Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis? Data from the IMI-APPROACH cohort.

OBJECTIVE: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). METHODS: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. RESULTS: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12). CONCLUSION: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.

Prolonged morning stiffness is common in hand OA and does not preclude a diagnosis of hand osteoarthritis.

OBJECTIVE: Prolonged morning stiffness (>60 min) is considered a symptom of inflammatory arthritis, but has a poor discriminative ability. Knowledge about morning stiffness in patients with hand osteoarthritis (OA) is lacking. We therefore studied morning stiffness in patients with hand OA. DESIGN: Patients with primary hand OA according to their treating rheumatologist in the Hand OSTeoArthritis in Secondary care (HOSTAS) cohort were studied. Severity of morning stiffness was examined with Australian/Canadian hand OA index (AUSCAN) and presence and duration of morning stiffness were examined with a standardized questionnaire. Association of patient and disease characteristics with prolonged morning stiffness (>60 min) were analyzed with logistic regression. RESULTS: In total 519 of 538 patients had available data about duration of morning stiffness, of whom 89 (17%) had prolonged morning stiffness. Severity of stiffness was mild in 158 of 525 (30%), intermediate in 194 (37%), severe in 97 (18%) and extreme in 19 (4%) patients. Patients with prolonged morning stiffness reported more pain, worse physical function and had a reduced mental and physical quality of life. Patients with prolonged morning stiffness also had more severe radiographic disease, although the association did not reach statistical significance. CONCLUSIONS: Prolonged and severe morning stiffness are frequently present in patients with hand OA. Patients with these symptoms report more pain in general and have a lower quality of life than patients that do not report these symptoms. Prolonged morning stiffness does not preclude a diagnosis of hand OA.

Serum tryptophan metabolites are associated with erosive hand osteoarthritis and pain: results from the DIGICOD cohort.

OBJECTIVE: To investigate host and gut-microbiota related Tryptophan metabolism in hand osteoarthritis (HOA). METHODS: The baseline serum concentration of 20 Tryptophan metabolites was measured in 416 HOA patients in a cross-sectional analysis of the DIGICOD cohort. Tryptophan metabolites levels, metabolite-ratios and metabolism pathway activation were compared between erosive (N = 141) and non-erosive HOA (N = 275) by multiple logistic regressions adjusted on age, BMI and sex. The association between Tryptophan metabolite levels and HOA symptoms was investigated by a Spearman's rank correlation analysis. RESULTS: Four serum Tryptophan metabolites, eight metabolite ratios and one metabolism pathway were associated with erosive HOA. Erosive HOA was negatively associated with Tryptophan (odds ratio (OR) = 0.41, 95% confidence interval [0.24-0.70]), indole-3-aldehyde (OR = 0.67 [0.51-0.90]) and 3-OH-anthranilic acid (OR = 1.32 [1.13-1.54]) and positively with 5-OH-Tryptophan levels (OR = 1.41 [1.13-1.77]). The pro-inflammatory kynurenine-indoleamine 2,3-dioxygenase pathway was upregulated in erosive HOA (OR = 1.60 [1.11-2.29]). Eleven metabolites were correlated with HOA symptoms and were mostly pain-related. Serotonin and N-acetyl serotonin levels were negatively correlated with number of tender joints. Indole-3-aldehyde level was negatively correlated and 3-OH-anthranilic acid, 3-OH-kynurenine and 5-OH-Tryptophan levels were positively correlated with number of patients-reported painful joints. Quinolinic acid and 3-OH-kynurenine levels correlated positively with AUSCAN pain. CONCLUSIONS: Tryptophan metabolites disturbance is associated with erosive HOA and pain and emphasize the role of low-grade inflammation and gut dysbiosis in HOA.

Test-retest precision and longitudinal cartilage thickness loss in the IMI-APPROACH cohort.

