Joint synovial macrophages as a potential target for intra-articular treatment of osteoarthritis-related pain.

Osteoarthritis is the most common form of joint disease and is one of the leading causes of chronic pain. Given the multi-factorial nature, numerous efforts have been made to clarify the multiple factors impacting the pain symptoms and joint pathology, including synovial macrophages in particular. Accumulating evidence from studies involving human participants and experimental animal models suggests that accumulating macrophages in synovial tissue are implicated in peripherally mediated pain sensitization of affected joints in osteoarthritis. Crosstalk between synovial macrophages and the innervating primary nociceptive neurons is thought to contribute to this facilitated pain processing by the peripheral nervous system. Due to high plasticity and complexity of synovial macrophages in the joint, safe therapies targeting single cells or molecules are currently lacking. Using advanced technologies (such as single-cell RNA sequencing and mass cytometry), studies have shown that diverse subpopulations of synovial macrophages exist in the distinct synovial microenvironments of specific osteoarthritis subtypes. Considerable progress has been made in delineating the molecular mechanisms of various subsets of synovial macrophages in the development of osteoarthritis. To develop a novel intra-articular treatment paradigm targeting synovial macrophages, we have summarized in this review the recent advances in identifying the functional consequences of synovial macrophage sub-populations and understanding of the molecular mechanisms driving macrophage-mediated remodeling.

Being overweight is associated with not reaching low disease activity in women but not men with psoriatic arthritis.

OBJECTIVE: To assess sex differences in disease activity parameters and health-related quality of life in PsA, and to assess whether determinants associated with not reaching treatment target differed between men and women. METHODS: Routine practice data of 855 PsA patients, who were all tightly monitored and treated, was used. Sex differences including, but not limited to, PsA Disease Activity Score (PASDAS), skin/nail disease, SF-12 PCS/MCS, and inflammatory back pain (IBP) were assessed. Multivariate analyses were used to examine determinants associated with not reaching treatment target (PASDAS ≤ 3.2) in men and women. RESULTS: Women had worse scores for-among others-swollen and tender joints, CRP, enthesitis and function (all P < 0.001). Higher PASDAS scores were found for women [3.5 (1.5)] than men [2.7 (1.5), P < 0.001]. Likewise, women were more often not at PASDAS treatment target (OR = 2.03, P < 0.001). No difference in current medication use was found. Nail disease, IBP, number of DMARDs used (past and current), and BMI were associated with not reaching treatment target in the overall sample. For women, but not men, BMI was associated with not reaching PASDAS low disease activity (LDA) (OR between 2.41 and 3.43, P < 0.001). CONCLUSIONS: Women with PsA in a tightly monitored and treated setting have more severe disease than men. This is demonstrated by worse scores for women in both subjective and objective disease activity measures, in addition to women less often reaching the treatment target. Notably, being overweight is associated with higher disease activity in women, but not men.

Do tender joints in active psoriatic arthritis reflect inflammation assessed by ultrasound and magnetic resonance imaging?

OBJECTIVE: To investigate the association between clinical joint tenderness and intra- and periarticular inflammation as assessed by ultrasound and MRI in patients with active PsA and to explore if the associations differ according to patient-reported outcomes (PROs) and structural damage. METHODS: Forty-one patients with active PsA and hand involvement had 76/78 joints examined for swelling/tenderness and ultrasound and MRI of 24 and 12 finger joints, respectively. Synovitis, tenosynovitis, periarticular inflammation and erosions were assessed using OMERACT definitions and scoring systems. Correlation between imaging inflammation sum-scores (intra-and periarticular) and tender/swollen joint counts were calculated using Spearman's rho, agreement at joint level was examined using prevalence and bias adjusted kappa (PABAK). Subgroup analyses explored the influence of PROs and radiographic erosive disease on these associations. RESULTS: No significant correlations were found between tender or swollen joint counts and imaging inflammation sum-scores (rho = -0.31-0.38). In patients with higher level of overall pain, disability and lower self-reported mental health, a tendency towards negative correlations were found. At joint level, intra- and periarticular imaging inflammatory lesions had slight agreement with joint tenderness (PABAK = 0.02-0.19) and slight to moderate with swelling (PABAK = 0.16-0.54). For tender joints, agreement with imaging inflammation was even weaker in patients with either high overall pain scores, high disability scores, and/or non-erosive disease. CONCLUSION: Joint tenderness had low association with imaging signs of inflammation in PsA patients, particularly in patients with high self-reported pain, disability and low mental health, indicating that tenderness is influenced by other parameters than local inflammation.

Associations between fluorescence optical imaging and magnetic resonance imaging and symptoms in hand osteoarthritis.

