoarthritis initiative.

PURPOSE: To investigate the association of the presence and severity of diabetes mellitus (DM) with articular cartilage composition, using magnetic resonance imaging (MRI)-based T2 relaxation time measurements, and structural knee abnormalities. MATERIALS AND METHODS: In the Osteoarthritis Initiative 208, participants with DM (age 63.0 ± 8.9 years; 111 females) and risk factors for osteoarthritis (OA) or mild radiographic tibiofemoral OA (Kellgren-Lawrence [KL] grade ≤2) were identified and group-matched with 208 controls without DM (age 63.3 ± 9.1 years; 111 females). Subjects with diabetes-related renal or ophthalmological complications or insulin treatment at baseline (n = 50) were defined as severe DM. 3T MR images of the right knee were assessed for articular cartilage T2 , including texture and laminar analyses derived from the patella, medial, and lateral femur and tibia and for structural abnormalities using the modified whole-organ magnetic resonance imaging score (WORMS). Clustered linear regression analyses were used to assess associations of DM with MRI findings. RESULTS: DM subjects had significantly higher cartilage T2 in the patella (mean difference 0.92 msec [95% confidence interval (CI) 0.79, 1.06]; P = 0.001) and medial femur (mean difference 0.36 msec [95% CI 0.27, 0.81]; P = 0.006) compared to controls. Averaged over all compartments, DM subjects showed significantly higher texture parameters (variance, P = 0.001; contrast, P = 0.002; entropy, P < 0.001). Subjects with severe DM additionally showed higher T2 in the medial tibial deep and superficial layers (P = 0.011 and P = 0.041) compared to controls. No significant differences in cartilage, meniscus, and overall WORMS were found between the groups (P > 0.05). CONCLUSION: In comparison to nondiabetic controls, cartilage in DM subjects showed higher and more heterogeneous cartilage T2 values, indicating increased articular cartilage degeneration. This affected even more compartments in subjects with severe DM. LEVEL OF EVIDENCE: 2 Technical Efficacy: 5 J. Magn. Reson. Imaging 2018;47:380-390.

Assessment of 3-month changes in bone microstructure under anti-TNFα therapy in patients with rheumatoid arthritis using high-resolution peripheral quantitative computed tomography (HR-pQCT).

BACKGROUND: Although one study showed minimal progression of erosions in patients with rheumatoid arthritis (RA) one year after TNFα inhibition therapy, no studies have investigated very early bone changes after initiation of anti-TNFα treatment. We investigated the effects of 3-month anti-TNFα treatment on bone erosion progression and bone microarchitecture in RA patients using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Patients with RA (n = 27) (17 in the anti-TNFα and 10 in the MTX-only group) underwent assessment of disease activity score in 28 joints (DAS-28), radiographs, 3-T magnetic resonance imaging (MRI) and HR-pQCT of metacarpophalangeal and wrist joints at baseline and 3 months. HR-pQCT-derived erosion volume, joint volume/width and bone microarchitecture were computed and joint destruction was assessed using Sharp and RAMRIS scorings on radiographs and MRI, respectively. RESULTS: Overall, 73 erosions were identified by HR-pQCT at baseline. Over 3 months, the anti-TNFα group had decreased mean erosion volume; increased erosion volume was observed in one clinical non-responder. The MTX-only group in contrast, trended toward increasing erosion volume despite low disease activity. In the anti-TNFα group, joint-space width and volume of MCP joints decreased significantly and was positively correlated with erosion volume changes (R 2 = 0.311, p = 0.013; R 2 = 0.527, p = 0.003, respectively). In addition, erosion volume changes were significantly negatively correlated with changes in trabecular bone mineral density (R 2 = 0.353, p = 0.020) in this group. We observed significant correlation between percentage change in erosion volume and change in DAS-28 erythrocyte sedimentation rate and C-reactive protein CRP scores (R 2 = 0.558, p < 0.001; R 2 = 0.745, p < 0.001, respectively) in all patients. CONCLUSIONS: Using HR-pQCT, our data suggest that anti-TNFα treatment prevents erosion progression and deterioration of bone microarchitecture within the first 3 months of treatment, one patient not responding to treatment, had significant progression of bone erosions within this short time period. Patients with low disease activity scores (<3.2) can have continuous HR-pQCT-detectable progression of erosive disease with MTX treatment only. HR-pQCT can be a sensitive, powerful tool to quantify bone changes and monitor RA treatment short term (such as 3 months).