OBJECTIVE: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine-learning-estimated structural progression score (s-score) for cartilage thickness loss in the IMI-APPROACH cohort - an exploratory, 5-center, 2-year prospective follow-up cohort. DESIGN: Quantitative cartilage morphology at baseline and at least one follow-up visit was available for 270 of the 297 IMI-APPROACH participants (78% females, age: 66.4 ± 7.1 years, body mass index (BMI): 28.1 ± 5.3 kg/m2, 55% with radiographic knee osteoarthritis (OA)) from 1.5T or 3T MRI. Test-retest precision (root mean square coefficient of variation) was assessed from 34 participants. To define progressor knees, smallest detectable change (SDC) thresholds were computed from 11 participants with longitudinal test-retest scans. Binary logistic regression was used to evaluate the odds of progression in femorotibial cartilage thickness (threshold: -211 µm) for the quartile with the highest vs the quartile with the lowest s-scores. RESULTS: The test-retest precision was 69 µm for the entire femorotibial joint. Over 24 months, mean cartilage thickness loss in the entire femorotibial joint reached -174 µm (95% CI: [-207, -141] µm, 32.7% with progression). The s-score was not associated with 24-month progression rates by MRI (OR: 1.30, 95% CI: [0.52, 3.28]). CONCLUSION: IMI-APPROACH successfully enrolled participants with substantial cartilage thickness loss, although the machine-learning-estimated s-score was not observed to be predictive of cartilage thickness loss. IMI-APPROACH data will be used in subsequent analyses to evaluate the impact of clinical, imaging, biomechanical and biochemical biomarkers on cartilage thickness loss and to refine the machine-learning-based s-score. GOV IDENTIFICATION: NCT03883568.

Subluxation of the first carpometacarpal joint and age are important factors in reduced hand strength in patients with hand osteoarthritis.

OBJECTIVE: To investigate the determinants of hand strength in patients with hand osteoarthritis (OA). METHOD: Pinch and cylinder grip strength were measured in 527 patients with hand OA diagnosed by their treating rheumatologist from the Hand OSTeoArthritis in Secondary care (HOSTAS) study. Radiographs of hands (22 joints) were scored 0-3 (scaphotrapeziotrapezoid and first interphalangeal joints 0-1) on osteophytes and joint space narrowing following the Osteoarthritis Research Society International atlas. The first carpometacarpal joint (CMC1) was scored 0-1 for subluxation. Pain was assessed with the Australian/Canadian Hand Osteoarthritis Index pain subscale, and health-related quality of life with the Short Form-36. Regression analysis served to investigate associations of hand strength with patient, disease, and radiographic features. RESULTS: Hand strength was negatively associated with female sex, age, and pain. Reduced hand strength was associated with reduced quality of life, although less after adjusting for pain. Radiographic features of hand OA were associated with reduced grip strength when solely adjusted for sex and body mass index, but only CMC1 subluxation in the dominant hand remained significantly associated with pinch grip adjusted additionally for age (-0.511 kg, 95% confidence interval -0.975; -0.046). Mediation analysis showed low and not significant percentages of mediation of hand OA in the association between age and grip strength. CONCLUSIONS: Subluxation of CMC1 is associated with reduced grip strength, whereas associations with other radiographic features seem to be confounded by age. In the relationship between age and hand strength, radiographic hand OA severity is not an important mediator.

The association of the lipid profile with knee and hand osteoarthritis severity: the IMI-APPROACH cohort.

OBJECTIVE: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. DESIGN: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. RESULTS: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. CONCLUSIONS: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity.

Administration of an adeno-associated viral vector expressing interferon-ß in patients with inflammatory hand arthritis, results of a phase I/II study.

OBJECTIVE: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-ß, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. METHODS: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 1012-1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-ß immune responses were evaluated. A data review committee provided safety recommendations. RESULTS: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-ß, nor IFN-ß antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. CONCLUSION: Single IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. TRIAL REGISTRATION: NCT02727764.

The association of clinical and structural knee osteoarthritis with physical activity in the middle-aged population: the NEO study.

