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.

Comparison between 1.5T and 3.0T MRI: both field strengths sensitively detect subclinical inflammation of hand and forefoot in patients with arthralgia.

OBJECTIVE: Magnetic resonance imaging (MRI) of small joints sensitively detects inflammation. This inflammation, and tenosynovitis in particular, has been shown to predict rheumatoid arthritis (RA) development in arthralgia patients. These data have predominantly been acquired on 1.0-1.5 T MRI. However, 3.0 T is now commonly used in practice. Evidence on the comparability of these field strengths is scarce and has never included subtle inflammation in arthralgia patients or tenosynovitis. Therefore, we assessed the comparability of 1.5 T and 3.0 T in detecting subclinical inflammation in arthralgia patients. METHOD: A total of 2968 locations (joints, bones, tendon sheaths) in the hands and forefeet of 28 patients with small-joint arthralgia, at risk for RA, were imaged on both 1.5 and 3.0 T MRI. Two blinded readers independently scored erosions, osteitis, synovitis, and tenosynovitis, in line with the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS). Features were summed into inflammation (osteitis, synovitis, tenosynovitis) and RAMRIS (inflammation and erosions). Agreement was assessed with intraclass correlation coefficients (ICCs) for continuous scores and after dichotomization into presence or absence of inflammation, on patient and location levels. RESULTS: Interreader ICCs were excellent (> 0.90). Comparing 1.5 and 3.0 T revealed an ICC of 0.90 for inflammation and RAMRIS. ICCs for individual inflammation features were: tenosynovitis 0.87 (95% confidence interval 0.74-0.94), synovitis 0.65 (0.24-0.84), and osteitis 0.96 (0.91-0.98). Agreement was 83% for inflammation and 89% for RAMRIS. Analyses on the location level showed similar results. CONCLUSION: Agreement on subclinical inflammation between 1.5 T and 3.0 T was excellent. Although synovitis scores were slightly different, synovitis often occurs simultaneously with other inflammatory signs, suggesting that scientific results on the predictive value of MRI-detected inflammation for RA, obtained on 1.5 T MRI, can be generalized to 3.0 T MRI.

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.

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.

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.

Bone marrow lesions and synovitis on MRI associate with radiographic progression after 2†years in hand osteoarthritis.

OBJECTIVE: To study the association of magnetic resonance (MR) features with radiographic progression of hand osteoarthritis over 2 years. METHODS: Of 87 primary patients with hand osteoarthritis (82% women, mean age 59 years), baseline distal and proximal interphalangeal joint contrast-enhanced MR images were scored 0-3 for bone marrow lesions (BMLs) and synovitis following the Oslo score. Baseline and 2-year follow-up radiographs were scored following Kellgren-Lawrence (KL) (0-4) and OsteoArthritis Research Society International (OARSI) scoring methods (0-3 osteophytes, joint space narrowing (JSN)). Increase ≥1 defined progression. Associations between MR features and radiographic progression were explored on joint and on patient level, adjusting for age, sex, body mass index, synovitis and BML. Joints in end-stage were excluded. RESULTS: Of 696 analysed joints, 324 had baseline KL=0, 28 KL=4 and after 2 years 78 joints progressed. BML grade 2/3 was associated with KL progression (2/3 vs 0: adjusted risk ratio (RR) (95% CI) 3.3 (2.1 to 5.3)) and with osteophyte or JSN progression, as was synovitis. Summated scores were associated with radiographic progression on patient level (RR crude BML 1.08 (1.01 to 1.2), synovitis 1.09 (1.04 to 1.1), adjusted synovitis 1.08 (1.03 to 1.1)). CONCLUSIONS: BMLs, next to synovitis, show, already after 2 years, graded associations with radiographic progression, suggesting that both joint tissues could be important targets for therapy.

Bone marrow lesions on magnetic resonance imaging in hand osteoarthritis are associated with pain and interact with synovitis.