Medial femur T2 Z-scores predict the probability of knee structural worsening over 4-8 years: Data from the osteoarthritis initiative.

OBJECTIVE: The purpose of this study was to determine the probability of structural worsening of knee cartilage and whole joint degeneration over 4-8 years based on cartilage T2 Z-scores at baseline. DESIGN: Right knees with Kellgren-Lawrence (KL) grades of 0-2 in 587 participants from the Osteoarthritis Initiative were studied. 3T MR images were used to perform baseline cartilage T2 quantification and assess 4-year changes in cartilage morphology (WORMS scoring) in 5 regions. Changes in joint space narrowing (JSN) and KL were assessed over 8 years. T2 Z-scores were based on a reference database of knees without morphologic cartilage degeneration at baseline. Odds ratios for, and predicted probabilities of any worsening in WORMS cartilage, JSN and KL grade were obtained from logistic regression models. RESULTS: A one-unit increase in the baseline medial femur T2 Z-score was associated with cartilage worsening in the same region (OR = 1.59; P < 0.0001) and in any region (OR = 1.37; P < 0.0001), and with worsening JSN (OR = 1.82; P < 0.0001) and KL grades (OR = 1.69; P < 0.0001). Predicted probabilities of worsening in knees with a medial femur T2 Z-score from 2-4 were 38% for medial femur cartilage WORMS, 70% for any cartilage region, 28% for increasing JSN and 31% for increasing KL grade. CONCLUSION: Knees with elevated cartilage T2 (especially in the medial femur and those that are 2 to 4 SDs above the mean reference values) are significantly more likely to have structural worsening over 4 to 8 years. Knowing cartilage T2 Z-scores may aid in targeting prevention efforts at early stages of osteoarthritis. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1128-1136.

Evaluation of Chondrocalcinosis and Associated Knee Joint Degeneration Using MR Imaging: Data from the Osteoarthritis Initiative.

OBJECTIVES: To evaluate the ability of different MRI sequences to detect chondrocalcinosis within knee cartilage and menisci, and to analyze the association with joint degeneration. METHODS: Subjects with radiographic knee chondrocalcinosis (n = 90, age 67.7 ± 7.3 years, 50 women) were selected from the Osteoarthritis Initiative and matched to controls without radiographic chondrocalcinosis (n = 90). Visualization of calcium-containing crystals (CaC) was compared between 3D T1-weighted gradient-echo (T1GE), 3D dual echo steady-state (DESS), 2D intermediate-weighted (IW), and proton density (PD)-weighted fast spin-echo (FSE) sequences obtained with 3T MRI and correlated with a semiquantitative CaC score obtained from radiographs. Structural abnormalities were assessed using Whole-Organ MRI Score (WORMS) and logistic regression models were used to compare cartilage compartments with and without CaC. RESULTS: Correlations between CaC counts of MRI sequences and degree of radiographic calcifications were highest for GE (rT1GE = 0.73, P < 0.001; rDESS = 0.68, P < 0.001) compared to other sequences (P > 0.05). Meniscus WORMS was significantly higher in subjects with chondrocalcinosis compared to controls (P = 0.005). Cartilage defects were significantly more frequent in compartments with CaC than without (patella: P = 0.006; lateral tibia: P < 0.001; lateral femur condyle: P = 0.017). CONCLUSIONS: Gradient-echo sequences were most useful for the detection of chondrocalcinosis and presence of CaC was associated with higher prevalence of cartilage and meniscal damage. KEY POINTS: • Magnetic resonance imaging is useful for assessing burden of calcium-containing crystals (CaC). • Gradient-echo sequences are superior to fast spin echo sequences for CaC imaging. • Presence of CaC is associated with meniscus and cartilage degradation.

Evaluating radiocarpal cartilage matrix changes 3-months after anti-TNF treatment for rheumatoid arthritis using MR T1ρ imaging.