OBJECTIVE: To investigate if knee osteoarthritis (OA) is associated with lower physical activity in the general middle-aged Dutch population, and if physical activity is associated with patient-reported outcomes in knee OA. DESIGN: Clinical knee OA was defined in the Netherlands Epidemiology of Obesity population using the ACR criteria, and structural knee OA on MRI. We assessed knee pain and function with the Knee Injury and Osteoarthritis Score (KOOS), health-related quality of life (HRQoL) with the Short Form-36, and physical activity (in Metabolic Equivalent of Task (MET) hours) with the Short Questionnaire to Assess Health-enhancing physical activity. We analysed the associations of knee OA with physical activity, and of physical activity with knee pain, function, and HRQoL in knee OA with linear regression adjusted for potential confounders. RESULTS: Clinical knee OA was present in 14% of 6,212 participants, (mean age 56 years, mean BMI 27 kg/m2, 55% women, 24% having any comorbidity) and structural knee OA in 12%. Clinical knee OA was associated with 9.60 (95% CI 3.70; 15.50) MET hours per week more physical activity, vs no clinical knee OA. Structural knee OA was associated with 3.97 (-7.82; 15.76) MET hours per week more physical activity, vs no structural knee OA. In clinical knee OA, physical activity was not associated with knee pain, function or HRQoL. CONCLUSIONS: Knee OA was not associated with lower physical activity, and in knee OA physical activity was not associated with patient-reported outcomes. Future research should indicate the optimal treatment advice regarding physical activity for individual knee OA patients.

Towards developing diagnostic criteria for early knee osteoarthritis: data from the CHECK study.

OBJECTIVES: There is a general consensus that a shift in focus towards early diagnosis and treatment of knee OA is warranted. However, there are no validated and widely accepted diagnostic criteria for early knee OA available. The current study aimed to take the first steps towards developing diagnostic criteria for early knee OA. METHODS: Data of 761 individuals with 1185 symptomatic knees at baseline were selected from the CHECK study. For CHECK, individuals with pain/stiffness of the knee, aged 45-65 years, who had no prior consultation or a first consultation with the general practitioner for these symptoms in the past 6 months were recruited and followed for 10 years. A group of 36 experts (17 general practitioners and 19 secondary care physicians) evaluated the medical records in pairs to diagnose the presence of clinically relevant knee OA 5-10 years after enrolment. A backward selection methods was used to create predictive models based on pre-defined baseline factors from history taking, physical examination, radiography and blood testing, using the experts' diagnoses as gold standard outcome. RESULTS: Prevalence of clinically relevant knee OA during follow-up was 37%. Created models contained 7-11 baseline factors and obtained an area under the curve between 0.746 (0.002) and 0.764 (0.002). CONCLUSION: The obtained diagnostic models for early knee OA had 'fair' predictive ability in individuals presenting with knee pain in primary care. Further modelling and validation of the identified predictive factors is required to obtain clinically feasible and relevant diagnostic criteria for early knee OA.

Osteoarthritis year in review 2019: epidemiology and therapy.

Over the past year many studies and clinical trials have been published in the osteoarthritis (OA) field. This review is based on systematic literature review covering the period May 1st, 2018 to April 19th, 2019; the final selection of articles was subjective. Specifically those articles considered to be presenting novel insights and of potential importance for clinical practice, are discussed. Further evidence has emerged that OA is a serious disease with increasing impact worldwide. Our understanding of development of pain in OA has increased. Detailed studies investigating widely used pharmacological treatments have shown the benefits to be limited, whereas the risks seem higher than expected, suggesting further studies and reconsideration of currently used guidelines. Promising new pharmacological treatments have been developed and published, however subsequent studies are warranted. While waiting for new treatment modalities to appear joint replacement is an effective alternative; new data have become available on how long they might last.

Percentile curves for the knee injury and osteoarthritis outcome score in the middle-aged Dutch population.