OBJECTIVE: To determine the association between bone marrow lesions (BMLs) and (teno)synovitis as assessed on magnetic resonance (MR) imaging in patients with pain in hand osteoarthritis (OA). METHODS: In 105 consecutive primary hand OA patients (83% women, mean age 59 years), who were diagnosed by rheumatologists and included in the HOSTAS (Hand OSTeoArthritis in Secondary care) cohort, contrast enhanced MR imaging of right distal and proximal interphalangeal joints were obtained. In 92 patients joint site specific pain upon palpation was assessed within 3 weeks of magnetic resonance imaging (MRI) examination. MR features were scored (0-3) following the Oslo hand OA score: BMLs, synovitis, cysts, flexor tenosynovitis (FTS). Additionally, extensor tendon inflammation (ETI) (0-3) was scored. Odds ratios (OR, 95% confidence interval (CI)) were calculated using generalized estimating equations for MR features with joint pain, adjusted for putative confounders. Stratified analyses were performed to investigate interaction. RESULTS: BMLs, synovitis, cysts, FTS and ETI were demonstrated in 56%, 90%, 22%, 16% and 30% of patients, respectively. BMLs (grade 2/3 vs 0: 3.5 (1.6-7.7)) and synovitis (3 vs 0: OR 3.6 (95% CI 1.9-6.6)) were severity-dependent associated with joint pain, but FTS and ETI were not. Stratified analyses showed that BMLs did not associate with pain in the absence of synovitis, whereas synovitis was associated with pain in the absence of BMLs. Interaction was seen between BMLs and synovitis grade 2 or 3. CONCLUSION: In hand OA patients severe synovitis is associated with joint pain, which is worsened when BMLs co-occur, suggesting synovitis as primary target of treatment.

Bone mineral density loss in clinically suspect arthralgia is associated with subclinical inflammation and progression to clinical arthritis.

OBJECTIVE: Peripheral bone mineral density (BMD) may be decreased in early rheumatoid arthritis (RA) but it is unknown whether BMD loss emerges before arthritis is clinically apparent. We aimed to study whether BMD loss occurs in patients with clinically suspect arthralgia (CSA), and whether it is associated with progression to clinical arthritis and magnetic resonance imaging (MRI)-detected subclinical inflammation. METHOD: Patients with CSA had arthralgia for <1 year and were at risk of progressing to RA according to their rheumatologists. At baseline, a 1.5 T MRI was performed of unilateral metacarpophalangeal, wrist, and metatarsophalangeal joints, and scored on synovitis, bone marrow oedema, and tenosynovitis;. summing these features yielded the total MRI inflammation score. Digital X-ray radiogrammetry (DXR) was used to estimate BMD on two sequential conventional hand radiographs (mean interval between radiographs 4.4 months). The change in BMD was studied; BMD loss was defined as a decrease of ≥2.5 mg/cm2/month. Patients were followed for arthritis development for a median of 18.4 months. RESULTS: In CSA patients (n = 108), change in BMD was negatively associated with age (ß = -0.03, p = 0.007). BMD loss in CSA patients was associated with arthritis development [adjusted for age hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.7 to 21.4] and was most frequently estimated in the months before clinical arthritis development. The total MRI inflammation scores were associated with the change in BMD (adjusted for age ß = -0.05, p = 0.047). The total MRI inflammation score and BMD loss were both independently associated with arthritis development (HR = 1.1, 95% CI 1.1 to 1.2, and HR = 4.6, 95% CI 1.2 to 17.2, respectively). CONCLUSION: In CSA patients, severe BMD loss is associated with MRI-detectable subclinical inflammation and with progression to clinical arthritis.

Prevalence and clinical significance of lumbosacral transitional vertebra (LSTV) in a young back pain population with suspected axial spondyloarthritis: results of the SPondyloArthritis Caught Early (SPACE) cohort.

OBJECTIVE: To determine in a cohort of young patients with suspected axial spondyloarthritis (axSpA), the prevalence of lumbosacral transitional vertebra (LSTV), its association with local bone marrow edema (BME) and lumbar spine degeneration, and the potential relationship with MRI findings and clinical signs of axSpA. MATERIALS AND METHODS: Baseline imaging studies and clinical information of patients from the SPondyloArthritis Caught Early-cohort (back pain ≥3 months, ≤2 years, onset <45 years) were used. Two independent readers assessed all patients for LSTV on radiography, and BME-like and degenerative changes on MRI. Patients with and without LSTV were compared with regard to the prevalence of MRI findings and the results of clinical assessment using Chi-squared test or t test. RESULTS: Of 273 patients (35.1% male, mean age 30.0), 68 (25%) patients showed an LSTV, without statistical significant difference between patients with and without axSpA (p = 0.327). Local sacral BME was present in 9 out of 68 (13%) patients with LSTV and absent in patients without LSTV (p < 0.001). Visual analogue scale (VAS) pain score and spinal mobility assessments were comparable. CONCLUSIONS: LSTV is of low clinical relevance in the early diagnosis of axSpA. There is no difference between patients with and without LSTV regarding the prevalence of axSpA, pain and spinal mobility, and a BME-like pattern at the pseudoarticulation does not reach the SI joints.

