Clinical, patient-reported, radiographic and magnetic resonance imaging findings 11 years after acute posterior cruciate ligament injury treated non-surgically.

BACKGROUND: Long-term consequences of posterior cruciate ligament (PCL) injury such as persistent posterior tibial translation and risk of osteoarthritis development are unclear. Additionally, little data is available describing the natural history of structural morphology of the ruptured PCL. The purpose of the study was to determine the long-term outcome after non-operatively treated PCL injury. METHODS: Over 6-years, all acute knee injuries were documented by subacute MRI (median 8 days [5-15, 25th - 75th percentile] from injury to MRI). Twenty-six patients with acute PCL injury were identified of whom 18 (69%) participated in the long-term follow-up after 11 years. Follow-up included radiographic posterior tibial translation (RPTT) determined using the Puddu axial radiograph. weight-bearing knee radiographs, MRI and KOOS (Knee injury and Osteoarthritis Outcome Score). RESULTS: On subacute MRI, 11 knees displayed total and 7 partial ruptures. At 11 (SD 1.9) years, the median RPTT was 3.7 mm (1.5-6.3, 25th - 75th percentile). Seven knees displayed radiographic osteoarthritis approximating Kellgren-Lawrence grade ≥ 2. All follow-up MRIs displayed continuity of the PCL. Patients with more severe RPTT (> 3.7 mm), had worse scores in the KOOS subscales for symptoms (mean difference 14.5, 95% CI 7-22), sport/recreation (30, 95% CI 0-65) and quality of life (25, 95% CI 13-57) than those with less severe RPTT (≤ 3.7 mm). This was also the case for the KOOS4 (22, 95% CI 9-34). CONCLUSION: Acute PCL injuries treated non-surgically display a high degree of PCL continuity on MR images 11 years after injury. However, there is a large variation of posterior tibial translation with higher values being associated with poorer patient-reported outcomes.

Factors associated with hand bone changes in early rheumatoid arthritis.

BACKGROUND: The aim of this research was to assess if hand bone mineral density (HBMD) changes associated with the appearance of erosions in early rheumatoid arthritis (ERA), compared with the population-based control group. Additionally, we tried to identify if there are novel factors that associate with HBMD and erosive changes (EC), and if they are dissimilar. The study was conducted as the data are limited. METHODS: The study group consisted of 83 ERA patients and 321 controls. Dual-Energy X-Ray Absorptiometry (DXA) machine was used to measure HBMD. EC of RA (rheumatoid arthritis) were assessed in X-rays of hands using Sharp scores. Life-style habits, inflammation markers were assessed to evaluate the effects of different factors. RESULTS: The presence of ERA was associated with lower HBMD compared with controls (adjusted for age, gender, height and weight; b -0.01, p = 0.045). 76% (95% CI 65.3-84.6) of ERA patients had EC in hand X-ray. Smoking habits and higher BMI (body mass index) were associated with an increased likelihood of having RA specific EC. In ERA, decreasing of HBMD was associated with the elevation of interleukin-6 (IL-6) and rheumatoid factor (RF) positivity. CONCLUSIONS: In ERA, HBMD changes were not associated with the appearance of erosions. Factors that associate in ERA with HBMD changes and appearance of erosions differ. HBMD assessment together with serum IL-6 level could be useful in everyday clinical practice for better surveillance of ERA patients who do not have EC in hand X-rays.

Relationship Between Magnetic Resonance Imaging Features and Knee Pain Over Six Years in Knees Without Radiographic Osteoarthritis at Baseline.