OBJECTIVE: To improve the interpretation of the Knee injury and Osteoarthritis Outcome Score (KOOS) in individual patients, we explored associations with age, sex, BMI, history of knee injury and presence of clinical knee osteoarthritis, and developed percentile curves. METHODS: We used cross-sectional data of middle-aged individuals from the population-based Netherlands Epidemiology of Obesity (NEO) study. Clinical knee osteoarthritis was defined using the ACR classification criteria. KOOS scores were handled according to the manual (zero = extreme problems, 100 = no problems). Patient characteristics associated with KOOS were explored using ordered logistic regression, and sex and body mass index (BMI)-specific percentile curves were developed using quantile regression with fractional polynomials. The curves were applied as a benchmark for comparison of KOOS scores of participants with knee osteoarthritis and comorbidities. RESULTS: The population consisted of 6,643 participants (56% women, mean (SD) age 56(6) years). Population-based KOOS subscale scores (median; interquartile range) near optimum: pain (100;94-100), symptoms (96;86-100), ADL function (100;96-100), sport/recreation function (100;80-100), quality of life (100;75-100). Worse KOOS scores were observed in women and in participants with higher BMI. Clinical knee osteoarthritis was defined in 15% of participants, and was, in comparison to other patient characteristics, associated with the highest odds of worse KOOS scores. Furthermore, presence of any comorbidity and cardiovascular disease specifically, was associated with worse KOOS scores, particularly in women. CONCLUSIONS: In the middle-aged Dutch population KOOS scores were generally good, but worse in women and with higher BMI. These percentile curves may be used as benchmarks in research and clinical practice.

The association of plasma fatty acids with hand and knee osteoarthritis: the NEO study.

OBJECTIVE: To investigate the association of postprandial and fasting plasma saturated fatty acid (SFAs), monounsaturated fatty acid (MUFAs) and polyunsaturated fatty acid (PUFAs) concentrations with hand and knee osteoarthritis (OA). DESIGN: In the population-based NEO study clinical hand and knee OA were defined by the ACR classification criteria. Structural knee OA was defined on MRI. Hand and knee pain was determined by Australian/Canadian Hand Osteoarthritis Index (AUSCAN) and KOOS, respectively. Plasma was sampled fasted and 150 min after a standardized meal, and subsequently analysed using a nuclear magnetic resonance platform. Logistic regression analyses were used to investigate the association of total fatty acid, SFA, MUFA, total PUFA, omega-3 PUFA and omega-6 PUFA concentrations with clinical hand and knee OA, structural knee OA and hand and knee pain. Fatty acid concentrations were standardized (mean 0, SD 1). Analyses were stratified by sex and corrected for age, education, ethnicity and total body fat percentage. RESULTS: Of the 5,328 participants (mean age 56 years, 58% women) 7% was classified with hand OA, 10% with knee OA and 4% with concurrent hand and knee OA. In men, postprandial SFAs (OR (95% CI)) 1.23 (1.00; 1.50), total PUFAs 1.26 (1.00; 1.58) and omega-3 PUFAs 1.24 (1.01; 1.52) were associated with hand OA. SFAs and PUFAs were associated with structural, but not clinical knee OA. Association of fasting fatty acid concentrations were weaker than postprandial concentrations. CONCLUSION: Plasma postprandial SFA and PUFA levels were positively associated with clinical hand and structural knee OA in men, but not in women.

In finger osteoarthritis, change in synovitis is associated with change in pain on a joint-level; a longitudinal magnetic resonance imaging study.

OBJECTIVE: To investigate determinants of decrease and increase in joint pain in symptomatic finger osteoarthritis (OA) on magnetic resonance (MR) imaging over 2 years. DESIGN: Eighty-five patients (81.2% women, mean age 59.2 years) with primary hand OA (89.4% fulfilling American College of Rheumatology (ACR) classification criteria) from a rheumatology outpatient clinic received contrast-enhanced MR imaging (1.5T) and physical examination of the right interphalangeal finger joints 2-5 at baseline and at follow-up 2 years later. MR images were scored paired in unknown time order, following the Hand OA MRI scoring system (HOAMRIS). Joint pain upon palpation was assessed by research nurses. Odds ratios (ORs; 95% confidence intervals) were estimated on joint level (n = 680), using generalized estimating equations (GEE) to account for the within patient effects. Additional adjustments were made for change in MR-defined osteophytes, synovitis, and bone marrow lesions (BMLs). RESULTS: Of 116 painful joints at baseline, at follow-up: 76 had less pain, 21 less synovitis, and 13 less BMLs. A decrease in synovitis (OR = 5.9; 1.12─31.0), but not in BMLs (OR = 0.39; 0.10─1.50), was associated with less pain. Of 678 joints without maximum baseline pain, at follow-up: 115 had increased pain, 132 increased synovitis, 96 increased BMLs, and 44 increased osteophytes. Increased synovitis (OR = 1.81; 1.11─2.94), osteophytes (OR = 2.75; 1.59─4.8), but not BMLs (OR = 1.14; 0.81─1.60), was associated with increased pain. Through stratification it became apparent that BMLs were mainly acting as effect modifier of the synovitis-pain association. CONCLUSION: Decrease in MR-defined synovitis is associated with reduced joint pain, identifying synovitis as a possible target for treatment of finger OA.