Radiological and clinical predictors of long-term outcome in rotator cuff calcific tendinitis.

OBJECTIVES: Knowledge on the epidemiology and long-term course of rotator cuff calcific tendinitis (RCCT) is scarce. We assessed demographics, radiological characteristics, and their association with long-term outcomes in a large patient group. METHODS: Baseline demographics, radiological characteristics and treatment were recorded in 342 patients. Interobserver agreement of radiological measures was analyzed. Long-term outcome was evaluated with questionnaires (WORC, DASH). The association of baseline characteristics with outcome was assessed. RESULTS: Mean age was 49.0 (SD = 10.0), and 59.5 % were female. The dominant arm was affected in 66.0 %, and 21.3 % had bilateral disease. Calcifications were on average 18.7 mm (SD = 10.1, ICC = 0.84 (p < 0.001)) and located 10.1 mm (SD = 11.8) medially to the acromion (ICC = 0.77 (p < 0.001)). Gärtner type I calcifications were found in 32.1 % (Kappa = 0.47 (p < 0.001)). After 14 years (SD = 7.1) of follow-up, median WORC was 72.5 (range, 3.0-100.0; WORC < 60 in 42 %) and median DASH 17.0 (range, 0.0-82.0). Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior WORC. DASH results were similar. CONCLUSIONS: Many subjects have persisting shoulder complaints years after diagnosis, regardless of treatment. Female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications were associated with inferior outcome. Radiological measures had moderate-to-good reliability and no prognostic value. KEY POINTS: • Most RCCT studies report on short-term outcome and/or small patients groups. • In this large, long-term observational study, RCCT appeared to not be self-limiting in many subjects. • Negative prognostic factors included female gender, more calcifications, dominant arm affected, and longer duration of symptoms. • Interobserver agreement of general radiological RCCT measures is moderate to good. • More rigorous diagnostics and treatment might be needed in specific RCCT cases.

Signal intensity loss of the intervertebral discs in the cervical spine of young patients on fluid sensitive sequences.

OBJECTIVE: To evaluate the signal intensity (SI) of the intervertebral discs of the cervical spine on magnetic resonance (MR) fluid sensitive sequences, and correlate this to secondary signs of degeneration on MR and radiographs as well as to age. MATERIAL AND METHODS: A total of 265 patients aged ≥16 with back pain (≥3-months, <2-year, onset <45-years) from the SPondyloArthritis Caught Early (SPACE) cohort were included. Sagittal 1.5 T MR images and lateral radiographs of the cervical spine were independently evaluated by two readers for: SI of the intervertebral discs using a grading system based of Pfirrmann (grade 1 normal/bright SI; 2 inhomogeneous/bright SI; 3 inhomogeneous/mildly decreased SI; 4 inhomogeneous/markedly decreased SI; 5 signal void), disc herniation and Modic changes (MRI) and disc space narrowing, osteophytes and sclerosis (radiograph). Readers were blinded for clinical information. Descriptive statistics were used for characteristics and prevalence of findings, and regression analysis was used for age and grades. RESULTS: Of 265 patients (36% male, mean age 30), 221 (83%) patients had 1 to 6 discs (median 4) with decreased SI. Of 1,590 discs, 737 (46%) were grade 1; 711 (45%) grade 2; 133 (8%) grade 3; 8 (1%) grade 4 and 1 (0%) grade 5. Secondary signs of degeneration were rare and seen predominantly in C5-C7 and appear to be related to signal loss grade 3 and 4. CONCLUSION: Low signal intensity of intervertebral discs in absence of secondary degenerative signs in the cervical spine on fluid sensitive MR images might be pre-existing and part of the natural course.

The diagnostic accuracy of the squeeze test to identify arthritis: a cross-sectional cohort study.