PURPOSE: To evaluate the feasibility of MR T1ρ in assessing radiocarpal cartilage matrix changes following rheumatoid arthritis (RA) treatment. MATERIALS AND METHODS: Five healthy controls and nine RA patients were studied: three RA patients with low disease activity that were treated with methotrexate (MTX) alone and six with active disease despite MTX treatment who were additionally treated with certolizumab pegol, an anti-tumor necrosis factor biologic. Wrist 3 Tesla MRI were acquired at baseline and 3-month follow-up. T1ρ were quantified for lunar, radius, and scaphoid cartilage. Reproducibility was evaluated using coefficients of variation (CV). Longitudinal changes were evaluated with t-test and relationships between T1ρ with clinical, MRI, and patient-reported outcomes were evaluated with Spearman's rho. RESULTS: Scan/re-scan CVs of T1ρ values were all <5%, and intra- and inter-reader CVs were all < 2.0%. Baseline scaphoid T1ρ values were significantly higher in RA patients compared with healthy controls (P = 0.032). Changes in T1ρ (baseline, 3-month) were correlated with EULAR treatment response criteria: -2.26 ± 0.75 ms, 1.08 ± 0.52 ms, and 2.18 ± 0.45 ms for good, moderate, and nonresponders, respectively. Significant correlations were found between changes in global T1ρ values and changes in DAS28-CRP (rs = 0.683; P = 0.042), MHQ (rs = -0.783; P = 0.013), and HAQ (rs = 0.833; P = 0.010). CONCLUSION: Despite the limited sample size and follow-up time points, there were significant correlations between changes in radiocarpal T1ρ and changes in disease activity as assessed by clinical and patient-reported outcomes. Our findings encourage further research into MR T1ρ assessment of RA disease activity and treatment response. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;45:1514-1522.

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue-Derived Mesenchymal Stem Cells In Vitro.

Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n = 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR-550a-5p inhibited this process (p < 0.001). Both miRNAs, miR-382-3p and miR-550a-5p, impaired adipogenic differentiation, whereas miR-188-3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone. © 2016 American Society for Bone and Mineral Research.

High-temporospatial-resolution dynamic contrast-enhanced (DCE) wrist MRI with variable-density pseudo-random circular Cartesian undersampling (CIRCUS) acquisition: evaluation of perfusion in rheumatoid arthritis patients.

This study is to evaluate highly accelerated three-dimensional (3D) dynamic contrast-enhanced (DCE) wrist MRI for assessment of perfusion in rheumatoid arthritis (RA) patients. A pseudo-random variable-density undersampling strategy, circular Cartesian undersampling (CIRCUS), was combined with k-t SPARSE-SENSE reconstruction to achieve a highly accelerated 3D DCE wrist MRI. Two healthy volunteers and 10 RA patients were studied. Two patients were on methotrexate (MTX) only (Group I) and the other eight were treated with a combination therapy of MTX and anti-tumor necrosis factor (TNF) therapy (Group II). Patients were scanned at baseline and 3 month follow-up. DCE MR images were used to evaluate perfusion in synovitis and bone marrow edema pattern in the RA wrist joints. A series of perfusion parameters was derived and compared with clinical disease activity scores of 28 joints (DAS28). 3D DCE wrist MR images were obtained with a spatial resolution of 0.3 × 0.3 × 1.5 mm(3) and temporal resolution of 5 s (with an acceleration factor of 20). The derived perfusion parameters, most notably transition time (dT) of synovitis, showed significant negative correlations with DAS28-ESR (r = -0.80, p < 0.05) and DAS28-CRP (r = -0.87, p < 0.05) at baseline and also correlated significantly with treatment responses evaluated by clinical score changes between baseline and 3 month follow-up (with DAS28-ESR r = -0.79, p < 0.05, and DAS28-CRP r = -0.82, p < 0.05). Highly accelerated 3D DCE wrist MRI with improved temporospatial resolution has been achieved in RA patients and provides accurate assessment of neovascularization and perfusion in RA joints, showing promise as a potential tool for evaluating treatment responses.

Femoral condyle insufficiency fractures: associated clinical and morphological findings and impact on outcome.

