Radiographic progression of knee osteoarthritis is associated with MRI abnormalities in both the patellofemoral and tibiofemoral joint.

OBJECTIVE: To investigate patterns of MRI abnormalities in the patellofemoral (PFJ) and tibiofemoral joint (TFJ) and their association with radiographic progression, using hypothesis free analyses. DESIGN: 205 patients from the GARP study with symptomatic OA at multiple sites (mean age 60 years, 80% woman, median BMI 26 kg/m(2)), underwent knee MRI at baseline. Cartilage damage, osteophytes, cysts, bone marrow lesions (BMLs) and effusion/synovitis were scored according to a validated scoring method. Baseline and 6-year TFJ and PFJ radiographs were scored (0-3) for JSN and osteophytes according to OARSI and Burnett atlases, respectively; progression was defined as ≥1 point increase. Baseline patterns of MRI abnormalities derived from principal component analysis (PCA) were associated with progression using adjusted generalized estimating equations (GEE). RESULTS: PCA resulted in extraction of six components, explaining 69% of variance. In 29% and 29% of 133 patients with follow-up the TFJ progressed, whereas in 15% and 9% the PFJ progressed for osteophytes and JSN, respectively. Component 1 (cartilage damage of the PFJ and osteophytes of both joints) was statistically significant associated with TFJ JSN progression and PFJ osteophyte progression. Component 2 (all lateral PFJ abnormalities except osteophytes) was associated with JSN/osteophyte progression in the PFJ alone, whereas component 3 (all medial TFJ abnormalities except osteophytes) was associated with JSN and osteophyte progression in both PFJ and TFJ. CONCLUSION: Baseline structural damage and bone turnover activity, as reflected by BMLs, seem to be involved in knee OA progression. Moreover, progression in PFJ and TFJ seems to be related.

Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women.

BACKGROUND: Several studies suggest a role of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. OBJECTIVE: To study associations between the d3-GHR polymorphism and symptomatic OA. METHODS: In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r(2)=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed. RESULTS: In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity. CONCLUSIONS: In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site.

Association study of candidate genes for the progression of hand osteoarthritis.

OBJECTIVE: Although a few consistent osteoarthritis (OA) susceptibility genes have been identified, little is known on OA progression. Since OA progression is clinically the most relevant phenotype, we investigate the association between asporin (ASPN), bone morphogenetic protein 5 (BMP5) and growth differentiation factor 5 (GDF5) polymorphisms and progression of hand OA. METHODS: Single-nucleotide polymorphisms (SNPs) ASPN rs13301537, BMP5 rs373444 and GDF5 rs143383 were genotyped in 251 hand OA patients from the Genetics osteoARthritis and Progression (GARP) study and 725 controls. In a case-control comparison we assessed the association between these SNPs and radiographic progression of hand OA over 6 years, which was based on change in osteophytes or joint space narrowing (JSN), above the smallest detectable change. SNPs with suggestive evidence for association were further analysed for their effect on progression over 2 years, and for the mean change in osteophytes and JSN. RESULTS: The minor allele of ASPN SNP rs13301537 was associated with hand OA progression over 6 years (odds ratio (OR) (95% CI) 1.49 (1.06-2.07); P = 0.020). The mean change in osteophytes and JSN was higher in carriers of the minor allele compared to homozygous carriers of the common allele with mean difference of 0.73 (95% CI - 0.07-1.56; P = 0.073) and 0.82 (95% CI 0.12-1.52; P = 0.022), respectively. An association with similar effect size was found between ASPN SNP rs13301537 and 2-year progression, and the mean change in osteophytes and JSN was significantly higher in homozygotes. CONCLUSION: ASPN is associated with hand OA progression. This gives insight in the pathogenesis of hand OA progression and identified a potential target for therapeutic approaches.

Validity of joint space width measurements in hand osteoarthritis.