OBJECTIVES: In daily practice, the squeeze test is used to screen for arthritis in metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints. This cross-sectional cohort study determined the diagnostic accuracy of this test. METHODS: Patients referred with arthralgia of recent onset that had either a clinical suspicion for progression to arthritis or clinically apparent arthritis were studied. The main outcome was swelling at physical examination of ≥1 MCP or MTP joint. Joint inflammation detected at extremity MRI was the secondary outcome. RESULTS: Both at MCP and MTP joints, a positive squeeze test associated with swollen joints (p<0.005). The sensitivity of the test at the MCP joints was 53%, specificity 82%, positive likelihood ratio (LR+) 3.0, negative likelihood ratio (LR-) 0.6 and area under the receiver operator characteristic curve (AUC) 0.68. At the MTP joints, the sensitivity was 54%, specificity 74%, LR+ 2.1, LR- 0.6 and AUC 0.64. With MRI-detected inflammation as outcome, the sensitivity and specificity were 39% and 86% and 31% and 69% for the test at the MCP and MTP joints, respectively. CONCLUSIONS: A positive squeeze test is associated with local joint inflammation but the sensitivity is low, indicating a high percentage of swollen joints with a negative squeeze test. When the test is used on its own, it is insufficient to detect early arthritis.

Concordance between inflammation at physical examination and on MRI in patients with early arthritis.

BACKGROUND: MRI is increasingly used to measure inflammation in rheumatoid arthritis (RA) research, but the correlation to clinical assessment is unexplored. This study determined the association and concordance between inflammation of small joints measured with MRI and physical examination. METHODS: 179 patients with early arthritis underwent a 68 tender joint count and 66 swollen joint count and 1.5T MRI of MCP (2-5), wrist and MTP (1-5) joints at the most painful side. Two readers scored synovitis and bone marrow oedema (BME) according to the OMERACT RA MRI scoring method and assessed tenosynovitis. The MRI data were first analysed continuously and then dichotomised to analyse the concordance with inflammation at joint examination. RESULTS: 1790 joints of 179 patients were studied. Synovitis and tenosynovitis on MRI were independently associated with clinical swelling, in contrast to BME. In 86% of the swollen MCP joints and in 92% of the swollen wrist joints any inflammation on MRI was present. In 27% of the non-swollen MCP joints and in 66% of the non-swollen wrist joints any MRI inflammation was present. Vice versa, of all MCP, wrist and MTP joints with inflammation on MRI 64%, 61% and 77%, respectively, were not swollen. BME, also in case of severe lesions, occurred frequently in clinically non-swollen joints. Similar results were observed for joint tenderness. CONCLUSIONS: Inflammation on MRI is not only present in clinically swollen but also in non-swollen joints. In particular BME occurred in clinically non-inflamed joints. The relevance of subclinical inflammation for the disease course is a subject for further studies.

MRI-detected subclinical joint inflammation is associated with radiographic progression.

BACKGROUND: We recently demonstrated that MRI inflammation is prevalent in clinically non-swollen joints of early arthritis patients. In this study, we assessed the relevance of this subclinical inflammation with regard to radiographic progression. METHODS: 1130 joints (unilateral metacarpophalangeal 2-5, wrist and metatarsophalangeal 1-5) of 113 early arthritis patients underwent clinical examination and 1.5 T MRI at baseline, and radiographs at baseline and 1 year. Two readers scored the MRIs for synovitis, bone marrow oedema (BME) and tenosynovitis according to Rheumatoid Arthritis (RA) Magnetic Resonance Imaging (MRI) Scoring System (RAMRIS). Radiographic progression over 1 year was determined using the Sharp-van der Heijde scoring method. RESULTS: On patient level, BME, synovitis and tenosynovitis were associated with radiographic progression, independent of known risk factors (p=0.003, 0.001 and 0.011, respectively). Of all non-swollen joints (n=932), 232 joints (26%) had subclinical inflammation (≥1 MRI-inflammation feature present). These joints were distributed among 91% of patients. Radiographic progression was present in 4% of non-swollen joints with subclinical inflammation compared to 1% of non-swollen joints without subclinical inflammation (relative risks (RR) 3.5, 95% CI 1.3 to 9.6). Similar observations were done for BME (RR5.3, 95% CI 2.0 to 14.0), synovitis (RR3.4, 95% CI 1.2 to 9.3) and tenosynovitis (RR3.0, 95% CI 0.7 to 12.7) separately. CONCLUSIONS: Radiographic progression was infrequent, but joints with subclinical inflammation had an increased risk of radiographic progression within year 1. This demonstrates the relevance of MRI-detected subclinical inflammation.

Follow-up study of inflammatory ultrasound features in hand osteoarthritis over a period of 3 months: variable as well as constant.