OBJECTIVES: To investigate whether Fluorescence Optical Imaging (FOI) enhancement and MRI-defined synovitis are associated with pain and physical function in hand OA patients. METHODS: Bilateral FOI scans and MRI of the dominant hand were available for 221 patients. Finger joints were examined for tenderness on palpation. Pain in individual finger joints during the last 24 h and last 6 weeks and hand pain intensity by the Australian/Canadian hand index and Numeric Rating Scale were self-reported. On joint level, we applied logistic regression with generalized estimating equations to examine whether FOI enhancement and MRI-defined synovitis were associated with pain in the same joint. On subject level, we applied linear regression to assess whether FOI and MRI sum scores were associated with pain intensity and physical function. RESULTS: Metacarpophalangeal and thumb base joints were excluded from analyses due to little/no FOI enhancement. Finger joints with FOI enhancement on the composite image had higher odds (95% CI) of pain during the last 6 weeks [grade 1: 1.4 (1.2-1.6); grade 2-3: 2.1 (1.7-2.6)]. Similar results were found for joint pain during the last 24 h and joint tenderness in fingers. Numerically stronger associations were found between MRI-defined synovitis and finger joint pain/tenderness. FOI and MRI sum scores demonstrated no/weak associations with hand pain and physical function. CONCLUSION: FOI enhancement and MRI-defined synovitis were associated with pain in the same finger joint. None of the imaging modalities demonstrated consistent associations with pain, stiffness and physical function on subject level.

Clinical features and outcomes from the Singapore Sjögren's syndrome study.

OBJECTIVE: To study the clinical features, treatment and outcomes of primary Sjögren's Syndrome (pSS) in a Singapore cohort from an outpatient rheumatology clinic. METHODS: Computerised Physician Order entry records of patients who fulfilled the 2016 ACR-EULAR classification criteria for pSS between 1993 and 2013 were retrospectively analysed. RESULTS: There were 102 patients, of which 96 (94.1%) were females, and 91 (89.2%) Chinese. Mean age at diagnosis was 49.3 ± 11.8 years, mean disease duration was 9.0 ± 4.6 years. The most common manifestations were keratoconjunctivitis sicca (99.0%), xerostomia (96.1%), arthralgia/arthritis (56.9%). Exocrine glandular enlargement comprised parotidomegaly (28, 27.5%), with concurrent submandibular and lacrimal gland enlargement in one. The nervous system (15.7%) was the most commonly affected internal organ, with peripheral nervous system (peripheral neuropathy, mononeuritis multiplex) involvement more common than central. Hydroxychloroquine was most frequently used (88.2%), followed by methotrexate (7.8%) and azathioprine (6.9%). Pulsed intravenous (IV) methylprednisolone 500 mg/day for 3 days was used in 5 patients followed by oral (4) or IV cyclophosphamide (1) for cardiomyopathy and interstitial lung disease (1), and neurological involvement (4). These comprised neuromyelitis optica, transverse myelopathy, cranial neuropathy, mononeuritis multiplex and/or peripheral neuropathy alone or in combination. Intravenous immunoglobulins (2.0%) was used for sensory neuropathy and mononeuritis multiplex; rituximab (1.0%) in 1 patient for treatment of non-Hodgkin's B-cell lymphoma. There were no deaths. CONCLUSION: Musculoskeletal manifestations were common, with the nervous system (peripheral more than central) the most common internal organ involved. Lymphoma was uncommon despite up to one-third of the cohort developing glandular enlargement.

Fatty acid sensing GPCR (GPR84) signaling safeguards cartilage homeostasis and protects against osteoarthritis.

It is well known that free fatty acids (FFAs) have beneficial effects on the skeletal system, however, which fatty acid sensing GPCR(s) and how the GPCR(s) regulating cartilage development and osteoarthritis (OA) pathogenesis is largely unknown. In this study, we found Gpr84, a receptor for medium-chain FFAs (MCFA), was the only FFA-sensing GPCR in human and mouse chondrocytes that exhibited elevated expression when stimulated by interleukin (IL)-1ß. Gpr84-deficiency upregulated cartilage catabolic regulator expression and downregulated anabolic factor expression in the IL-1ß-induced cell model and the destabilization of the medial meniscus (DMM)-induced OA mouse model. Gpr84-/- mice exhibited an aggravated OA phenotype characterized by severe cartilage degradation, osteophyte formation and subchondral bone sclerosis. Moreover, activating Gpr84 directly enhanced cartilage extracellular matrix (ECM) generation while knockout of Gpr84 suppressed ECM-related gene expression. Especially, the agonists of GPR84 protected human OA cartilage explants against degeneration by inducing cartilage anabolic factor expression. At the molecular level, GPR84 activation inhibited IL-1ß-induced NF-κB signaling pathway. Furthermore, deletion of Gpr84 had little effect on articular and spine cartilaginous tissues during skeletal growth. Together, all of our results demonstrated that fatty acid sensing GPCR (Gpr84) signaling played a critical role in OA pathogenesis, and activation of GPR84 or MCFA supplementation has potential in preventing the pathogenesis and progression of OA without severe cartilaginous side effect.