OBJECTIVE: To investigate the validity of joint space width (JSW) measurements in millimeters (mm) in hand osteoarthritis (OA) patients by comparison to controls, grading of joint space narrowing (JSN), and clinical features. METHODS: Hand radiographs of 235 hand OA patients (mean age 65 years, 83% women) and 471 controls were used. JSW was measured with semi-automated image analysis software in the distal, proximal interphalangeal and metacarpal joints (DIPJs, PIPJs and MCPJs). JSN (grade 0-3) was assessed using the osteoarthritis research society international (OARSI) atlas. Associations between the two methods and clinical determinants (presence of pain, nodes and/or erosions, decreased mobility) were assessed using Generalized Estimating Equations with adjustments for age, sex, body mass index (BMI) and mean width of proximal phalanx. RESULTS: JSW was measured in 5631 joints with a mean JSW of 0.98 mm (standard deviation (SD) 0.21), being the smallest for DIPJs (0.70 (SD 0.25)) and largest for MCPJs (1.40 (SD 0.25)). The JSN=0 group had a mean JSW of 1.28 mm (SD 0.34), the JSN=3 group 0.17 mm (SD 0.23). Controls had larger JSW than hand OA patients (P-value<0.001). In hand OA, females had smaller JSW than men (ß -0.08, (95% confidence interval (95% CI) -0.15 to -0.01)) and lower JSW was associated with the presence of pain, nodes, erosions and decreased mobility (adjusted ß -0.21 (95% CI -0.27, -0.16), -0.37 (-0.40, -0.34), -0.61 (-0.68, -0.54) and -0.46 (-0.68, -0.24) respectively). These associations were similar for JSN in grades. CONCLUSION: In hand OA the quantitative JSW measurement is a valid method to measure joint space and shows a good relation with clinical features.

Body mass index and alignment and their interaction as risk factors for progression of knees with radiographic signs of osteoarthritis.

OBJECTIVE: To investigate in which way body mass index (BMI) and alignment affect the risk for knee osteoarthritis (OA) progression. METHODS: Radiographs of 181 knees from 155 patients (85% female, mean age 60 years) with radiographic signs of OA were analyzed at baseline and after 6 years. Progression was defined as 1-point increase in joint space narrowing score in the medial or lateral tibiofemoral (TF) compartment or having knee prosthesis during the follow-up for knees with a Kellgren and Lawrence score ≥ 1 at baseline. BMI at baseline was classified as normal (<25 kg/m(2)), overweight (25-30) and obese (>30). Knee alignment on baseline radiographs was categorized as normal (TF angle between 182° and 184°) and malalignment (<182° or >184°). We estimated the risk ratio (RR) with 95% confidence interval for knee OA progression for overweight and obese patients and for malaligned knees relative to normal using generalized estimating equations (GEE). Additionally, we estimated the added effect when BMI and malalignment were present together on progression of knee OA. Adjustments were made for age and sex. RESULTS: Seventy-six knees (42%) showed progression: 27 in lateral and 66 in medial compartment. Knees from overweight and obese patients had an increased risk for progression (RR 2.4 (1.-3.6) and 2.9 (1.7-4.1), respectively). RRs of progression for malaligned, varus and valgus knee were 2.0 (1.3-2.8), 2.3 (1.4-3.1), and 1.7 (0.97-2.6), respectively. When BMI and malalignment were included in one model, the effect of overweight, obesity and malalignment did not change. The added effect when overweight and malalignment were present was 17%. CONCLUSION: Overweight is associated with progression of knee OA and shows a small interaction with alignment. Losing weight might be helpful in preventing the progression of knee OA.

Accelerated metacarpal bone mineral density loss is associated with radiographic progressive hand osteoarthritis.

OBJECTIVE: To study the association between metacarpal bone mineral density (BMD) loss and progressive hand osteoarthritis (OA) over 2 years. METHODS: Using the Kellgren-Lawrence (KL) grading scale and the Osteoarthritis Research Society International Atlas, standardised hand radiographs of 181 patients with primary OA at multiple sites (mean age 60 years, 80% women, mean body mass index 27 kg/m(2)) were assessed for hand OA at baseline (KL ≥ 2 in two or more hand joints) and progressive hand OA over 2 years (≥ 1 point increase in total osteophyte and joint space narrowing score in patients with hand OA at baseline). Changes in BMD were measured over 2 years in metacarpals 2-4 by digital x-ray radiogrammetry. Accelerated BMD loss was defined as loss of >3 mg/cm(2)/year. Logistic regression analyses were performed to assess the associations between BMD loss and progressive hand OA. RESULTS: The baseline prevalence of hand OA was 68% and, after 2 years, 32% of these patients had progressive hand OA. Accelerated BMD loss was present in 79% of the patients with progressive hand OA compared with 60% and 57% of the patients with non-progressive hand OA and no hand OA, respectively. BMD loss was independently associated with progressive hand OA compared with non-progressive hand OA with a RR (95% CI) of 2.1 (1.1 to 4.3). CONCLUSION: Accelerated metacarpal BMD loss is associated with progressive hand OA over a period of 2 years; knowledge of common mechanisms may lead to development of therapeutic interventions for hand OA.