OBJECTIVE: To study inflammatory ultrasound (US) features and pain over a 3-month period in hand osteoarthritis (HOA). DESIGN: In 25 consecutive HOA patients (mean age 60 years, 76% female), fulfilling the American College of Rheumatology (ACR) criteria, visual analogue scale (VAS) pain scores were collected at baseline and 3 months. In 750 [all first carpometacarpal (CMC), metacarpalphalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) and first interphalangeal (IP)] joints, pain was assessed upon palpation and synovial thickening, effusion and power Doppler signal (PDS) were scored with standardized methods by US. Associations between inflammatory features and painful joints were analysed using generalized estimated equations to account for patient effects, adjusting for confounders, and presented as odds ratios (ORs) with 95% confidence intervals (95%CI). RESULTS: Inflammatory US features were seen in (nearly) all patients. The median number (range) of inflammatory joints per patient did not change over time: 9 (0-16) to 9 (2-18). In 18.7% of joints inflammatory features were present at both time points; in 20.5% inflammatory features occurred only at baseline or follow-up. Pain decreased over time: median VAS pain 49-39 mm; median number of painful joints 8-3. Synovial thickening, effusion and PDS were associated with pain upon palpation both at baseline and follow-up: OR 2.9 (1.4, 5.7), 2.7 (1.7, 4.3), 3.6 (2.1, 6.3) and 7.3 (3.2, 16.5), 3.3 (2.3, 4.7), 4.1 (2.1, 7.9). respectively. CONCLUSIONS: In HOA inflammatory US features are stable over time at patient level, but vary on joint level. Pain diminished after 3 months, while associations between painful joints and inflammation seem to increase, emphasizing the multifactorial aetiology of pain.

The role of fat mass and skeletal muscle mass in knee osteoarthritis is different for men and women: the NEO study.

OBJECTIVE: To investigate if the amount of fat mass (FM) or skeletal muscle mass (SMM) is more strongly associated with knee osteoarthritis (OA), in both men and women. METHODS: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45-65 years, including 5313 participants (53% female, median body mass index (BMI) 29.9 kg/m(2)). FM (kg), fat percentage, SMM (kg) and skeletal muscle (SM) percentage were estimated using bioelectrical impedance analysis (BIA). Clinical OA was defined following the ACR criteria. Structural OA was defined based on magnetic resonance imaging (MRI) in 1142 participants. Logistic regression analyses were used to examine the associations of all body composition measures with clinical and structural knee OA per standard deviation (SD), stratified by sex and adjusted for age and height. RESULTS: Clinical or structural OA was present in 25% and 14% of women and 12% and 13% of men, respectively. FM and fat percentage were positively associated with clinical knee OA in men and women. SMM was positively associated, while the SM percentage was negatively associated with clinical OA in both men and women. The FM/SMM ratio was positively associated with clinical OA. All determinants showed even stronger ORs for structural knee OA. In men, SMM was more strongly associated with knee OA as compared to FM whereas in women, FM was most strongly associated. CONCLUSION: Especially a high FM/SMM ratio seems to be unfavorable in knee OA. In men, SMM is most strongly associated with knee OA whereas in women FM seems to be of most importance.

Magnetic resonance imaging of the hand joints in patients with inflammatory bowel disease and arthralgia: a pilot study.

OBJECTIVES: To assess whether subclinical inflammatory changes are present on magnetic resonance imaging (MRI) in patients with inflammatory bowel disease (IBD) and arthralgia. METHOD: In this pilot study, painful hand joints [metacarpophalangeal (MCP), proximal interphalangeal (PIP), and/or distal interphalangeal (DIP)] of 11 IBD patients (age 18-45 years) with continuous pain for > 6 weeks were scanned on a 1.5-T extremity MRI system. A control group of 11 IBD patients without joint pain who were matched for type and disease duration of IBD, gender, and age was included. All patients were clinically examined by a rheumatologist for the presence of pain and arthritis. Imaging was performed according to a standard arthritis protocol with intravenous contrast administration on the same day. Images (blinded for clinical information) were evaluated by two readers in consensus for the presence of joint fluid, synovitis, tenosynovitis, enthesitis, erosions, cartilage defects, and bone marrow oedema. RESULTS: Enthesitis was seen in three hand joints (MCP 2, MCP 3, PIP 3) of 2/11 (18%) arthralgia patients and in none of the control group (p = 0.48). A small amount of subchondral bone marrow oedema was seen in the metacarpal head of two controls. No other abnormalities were observed. CONCLUSIONS: Several young IBD patients with chronic hand pain had subclinical inflammation on MRI, which invites for further study in a larger group of patients.

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.