OBJECTIVE: To explore whether magnetic resonance imaging (MRI) features suggestive of knee osteoarthritis (OA) are associated with presence of knee pain in possible early-stage OA development. METHODS: We included 294 participants from the Osteoarthritis Initiative (mean ± SD age 50 ± 3 years; 50% women) with baseline Kellgren/Lawrence grade of 0 in both knees, all of whom had received knee MRIs at 4 different time points over 6 years (baseline, 24, 48, and 72 months). Using a linear mixed model (knees matched within individuals), we studied whether MRI features (meniscal body extrusion [in mm], cartilage area loss [score 0-39], cartilage full thickness loss [range 0-16], osteophytes [range 0-29], meniscal integrity [range 0-10], bone marrow lesions [BMLs] including bone marrow cysts [range 0-20], Hoffa- or effusion-synovitis [absent/present], and popliteal cysts [absent/present]) were associated with knee-specific pain as reported on the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire using a 0-100 scale (worst to best). RESULTS: The differences in KOOS knee pain score for a knee with a 1 unit higher score on MRI were the following: meniscal extrusion -1.52 (95% confidence interval [95% CI] -2.35, -0.69); cartilage area loss -0.23 (95% CI -0.48, 0.02); cartilage full thickness loss -1.04 (95% CI -1.58, -0.50); osteophytes -0.32 (95% CI -0.61, -0.03); meniscal integrity -0.28 (95% CI -0.58, 0.02); BMLs including potential cysts -0.19 (95% CI -0.55, 0.16); synovitis 0.23 (95% CI -1.14, 1.60); and popliteal cysts 0.86 (95% CI -0.56, 2.29). CONCLUSION: Meniscal extrusion, full thickness cartilage loss, and osteophytes are associated with having more knee pain. Although these features may be relevant targets for future trials, the clinical relevance of our findings is unclear because no feature was associated with a clinically important difference in knee pain.

Arthroscopic partial meniscectomy for a degenerative meniscus tear: a 5 year follow-up of the placebo-surgery controlled FIDELITY (Finnish Degenerative Meniscus Lesion Study) trial.

OBJECTIVES: To assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up. DESIGN: Multicentre, randomised, participant- and outcome assessor-blinded, placebo-surgery controlled trial. SETTING: Orthopaedic departments in five public hospitals in Finland. PARTICIPANTS: 146 adults, mean age 52 years (range 35-65 years), with knee symptoms consistent with degenerative medial meniscus tear verified by MRI scan and arthroscopically, and no clinical signs of knee osteoarthritis were randomised. INTERVENTIONS: APM or placebo surgery (diagnostic knee arthroscopy). MAIN OUTCOME MEASURES: We used two indices of radiographic knee osteoarthritis (increase in Kellgren and Lawrence grade ≥1, and increase in Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing and osteophyte sum score, respectively), and three validated patient-relevant measures of knee symptoms and function (Western Ontario Meniscal Evaluation Tool (WOMET), Lysholm, and knee pain after exercise using a numerical rating scale). RESULTS: There was a consistent, slightly greater risk for progression of radiographic knee osteoarthritis in the APM group as compared with the placebo surgery group (adjusted absolute risk difference in increase in Kellgren-Lawrence grade ≥1 of 13%, 95% CI -2% to 28%; adjusted absolute mean difference in OARSI sum score 0.7, 95% CI 0.1 to 1.3). There were no relevant between-group differences in the three patient-reported outcomes: adjusted absolute mean differences (APM vs placebo surgery), -1.7 (95% CI -7.7 to 4.3) in WOMET, -2.1 (95% CI -6.8 to 2.6) in Lysholm knee score, and -0.04 (95% CI -0.81 to 0.72) in knee pain after exercise, respectively. The corresponding adjusted absolute risk difference in the presence of mechanical symptoms was 18% (95% CI 5% to 31%); there were more symptoms reported in the APM group. All other secondary outcomes comparisons were similar. CONCLUSIONS: APM was associated with a slightly increased risk of developing radiographic knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01052233 and NCT00549172).

Structural abnormalities detected by knee magnetic resonance imaging are common in middle-aged subjects with and without risk factors for osteoarthritis.

Background and purpose - Few data are available regarding structural changes present in knees without radiographically evident osteoarthritis (OA). We evaluated the prevalence of findings suggestive of knee OA by magnetic resonance imaging (MRI) in middle-aged subjects without radiographic OA with or without OA risk factors. Patients and methods - 340 subjects from the Osteoarthritis Initiative, aged 45-55 years (51% women) with Kellgren-Lawrence grade 0 in both knees, who had 3T knee MR images were eligible. 294 subjects had risk factors and 46 were without risk factors. MR images were assessed using the MOAKS scoring system. Results - At least 1 MR-detected feature was found in 96% (283/294) of subjects with risk factors and in 87% (40/46) of those without. Cartilage damage (82%), bone marrow lesions (60%), osteophytes (45%), meniscal body extrusion (32%), and synovitis-effusion (29%) were the most common findings in subjects with risk factors, while cartilage damage (67%), osteophytes (46%), meniscal body extrusion (37%), and bone marrow lesions (35%) were most common in subjects without. The prevalence of any abnormality was higher in subjects with OA risk factors than in subjects without (prevalence ratio adjusted for age and sex 1.3 [95% CI 1.1-1.6]), so was prevalence of subchondral cysts and bone marrow lesions. MR-detected structural changes were more frequent in patellofemoral joints. Interpretation - Our findings highlight the great challenge in distinguishing pathological features of early knee OA from what could be considered part of "normal ageing." Bone marrow lesions were more frequently found in subjects with multiple OA risk factors.