Assessment of osteoarthritic features in the thumb base with the newly developed OMERACT magnetic resonance imaging scoring system is a valid addition to standard radiography.

OBJECTIVE: To investigate the construct validity of the new thumb base OA magnetic resonance imaging (MRI) scoring system (TOMS) by comparing TOMS scores with radiographic scores in patients with primary hand OA. DESIGN: In 200 patients (83.5% women, mean (SD) age 61.0 (8.4) years), postero-anterior radiographs and MR scans (1.5 T) of the right first carpometacarpal (CMC-1) and scaphotrapeziotrapezoid (STT) joints, were scored using the OARSI atlas and TOMS, respectively. The distributions of the TOMS scores (specified in results section) were stratified for the OARSI scores of corresponding radiographic features and investigated using boxplots and non-parametric tests. Furthermore, Spearman's rank or Phi correlation coefficients (ρ/φ) were calculated. RESULTS: For all features, especially for erosions and osteophytes, the prevalence found with MRI was higher than with radiography. TOMS osteophyte and cartilage loss scores differed statistically significant between corresponding OARSI scores in CMC-1 (0 vs 1; 1 vs 2). TOMS scores were positively correlated with radiographic scores in CMC-1 for osteophytes (coefficient [95% confidence interval], ρ = 0.75 [0.69; 0.81]), cartilage loss/joint space narrowing (ρ = 0.70 [0.62; 0.76]), subchondral bone defects (SBDs)/erosion-cyst (ρ = 0.41 [0.29; 0.52]), bone marrow lesions (BMLs)/subchondral sclerosis (ρ = 0.65 [0.56; 0.73]) and subluxation (φ = 0.65 [0.57; 0.73]); and in STT for osteophytes (ρ = 0.30 [0.17; 0.42]) and cartilage loss/joint space narrowing (ρ = 0.53 [0.42; 0.62]). CONCLUSIONS: In patients with hand OA, TOMS scores positively correlated with radiographic scores, indicating good construct validity. However, the prevalence of features on MR images was higher compared to radiographs, suggesting that TOMS might be more sensitive than radiography. The clinical meaning of these extra MR detected cases is currently still unknown.

The role of leptin and adiponectin as mediators in the relationship between adiposity and hand and knee osteoarthritis.

OBJECTIVES: To investigate associations of leptin and adiponectin levels with knee and hand osteoarthritis, and explore whether these mediate the association between adiposity and osteoarthritis. METHODS: This is a cross-sectional analysis of baseline data from the population-based Netherlands Epidemiology of Obesity study. Adiposity was assessed with body mass index (BMI) and percentage total body fat (%TBF). Osteoarthritis, defined as hand or knee osteoarthritis, was determined using American College of Rheumatology criteria. Fasting serum adipokine levels were measured using immunoassays. Associations between adiposity and osteoarthritis were examined with logistic regression, adjusted for age, sex, ethnicity and education, and additionally for leptin and adiponectin as potential mediators. RESULTS: In 6408 participants (56% women, median age 56 years), prevalence of osteoarthritis was 22% (10% isolated knee and 8% isolated hand osteoarthritis). Leptin levels were positively associated with osteoarthritis, while adiponectin levels were not. Leptin partially mediated the association of adiposity with osteoarthritis (OR 1.40 (95%CI 1.30; 1.52) attenuated to 1.38 (1.24; 1.54) per 5 units BMI and OR 1.25 (1.17; 1.35) to 1.20 (1.10; 1.32) per 5 units %TBF, representing 4% and 17% mediation, respectively). Larger proportion mediation by leptin was found in knee (13%/27%) than in hand osteoarthritis (9%/18%). Sex-stratified analyses generally showed stronger associations between adiposity, leptin and osteoarthritis in women than in men. CONCLUSIONS: Serum leptin levels were associated with osteoarthritis, and partially mediated the association between adiposity and osteoarthritis, while adiponectin levels were not associated with osteoarthritis. These findings provide evidence for systemic effects of adipose tissue in osteoarthritis.