The New Bern Chondrolabral Classification Is Reliable and Reproducible.

BACKGROUND: Several classification systems have been used to describe early lesions of hip cartilage and the acetabular labrum in young adults with hip pain. Some of them were introduced before the concept of femoroacetabular impingement was proposed. Others were developed for other joints (such as the patellofemoral joint). However, these often demonstrate inadequate reliability, and they do not characterize all possible lesions. Therefore, we developed a novel classification system. QUESTION/PURPOSE: We asked: What is the (1) intraobserver reliability, (2) interobserver reproducibility, and (3) percentage of nonclassifiable lesions of the new classification system for damage to the hip cartilage and labrum compared with six established classification systems for chondral lesions (Beck et al. [4], Konan et al. [10], Outerbridge et al. [14]) and labral lesions (Beck et al. [3], Lage et al. [12], Peters and Erickson [15])? METHODS: We performed a validation study of a new classification system of early chondrolabral degeneration lesions based on intraoperative video documentation taken during surgical hip dislocations for joint-preserving surgery in 57 hips (56 patients) performed by one surgeon with standard video documentation of intraarticular lesions. The exclusion criteria were low-quality videos, inadequate exposure angles, traumatic lesions, and incomplete radiographic documentation. This left 42 hips (41 patients) for the blinded and randomized analysis of six raters, including those with cam-pincer-type femoroacetabular impingement (FAI) (19 hips in 18 patients), isolated cam-type FAI (10 hips), extraarticular FAI due to femoral anteversion (seven hips), isolated pincer-type FAI (two hips), focal avascular necrosis (two hips), localized pigmented villonodular synovitis (one hip), and acetabular dysplasia as a sequelae of Perthes disease (one hip). The raters had various degrees of experience in hip surgery: Three were board-certified orthopaedic fellows and three were orthopaedic residents, in whom we chose to prove the general usability of the classification systems in less experienced readers. Every rater was given the original publication of all existing classification systems and a visual guide of the new Bern classification system. Every rater classified the lesions according the existing classifications (cartilage: Beck et al. [4], Konan et al. [10], and Outerbridge et al. [14]; labrum: Beck et al. [3], Peters and Erickson [15], and Lage et al. [12]) and our new Bern chondrolabral classification system. The intraclass correlation coefficient with 95% confidence interval was used to assess the intraobserver reliability and interobserver reproducibility. The percentage of nonclassifiable lesions was calculated as an absolute number and percentage. RESULTS: The intraobserver intercorrelation coefficients (ICCs) for cartilage lesions were as follows: the Bern classification system (0.68 [95% CI 0.61 to 0.70]), Beck (0.44 [95% CI 0.34 to 0.54]), Konan (0.39 [95% CI 0.29 to 0.49]), and the Outerbridge classification (0.57 [95% CI 0.48 to 0.65]). For labral lesions, the ICCs were as follows: the Bern classification (0.70 [95% CI 0.63 to 0.76]), Peters (0.42 [95% CI 0.31 to 0.51]), Lage (0.26 [95% CI 0.15 to 0.38]), and Beck (0.59 [95% CI 0.51 to 0.67]). The interobserver ICCs for cartilage were as follows: the Bern classification system (0.63 [95% CI 0.51 to 0.75), the Outerbridge (0.14 [95% CI 0.04 to 0.28]), Konan (0.58 [95% CI 0.40 to 0.76]), and Beck (0.52 [95% CI 0.39 to 0.66]). For labral lesions, the ICCs were as follows: the Bern classification (0.61 [95% CI 0.49 to 0.74]), Beck (0.31 [95% CI 0.19 to 0.46]), Peters (0.28 [95% CI 0.16 to 0.44]), and Lage (0.20 [95% CI 0.09 to 0.35]). The percentage of nonclassifiable cartilage lesions was 0% for the Bern, 0.04% for Beck, 17% for Konan, and 25% for the Outerbridge classification. The percentage of nonclassifiable labral lesions was 0% for Bern and Beck, 4% for Peters, and 25% for Lage. CONCLUSION: We have observed some shortcomings with currently used classification systems for hip pathology, and the new classification system we developed seems to have improved the intraobserver reliability compared with the Beck and Konan classifications in cartilage lesions and with the Peters and Lage classifications in labral lesions. The interrater reproducibility of the Bern classification seems to have improved in cartilage lesions compared with the Outerbridge classification and in labral lesions compared with the Beck, Peters, and Lage classifications. The Bern classification identified all present cartilage and labral lesions. It provides a solid clinical basis for accurate descriptions of early degenerative hip lesions independent of etiology, and it is reproducible enough to use in the reporting of clinical research. Further studies need to replicate our findings in the hands of nondevelopers and should focus on the prognostic value of this classification and its utility in guiding surgical indications. LEVEL OF EVIDENCE: Level II, diagnostic study.