Natural History of Intrameniscal Signal Intensity on Knee MR Images: Six Years of Data from the Osteoarthritis Initiative.

PURPOSE: To assess the natural history of intrameniscal signal intensity on magnetic resonance (MR) images of the medial compartment. MATERIALS AND METHODS: Both knees of 269 participants (55% women, aged 45-55 years) in the Osteoarthritis Initiative without radiographic knee osteoarthritis (OA) and without medial meniscal tear at baseline were studied. One radiologist assessed 3-T MR images from baseline and 24-, 48-, and 72-month follow-up for intrameniscal signal intensity and tears. A complementary log-log model with random effect was used to evaluate the risk of medial meniscal tear, adjusting for age, sex, body mass index, and knee side. RESULTS: At baseline, linear intrameniscal signal intensity in the medial compartment was present in 140 knees (26%). Once present, regression only in a single knee was observed. In 31 knees (19%) with linear intrameniscal signal intensity at any of the first three time points, the signal intensity progressed to a tear in the same segment, and in a single knee, the tear occurred in an adjacent segment. The corresponding number of tears without prior finding of intrameniscal signal intensities was 11 (3%). In the adjusted model, the hazard ratio for developing medial meniscal tear was 18.2 (95% confidence interval: 8.3, 39.8) if linear intrameniscal signal intensity was present, compared when there was no linear signal intensity. There was only one of 43 knees with injury reported in conjunction with the incident tear. CONCLUSION: In middle-aged persons without OA, linear intrameniscal signal intensity on MR images is highly unlikely to resolve and should be considered a risk factor for medial degenerative meniscal tear.

The ADAM12 is upregulated in synovitis and postinflammatory fibrosis of the synovial membrane in patients with early radiographic osteoarthritis.

OBJECTIVE: To investigate the possible association between ADAM12 (disintegrin and metalloproteinase domain12) expression in the synovium and the histological synovitis of patients with radiographic knee osteoarthritis (rKOA). METHODS: The synovial biopsy samples were harvested from 44 subjects with chronic knee complaints during arthroscopy. In all subjects, the radiographs of both knee joints were performed for rKOA assessment. Histological features of synovitis were graded 0-3 in synovial samples. Messenger RNA (mRNA) of two ADAM12 splice variants [ADAM12-S(hort) and ADAM12-L(ong)] and the identical region for both-ADAM12-B(oth) were measured by real-time reverse transcription-PCR in all synovial samples (TaqMan® gene expression assay). Immunohistochemical staining of the synovial membrane with ADAM12 antibody was performed in 42 subjects. RESULTS: ADAM12 mRNA was expressed in all synovial samples, whereas the main part of overall expression consisted of its long isoform (ADAM12-L). ADAM12 protein expression was detected in 80% of the synovial samples and correlated with mRNA expression (ρ=0.30, P<0.05). The expression of ADAM12 mRNA and protein in synovium correlated with the severity of histological synovitis (ρ=0.28, P<0.05 for ADAM12-B mRNA, R2=0.20, P<0.05 for ADAM12 protein). Out of several features of synovitis the expression level of both splice variants correlated only with the grade of fibrosis in the synovium (ρ=0.30, P<0.05 for ADAM12-L and ρ=0.33, P<0.05 for ADAM12-S). CONCLUSIONS: ADAM12 is upregulated in the synovial tissue during synovitis on mRNA and protein level. We suggest that ADAM12 could be implicated in the development of KOA-associated synovitis, especially in the occurrence of postinflammatory fibrosis.

Two Single-Nucleotide Polymorphisms in ADAM12 Gene Are Associated with Early and Late Radiographic Knee Osteoarthritis in Estonian Population.