Exploring longitudinal associations of histologically assessed inflammation with symptoms and radiographic damage in knee osteoarthritis: combined results of three prospective cohort studies.

OBJECTIVE: To explore the associations between different histologically assessed, inflammatory synovial characteristics and subsequent clinical and structural aspects in knee osteoarthritis (OA). DESIGN: Knee OA patients, ranging in stage from early to advanced, were recruited from three different ongoing studies. Synovial tissue biopsies were taken and histologically assessed for six features (four inflammatory related aspects, fibrosis and fibrin deposition). Clinical aspects (WOMAC pain, functioning and stiffness and SF-36 vitality) and structural aspects (Kellgren and Lawrence (KL)-grade, joint space narrowing (JSN; 0-3) and osteophytes (0-3), and reception of total knee replacement (TKR)) were repeatedly assessed during follow-up. Associations between histology and clinical and structural aspects were analysed using linear mixed model analyses and cox proportional hazards analysis. RESULTS: Biopsies of 83 patients (median complaint duration: 5 [2-8] years) were analysed. Follow-up was a median of 1.4 [0.8-2.7] years for clinical and 1.8 [0.2-5.2] years for structural aspects. Fibrosis and fibrin deposition were inversely correlated with the inflammatory features. A higher fibrosis score was associated with a lower scores for KL-grade, JSN and osteophytes, while higher scores for perivascular oedema, synovial lining thickness and vascularisation were associated with higher scores for structural aspects during follow-up. No associations were found between each of the histological features and any of the clinical aspects or the chance for TKR during follow-up. CONCLUSIONS: Inflammatory related histological aspects are associated with subsequent increased radiological severity in knee OA, while fibrosis seems to protect against this, providing a potential therapeutic target for OA treatment.

Performance of the Michigan Hand Outcomes Questionnaire in hand osteoarthritis.

OBJECTIVE: To investigate the performance of the Michigan Hand Outcomes Questionnaire (MHQ) in hand osteoarthritis (OA) by evaluating truth, discrimination and feasibility. DESIGN: Symptomatic hand OA patients from the Hand Osteoarthritis in Secondary Care (HOSTAS) cohort completed questionnaires (demographics, MHQ, Australian/Canadian Hand Osteoarthritis Index [AUSCAN], Functional Index for Hand Osteoarthritis [FIHOA] and visual analogue scale [VAS] pain) at baseline (n = 383), 1- and 2-year follow-up (n = 312, n = 293). Anchor questions at follow-up assessed whether pain/function levels were (un)acceptable and had changed compared to baseline. Correlations between MHQ and other pain/function questionnaires were calculated. Validity of unique MHQ domains (work performance, aesthetics, satisfaction), discrimination across disease stages, and responsiveness were assessed by categorizing patients by external anchors (employment, joint deformities, erosions, and anchor questions). Between-group differences were assessed with linear regression, probability plots and comparison of medians. RESULTS: MHQ pain and function subscales correlated moderately-to-good with other instruments (rs 0.63-0.81). Work performance scores were worse in patients with reduced working capacity than in employed patients. Aesthetics scores were worse in patients with more deformities. Patients with unacceptable complaints had worse satisfaction scores. All pain/function instruments discriminated between patients with acceptable vs unacceptable pain/function, while only MHQ activities of daily living (ADL), FIHOA, and MHQ aesthetics could discriminate between erosive and non-erosive disease. MHQ and AUSCAN were most responsive. CONCLUSIONS: MHQ has several unique aspects and advantages justifying its use in hand OA, including the unique assessment of work performance, aesthetics, and satisfaction. However, MHQ, AUSCAN and FIHOA appear to measure different aspects of pain and function.