Reliability, sensitivity to change and feasibility of three radiographic scoring methods for hand osteoarthritis.

OBJECTIVE: To compare the reliability, sensitivity to change and feasibility of three radiographic scoring methods for hand osteoarthritis (OA). METHODS: Baseline, 2-year and 6-year hand radiographs of 90 patients with hand OA were read in triplicate in chronological order by three readers from different European centres using the OARSI atlas (OARSI), Kellgren--Lawrence grading scale (KL) and Verbruggen--Veys anatomical phase score (VV). Reliability was determined using intraclass correlation coefficients and smallest detectable change (SDC). Sensitivity to change was assessed by the proportion of progression above the SDC. Feasibility was reflected by the mean performance time. RESULTS: Intra- and inter-reader reliability was similar across methods. Inter-reader SDCs (% maximum score) for KL, OARSI and VV were 2.9 (3.2), 4.1 (2.9) and 2.7 (1.8) over 2 years and 3.8 (4.1), 4.6 (3.3) and 4.0 (2.5) over 6 years, respectively. KL detected a slightly higher proportion of progression. There were differences between readers, despite methods to enhance consistency. The mean performance time (SD, minutes) for KL, OARSI and VV was 4.3 (2.5), 9.3 (6.0) and 2.8 (1.5), respectively. CONCLUSION: Methods had comparable reliability and sensitivity to change. Global methods were fastest to perform. For multicentre trials use of a central reading centre and multiple readers may minimise inter-reader variation.

Clinical and radiographic disease course of hand osteoarthritis and determinants of outcome after 6 years.

OBJECTIVE: To investigate the long-term clinical and radiographic disease course of hand osteoarthritis (OA) and determinants of outcome. METHODS: Clinical and radiographic measures were obtained at baseline and after 6 years in 289 patients with hand OA (mean age 59.5 years, 83.0% women). Clinical outcomes were self-reported pain and functional limitations assessed with the Australian/Canadian Osteoarthritis Hand Index (AUSCAN). Poor clinical outcome was defined as a follow-up score not fulfilling the Patient Acceptable Symptom State. Radiographic outcome was assessed by osteophytes and joint space narrowing (JSN) on standardised hand radiographs using the Osteoarthritis Research Society International (OARSI) atlas. Radiographic progression was defined as a change in osteophytes or JSN, above the smallest detectable change. Change in outcome measures was calculated and baseline determinants for poor clinical outcome and radiographic progression were assessed using logistic regression analysis. RESULTS: Clinical change showed great variation, with half of the population reporting deterioration. Poor outcome in pain was related to high levels of functional limitations and a high number of painful joints at baseline. Poor outcome on functional limitations was related to high baseline pain levels. Radiographic progression was present in 52.5% of patients and associated with high baseline levels of pain, nodes, osteophytes and the presence of erosive OA and nodal OA. Clinical change and radiographic progression were not related. CONCLUSIONS: This study gives insight in the clinical and radiographic course of hand OA as well as determinants of outcome. These findings enable better patient information on prognosis. The relationship between clinical and radiographic outcome needs further investigation.

Arthropathy in long-term cured acromegaly is characterised by osteophytes without joint space narrowing: a comparison with generalised osteoarthritis.