Objectives. To investigate associations of selected single-nucleotide polymorphisms (SNPs) in ADAM12 gene with radiographic knee osteoarthritis (rKOA) in Estonian population. Methods. The rs3740199, rs1871054, rs1278279, and rs1044122 SNPs in ADAM12 gene were genotyped in 438 subjects (303 women) from population-based cohort, aged 32 to 57 (mean 45.4). The rKOA features were evaluated in the tibiofemoral joint (TFJ) and patellofemoral joint. Results. The early rKOA was found in 51.4% of investigated subjects (72% women) and 12.3% of participants (63% women) had advanced stage of diseases. The A allele of synonymous SNP rs1044122 was associated with early rKOA in TFJ, predominantly with the presence of osteophytes in females (OR 1.57; 95% CI 1.08-2.29, P = 0.018). The C allele of intron polymorphism rs1871054 carried risk for advanced rKOA, mostly to osteophyte formation in TFJ in males (OR 3.03; 95% CI 1.11-7.53, P = 0.018). Also the CCAA haplotype of ADAM12 was associated with osteophytosis, again mostly in TFJ in males (P = 0.014). For rs3740199 and rs1278279, no statistically significant associations were observed. Conclusion. ADAM12 gene variants are related to rKOA risk during the early and late stages of diseases. The genetic risk seems to be predominantly associated with the appearance of osteophytes-a marker of bone remodelling and neochondrogenesis.

The value of cartilage biomarkers in progressive knee osteoarthritis: cross-sectional and 6-year follow-up study in middle-aged subjects.

To determine the possible diagnostic and prognostic value of cartilage biomarkers in early-stage progressive and nonprogressive knee osteoarthritis (OA) in a population-based cohort of middle-aged subjects with chronic knee pain. Design tibiofemoral (TF) and patellofemoral (PF) radiographs were graded in 128 subjects (mean age at baseline, 45 ± 6.2 years) in 2002, 2005, and 2008. Cartilage degradation was assessed by urinary C-telopeptide fragments of type II collagen (uCTx-II), synthesis by serum type II A procollagen N-terminal propeptide (sPIIANP), and articular tissue turnover in general by cartilage oligomeric matrix protein (sCOMP). Several diagnostic associations were found between all studied biomarkers and progressive osteophytosis. COMP and CTx-II had a predictive value for subsequent progressive osteophytosis in multiple knee compartments and in case of CTx-II-also for progressive JSN. Over the first 3 years (2002-2005), significant associations were observed between COMP and progressive osteophytosis, whereas 3 years later (2005-2008) between CTx-II and progressive JSN. Thus, the associations between cartilage markers (COMP, CTx-II) and progression of radiographic OA features--osteophytes and JSN--were different between 2002-2005 and 2005-2008. Logistic regression revealed that for every unit increase in COMP level, there was 33 % higher risk for TF osteophyte progression. During early-stage OA, the presence and progression of osteophytosis is accompanied by increased level of cartilage biomarkers. This is the first study to demonstrate biochemical differences over the course of knee OA, illustrating a phasic nonpersistent character of OA with periods of progression and stabilization.

The prevalence and progression of radiographic knee osteoarthritis over 6 years in a population-based cohort of middle-aged subjects.

Details of the development of early knee osteoarthritis (OA) are largely unknown. The prevalence and progression of radiographic knee OA over 6 years in middle-aged subjects with chronic knee pain is investigated. In a prospective population-based study, tibiofemoral (TF) and patellofemoral (PF) radiographs were graded in 128 subjects (mean age 45 ± 6.2 years) for the presence of osteophytes and joint space narrowing (JSN). Radiographic progression was defined as: (i) the presence of osteophytes and/or JSN in subjects with no previous OA or (ii) an increase in the grade and/or number of already existing osteophytes and/or JSN. Altogether 56% (72/128) of subjects had knee OA, the majority of them was diagnosed with OA grade 1. In 57% of cases, radiographic OA was based on the presence of osteophytes alone versus 13% on JSN. More than 1/3 of subjects had isolated PF joint involvement. Knee OA progression rate over 6 years was 56% (71/128). During 6 years, a non-linear course of radiographic OA progression with intermittent periods of progression and stabilization was observed. Individual course of OA revealed distinct subsets of radiographic progression. Osteophytosis is an important early radiographic sign of OA and its progression. Isolated PF joint involvement is a frequent expression of knee OA. In middle-aged subjects, the progression rate of knee OA over 6 years was 56%. A non-linear course of radiographic OA progression was observed. Several radiographic subsets refer to the heterogeneity of the OA process.

Impact of cryopreservation on serum concentration of matrix metalloproteinases (MMP)-7, TIMP-1, vascular growth factors (VEGF) and VEGF-R2 in Biobank samples.