Comparison of histological and morphometrical changes underlying subchondral bone abnormalities in inflammatory and degenerative musculoskeletal disorders: a systematic review.

OBJECTIVE: Subchondral bone abnormalities (SBAs) on magnetic resonance imaging (MRI) are observed frequently and associated with disease course in various musculoskeletal disorders. This review aims to map the existing knowledge of their underlying histological features, and to identify needs for future research. DESIGN: We conducted a systematic review following PRISMA guidelines until September 2017, including all studies correlating histological features to on MRI defined SBAs in patients with osteoarthritis (OA), rheumatoid arthritis (RA), spondyloarthritis (SpA) and degenerative disc disease (DDD). Two authors independently retrieved articles and assessed study quality. RESULTS: A total of 21 studies (466 patients) correlated histological features to SBAs in OA (n = 13), RA (n = 3), ankylosing spondylitis (AS) (n = 1) and DDD (n = 4). Reported changes in OA were substitution of normal subchondral bone with fibrosis and necrosis, and increased bone remodeling. In contrast, in RA, AS or DDD fibrosis was not reported and SBAs correlated to an increase in inflammatory cell number. In DDD necrosis was observed. Similar to OA, increased bone remodeling was shown in RA and DDD. The risk of bias assessment showed a lack in described patient criteria, blinding and/or adequate topographic correlation in approximately half of studies. There was heterogeneity regarding the investigated histological features between the different disorders. CONCLUSIONS: Current studies suggest that SBAs correlate to various histological features, including fibrosis, cell death, inflammation and bone remodeling. In the majority of studies most quality criteria were not met. Future studies should aim for high quality research, and consistency in investigated features between different disorders.

In thumb base osteoarthritis structural damage is more strongly associated with pain than synovitis.

OBJECTIVE: Osteoarthritis in thumb base joints (first carpometacarpal (CMC-1), scaphotrapeziotrapezoid (STT)) is prevalent and disabling, yet focussed studies are scarce. Our aim was to investigate associations between ultrasonographic and magnetic resonance imaging (MRI) inflammatory features, radiographic osteophytes, and thumb base pain in hand osteoarthritis patients. DESIGN: Cross-sectional analyses were performed in cohorts with MRI (n = 202) and ultrasound measurements (n = 87). Pain upon thumb base palpation was assessed. Radiographs were scored for CMC-1/STT osteophytes. Synovial thickening, effusion and power Doppler signal in CMC-1 joints were assessed with ultrasound. MRIs were scored for synovitis and bone marrow lesions (BMLs) in CMC-1 and STT joints using OMERACT-TOMS. Associations between ultrasound/MRI features, osteophytes, and thumb base pain were assessed. Interaction between MRI features and osteophytes was explored. RESULTS: In 289 patients (mean age 60.2, 83% women) 139/376 thumb bases were painful. Osteophyte presence was associated with pain (MRI cohort: odds ratio (OR) 5.1 (2.7-9.8)). Ultrasound features were present in 25-33% of CMC-1 joints, though no associations were seen with pain. MRI-synovitis and BMLs grade ≥2 were scored in 25% and 43% of thumb bases, and positively associated with pain (OR 3.6 (95% CI 1.7-7.6) and 3.0 (1.6-5.5)). Associations attenuated after adjustment for osteophyte presence. Combined presence of osteophytes and MRI-synovitis had an additive effect. CONCLUSIONS: Ultrasonographic and MRI inflammatory features were often present in the thumb base. Osteophytes were more strongly associated with thumb base pain than inflammatory features, in contrast to findings in finger OA studies, supporting thumb base osteoarthritis as a distinct phenotype.

Lack of beneficial effects of low-dose radiation therapy on hand osteoarthritis symptoms and inflammation: a randomised, blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures. DESIGN: Hand OA patients, ≥50 years, with pain ≥5 (scale 0-10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0-3). RESULTS: Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference -7% (95%CI -31-17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant. CONCLUSIONS: We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA. CLINICAL TRIAL REGISTRATION NUMBER: NTR4574 (Dutch Trial Register).