OBJECTIVE: To compare the distribution of osteophytes and joint space narrowing (JSN) between patients with acromegaly and primary generalised osteoarthritis to gain insight into the pathophysiological process of growth hormone (GH) and insulin-like growth factor type I (IGF-I)-mediated osteoarthritis. METHODS: We utilised radiographs of the knee and hip joints of 84 patients with controlled acromegaly for a mean of 14.0 years with 189 patients with primary generalised osteoarthritis. Hips and knees with with doubtful or definite osteoarthritis (Kellgren-Lawrence score of ≥ 1) were compared in the current study. For a semiquantitative assessment of radiological osteoarthritis (range 0-3) osteophytes and JSN of the medial and lateral tibiofemoral and hip joints were scored according to the Osteoarthritis Research Society International atlas. Logistic regression analysis was performed with adjustment for age, sex, body mass index and intrapatient effect. RESULTS: Knee and hip osteoarthritis in patients with cured acromegaly was characterised by more osteophytosis (OR 4.1-9.9), but less JSN (OR 0.3-0.5) in comparison with patients with primary osteoarthritis. Patients with acromegaly and osteoarthritis had significantly less self-reported functional disability than patients with primary osteoarthritis (p < 0.001). Self reported functional disability was associated with JSN rather than with osteophytosis. CONCLUSION: Arthropathy caused by GH oversecretion results in osteophytosis and to a lesser extent in JSN. This observation suggests that the GH-IGF-I system is mainly involved in bone formation resulting in osteophytosis, but may possibly protect against cartilage loss.

Systemic and local factors are involved in the evolution of erosions in hand osteoarthritis.

OBJECTIVE: In order to gain insight in the pathogenesis of erosive hand osteoarthritis (OA), the evolution of erosions in hand OA and risk factors involved were investigated. METHODS: The 6-year evolution in radiographic Verbruggen-Veys anatomical phase was assessed in interphalangeal joints of 236 patients with hand OA (mean age 59 years, 83% women) from the GARP (for 'Genetics ARthrosis and Progression') sibling pair study. Erosive evolution comprised phase transitions from non-erosive to erosive phases and from active erosions to remodelling. Clustering of erosive evolution within patients was assessed using the χ² test. Familial aggregation was evaluated in sibling pairs by estimating ORs for siblings and probands sharing erosive evolution. Local baseline determinants and the effect of high sensitivity C reactive protein were assessed using generalised estimating equations. RESULTS: Erosive evolution took place in 181 of 4120 interphalangeal joints at risk (4.4%), corresponding to 60 patients (25.4% of study sample). Erosive evolution was found more often in multiple interphalangeal joints in one patient than would be expected by chance (χ² 373.0, p < 0.001). The adjusted OR (95% CI) for a sibling having erosive evolution if the proband had erosive evolution was 4.7 (1.4 to 15.8). Systemic inflammation was not associated with erosive activity. Independent local determinants were joint space narrowing (OR (95% CI) 8.9 (4.8 to 16.4)) and self-reported pain (OR (95%CI) 2.3 (1.1 to 4.7)). CONCLUSIONS: rosive evolution was clustered within patients and families. Local factors were also involved in the evolution. This increase in insight in the pathogenesis of erosive hand OA will contribute to the development of new treatments.

Doyle Index is a valuable additional pain measure in osteoarthritis.

OBJECTIVE: To determine reliability, feasibility, and validity of the Doyle Index (DI), a pain score proposed for osteoarthritis (OA). METHODS: The DI was performed in 260 patients with OA at multiple sites (mean age 64.9 years, 84% women) by grading pain (0-3) in 48 joints and joint groups by pressure or passive movement. Reliability and feasibility were determined in a random sample of 18 patients, by examining them twice using four raters. Intraclass correlation coefficients (ICCs) for intra- and interrater reliability were calculated, as well as the mean time to perform the DI. Validity was assessed in 260 patients, by correlating DI total scores and DI scores for the hand and knee/hip joints separately, to the pain and function subscales of the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), using Spearman's rank coefficient (r). RESULTS: In the total population the median (interquartile range) DI score was 11.0 (5.0-19.0). Intraobserver ICCs [95% confidence interval (CI)] ranged from 0.94 (0.84, 0.98) to 0.97 (0.93, 0.99). Interobserver ICC was 0.88 (0.77, 0.94). The mean time to perform the total DI was 5.1min (range 2.4-7.8). DI total scores as well as scores for the hand and knee/hip joints separately were related to AUSCAN (r range 0.61-0.65) and WOMAC (r range 0.43-0.51), although the level of correlation was moderate. CONCLUSION: The DI is a reliable, easy to perform, and valid measure for OA pain during physical examination and therefore a promising additional outcome measure not only for OA research but also for clinical practice.

Clinical burden of erosive hand osteoarthritis and its relationship to nodes.