BACKGROUND: Blood biomarkers are subject to pre-analytical variability. In many cases, the stability of important new tissue biomarkers during freeze cycles and storage has not been studied sufficiently. METHODS: To test the stability of matrix metalloproteinases-7 (MMP-7) and their tissue inhibitors (TIMP-1), vascular growth factors (VEGF) and VEGF-receptor, serum samples were frozen and then thawed up to six times. The impact of storage temperature was investigated using an accelerated stability testing protocol. Stability at -20°C and -75°C was calculated using the Arrhenius equation. RESULTS: The average concentration of TIMP-1 was stable, even after six freeze/thaw cycles. One thawing did not change the concentration of MMP-7 and VEGF-receptor. However, repeated freeze/thaw cycles increased the measured values significantly. Decreases in VEGF concentrations were dramatic, even after the first freeze/thaw cycle. According to the Arrhenius calculation, MMP-7 showed excellent stability, at least 5 years at -20°C and several 100 years at -75°C. The VEGF-receptor maintains 90% of its initial concentration at -20°C over 3 months, and decades at -75°C. TIMP-1 and VEGF showed poor stability with cryopreservation, even at -75°C. CONCLUSIONS: The stability of MMP-7, TIMP-1, VEGF or VEGF-receptor in biobanking is highly variable, and this should be taken into account in the interpretation of results. A temperature -20°C is unsuitable for prolonged storage of the biomarkers investigated, and repeated thawing of sera is not recommended. VEGF is especially unstable and should be quantitated using serum that has never been frozen.

Association between ultrasonographic findings and bone/cartilage biomarkers in patients with early-stage knee osteoarthritis.

Little is known regarding the association between ultrasonographic (US) findings and biomarkers of bone and cartilage in individuals with knee osteoarthritis (OA). We investigated (1) US findings in early-stage knee OA and (2) the association between US findings and bone/cartilage biomarkers. A population cohort aged 35-55 years (n = 106) with early-stage knee OA was investigated. US examination was performed according to European League against Rheumatism (EULAR) guidelines using a 7.5-MHz probe. Biomarkers of bone resorption (CTx-I) and formation (PINP), cartilage resorption (U-CTx-II) and synthesis (S-PIIANP), and general bone and cartilage biomarkers (OC, COMP) were assessed. The most prevalent US findings were tendon calcification, synovial thickening, and suprapatellar effusion. In women, the presence of tendon calcification and Baker's cysts could predict 36% of the variability in U-CTx-II levels. The presence of osteophytes and tendon calcification predicted up to 38% of the variability of PIIANP concentration. Defects in subchondral bone, meniscal changes, and effusion predicted up to 29% of the variability in COMP levels. Tendon calcification was related to cartilage synthesis (based on PIIANP levels) in men and to cartilage degradation (based on U-CTx-II concentrations) in women. US signs of synovitis were reflected metabolically by markers of joint tissue metabolism. Tendon calcification, synovial thickening, and effusion were common US findings in early-stage knee OA. US-detectable findings were substantially responsible for the variability in bone and cartilage biomarkers, associations reflective of the active metabolism of soft tissues in early-stage OA.

Urinary osteocalcin and other markers of bone metabolism: the effect of risedronate therapy.

OBJECTIVE: Serum osteocalcin (S-OC) is widely used as an index of bone formation. However, there is evidence that some urinary fragments of OC reflect resorption and might be useful in monitoring antiresorptive therapy. Here, we report 6-month changes in urinary midfragments of osteocalcin (U-MidOC) and other bone turnover markers in response to risedronate treatment. MATERIAL AND METHODS: The study group comprised 19 patients with postmenopausal osteoporosis, aged 49-66 years, and receiving risedronate therapy. Fifty-four premenopausal women served as controls. Osteoporosis was diagnosed by lumbal bone mineral density (BMD). Urinary osteocalcin was measured by the U-MidOC assay for midfragments. Bone formation was assessed by S-PINP and S-OC, and resorption by S-CTx-I. RESULTS: At baseline, U-MidOC was significantly correlated only with S-OC. After the 1st month of therapy, a similar decrease was observed in the values of U-MidOC and S-CTx-I, but in formation markers S-P1NP and S-OC only after three months. The rapid decrease in U-MidOC, analogous to S-CTX-I, and the different kinetics for urinary and serum OC suggest that urinary OC midfragments are more associated with resorption than S-OC. An association was also observed between the 1-month change in U-MidOC and 12-month gain in lumbar BMD. The response in U-MidOC after only the 1st month of therapy makes it a potential marker for monitoring the effect of risedronate, presumably reflecting different aspects of bone resorption than S-CTx-I does.