OBJECTIVE: To determine the characteristics of femoral condyle insufficiency fracture (FCIF) lesions and their relative associations with the risk of clinical progression. MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by our Institutional Review Board. Seventy-three patients (age range, 19-95) were included after excluding patients with post-traumatic fractures, bone marrow infarct, osteochondritis dissecans, or underlying tumor. Two board-certified musculoskeletal radiologists classified morphologic findings including lesion diameter, associated bone marrow edema pattern, and associated cartilage/meniscus damage. Electronic medical charts were evaluated for symptoms, risk factors, and longitudinal outcomes, including total knee arthroplasty (TKA). Imaging characteristics were correlated with clinical findings, and comparison of outcome groups was performed using a regression model adjusted for age. RESULTS: The majority of patients with FCIF were women (64.4%, 47/73), on average 10 years older than men (66.28 ± 15.86 years vs. 56.54 ± 10.39 years, p = 0.005). The most common location for FCIF was the central weight-bearing surface of the medial femoral condyle; overlying full thickness cartilage loss (75.7%, 53/70) and ipsilateral meniscal injury (94.1%, 64/68) were frequently associated. Clinical outcomes were variable, with 23.9% (11/46) requiring TKA. Cartilage WORMS score, adjacent cartilage loss, and contralateral meniscal injury, in addition to decreased knee range of motion at presentation, were significantly associated with progression to TKA (p < 0.05). CONCLUSIONS: FCIF are frequently associated with overlying cartilage loss and ipsilateral meniscal injury. The extent of cartilage loss and meniscal damage, in addition to loss of knee range of motion at the time of presentation, are significantly associated with clinical progression.

MR imaging characteristics and clinical symptoms related to displaced meniscal flap tears.

OBJECTIVES: The purpose of our study was (1) to analyze the flap tear location, direction of displacement and size on magnetic resonance (MR) imaging, (2) to describe associated knee abnormalities including presence of effusion, synovitis, bone marrow edema pattern or ligamentous tear, and (3) to assess clinical findings found with flap tears, including the pain score, and determine differences between operative and nonoperative groups. MATERIALS AND METHODS: A retrospective radiology database search over the last 3 years identified 238 patients with flap tears, of which ultimately 58 with isolated flap tears were included after exclusion of patients with other significant knee internal derangement, severe degenerative change or prior surgery. MR studies of the knee were analyzed by two radiologists. Imaging characteristics were correlated with associated knee abnormalities and clinical findings. Statistical analysis employed linear and logistic regression models. Inter- and intrareader reliability was calculated. RESULTS: The medial meniscus was the most common site of flap tears (52/60, 87 %), with inferior displacement (47/60, 78 %). The degree of tibial cartilage loss had a positive correlation with the visual analog pain scale (p = 0.03). Patients who underwent arthroscopy were younger than those who did not (p = 0.01) and more likely to have a positive clinical McMurray test (p = 0.01). CONCLUSION: Medially and inferiorly displaced flap tears are the most common tear pattern. Those undergoing arthroscopy are more likely to have positive meniscal signs on clinical examination. A greater degree of cartilage loss involving the tibia on MR imaging was associated with increasing visual analog pain scores.

Induction of Raf kinase inhibitor protein contributes to macrophage differentiation.

Differential gene expression analysis of human blood monocytes has identified the Raf kinase inhibitor protein (RKIP) as a continuously upregulated gene in macrophage and dendritic cell maturation. Using realtime RT-PCR and Western blot analysis we were able to confirm the initial DNA-microarray findings of RKIP induction on mRNA and protein levels. RKIP upregulation in primary cells and overexpression in THP-1 cells did not alter ERK activity but strongly reduced the amount of the NFkappaB subunit p65 in the nucleus. mRNA levels and cell surface expression of maturation markers including the integrin CD11c and the scavenger receptor CD36 were significantly increased in RKIP transfected THP-1 cells. Our data show for the first time that RKIP is upregulated during macrophage and dendritic cell differentiation on mRNA and protein levels and we conclude that RKIP contributes to the monocytic differentiation process via inhibition of the NFkappaB signaling cascade independent from the canonical Ras/Raf/MEK/ERK pathway.