OBJECTIVE: To describe the clinical burden of erosive osteoarthritis (EOA) of the hand in terms of pain, functioning and health-related quality of life (HRQL) and its relationship to nodal osteoarthritis (OA). METHODS: Patients with EOA (n=42) and non-EOA (n=194) of the hand were compared. Pain was assessed with the Australian/Canadian Osteoarthritis Hand Index (AUSCAN), the Michigan Hand Outcome Questionnaire (MHQ) and pain intensity upon pressure. Functioning was evaluated with AUSCAN, MHQ, grip strength, pinch grip and hand mobility tests. HRQL was measured with the Short Form-36. Patient satisfaction with hand function and aesthetics were also evaluated. The presence of nodal OA as well as its extent (reflected by the number of nodes) was assessed. Mean differences between patient groups were estimated with linear mixed models. To determine whether differences were independent of the nodal character of the disease, adjustments were made for the number of nodes. RESULTS: Patients with EOA experienced more pain, more functional limitation, less satisfaction with hand function and aesthetics and worse hand mobility than patients with non-EOA. HRQL was similar for the two groups. Patients with EOA had more nodes. A higher number of nodes was associated with worse outcome. After correction for the number of nodes, only hand mobility and patient satisfaction remained different between the groups. CONCLUSION: Patients with EOA have a higher clinical burden than those with non-erosive disease. This higher burden is only partly attributed to the erosive disease itself, but mainly to the nodal character of the disease.

Illness perceptions in patients with osteoarthritis: change over time and association with disability.

OBJECTIVE: To investigate changes in illness perceptions in patients with osteoarthritis (OA) and the association of those changes with disability, and to determine the predictive value of illness perceptions in disability. METHODS: Illness perceptions and disability were measured at baseline and after 6 years in 241 patients with OA at multiple sites (mean age 59.0 years, 82.2% women) using the revised Illness Perception Questionnaire (IPQ-R) and the Health Assessment Questionnaire (HAQ), respectively. Mean changes for each IPQ-R dimension were reported and related to progression of disability, defined as the highest quartile of HAQ score change. The predictive value of baseline illness perceptions in disability at 6 years (with high disability defined as the highest quartile of HAQ score) was assessed using logistic regression. RESULTS: Illness perceptions changed over time, and these changes were related to the progression of disability. Patients with progression of disability had an increase in symptoms attributed to OA, perceived consequences, perceived disease chronicity, negative emotions associated with OA and beliefs about immunity as causal factor, and a decrease in perceived control and understanding of OA compared with patients without progression of disability. Moreover, a higher number of symptoms attributed to OA, less perceived control, and more perceived consequences of OA at baseline were predictive of high disability after 6 years. CONCLUSION: Illness perceptions in patients with OA changed over time, and these changes were related to outcome. Moreover, illness perceptions were predictive of disability. This may imply that interventions aimed at changing illness perceptions can contribute to better functional outcome.

Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis.

OBJECTIVES: We examined the effects of four different treatment strategies on bone mineral density (BMD) in patients with recently diagnosed, active rheumatoid arthritis (RA) and the influence of disease-related and demographic factors on BMD loss after 1 year of follow-up in the BeSt trial. METHODS: BMD measurements of the lumbar spine and total hip were performed in 342 patients with recent onset RA at baseline and after 1 year. Multivariable regression analyses were performed to determine independent associations between disease and demographic parameters and BMD loss after 1 year. RESULTS: Median BMD loss after 1 year was 0.8% and 1.0% of baseline in the spine and the hip, respectively. No significant differences between the treatment groups, including corticosteroids and the anti-tumour necrosis factor-alpha infliximab, were observed with regard to BMD loss after 1 year of treatment. Joint damage at baseline and joint damage progression according to the Sharp-van der Heijde score were independently associated with more BMD loss after 1 year. The use of bisphosphonates independently protected against BMD loss. CONCLUSIONS: After 1 year of follow-up in the BeSt study, we did not find differences in BMD loss between the four treatment strategies, including high doses of corticosteroids and anti-tumour necrosis factor-alpha. Joint damage and joint damage progression are associated with high BMD loss, which emphasises that BMD loss and erosive RA have common pathways in their pathogenesis.

Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis.

OBJECTIVES: Osteoporosis is a well-known extra-articular phenomenon in patients with uncontrolled, long-standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease-related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA. METHODS: BMD of the total hip and the lumbar spine was measured using dual-energy x ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score