Population-based prevalence of femoroacetabular impingement in Japan.

OBJECTIVES: The prevalence of femoroacetabular impingement (FAI) was evaluated using a Japanese population-based cohort of participants aged ≥50 years. METHODS: Radiographs (n = 854) of bilateral hips of 427 participants (279 women, 148 men) were used for the analysis. The prevalence of cam type, pincer type, and mixed type FAI as well as osteoarthritis was evaluated. The association of FAI and osteoarthritis (OA), and pain were also evaluated. RESULTS: The prevalence of cam type and pincer type FAI were 4.2% and 20.3%, respectively. Mixed type FAI was 0.7%. OA was found in 4.0% of patients, and 17 hips (2.0%) with any FAI also had OA. A significant relationship between cam type FAI and OA was found, whereas no significant relationship between pincer type FAI and OA was seen. Sixty (7.0%) of all the hips were reported to be painful, and 14 of those painful hips (1.6%) had FAI. No significant relationship between FAI and hip pain was found. CONCLUSION: We reported the first population-based prevalence of FAI in Japan. Radiological FAI was common, and pincer type was more common than cam type. The anatomical abnormalities associated with FAI, although often asymptomatic, are risk factors for OA.

Lack of evidence that beta blocker use reduces knee pain, areas of joint pain, or analgesic use among individuals with symptomatic knee osteoarthritis.

OBJECTIVE: The potential for beta blocker use to reduce joint pain and analgesic use in osteoarthritis (OA) patients has not been well established. The objective of this study was to estimate the association between beta blocker use and knee pain, areas of joint pain, and analgesic use among participants with symptomatic knee OA. DESIGN: We selected participants with symptomatic knee OA from the Osteoarthritis Initiative. Outcome measures included knee pain (e.g., WOMAC pain subscale), areas of joint pain (e.g., widespread joint pain), and analgesic use (e.g., use of strong pain prescriptions including opioids). We decomposed time-varying beta blocker use into within-person and between-person variation, and included these components in linear mixed effects models for repeated outcome measures of knee pain, joint pain, and analgesic use over 8 years. RESULTS: Among 1,168 participants, 15% reported beta blocker use at baseline. Beta blocker users (5.2, 95% CI [4.7, 5.8]) had similar estimated mean WOMAC pain scores as other anti-hypertensive users (4.9, 95% CI [4.6, 5.2]), with an estimated within-person difference of 0.1 (95% CI [-0.3, 0.4]). Proportion of participants reporting widespread joint pain was similar between beta blocker users and other anti-hypertensive users (40.1% vs 40.3%; within-person effect, odds ratio [OR] = 0.87, 95% CI [0.63, 1.22]). Reported use of strong prescription pain medication was also similar between beta blocker users and other anti-hypertensive users (7.7% vs 8.2%; within-person effect, OR = 1.39, 95% CI [0.75, 2.55]). CONCLUSIONS: We found no evidence that beta blockers confer a clinically meaningful reduction in knee pain severity, areas of joint pain, or analgesic use among participants with symptomatic knee OA.

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial.

OBJECTIVE: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.

The contribution of age and obesity to the number of painful joint sites in individuals reporting osteoarthritis: a population-based study.

OBJECTIVE: To investigate the association of OA risk factors with number of painful joint sites in a representative population sample. METHODS: Analysis of the 2009 Survey on Living with Chronic Diseases in Canada - Arthritis Component (n = 1614) for respondents reporting symptomatic OA. Variables: painful joints sites (hands, wrists, elbows, shoulders, hips, knees, ankles, feet, back, neck), joint symptom duration, sociodemographic characteristics, smoking, comorbidities and BMI. Zero-truncated negative binomial regressions were used to investigate the association between number of painful joint sites and the variables. Generalizability of findings was assessed by a similar analysis in a clinical hip/knee OA sample. RESULTS: The sample comprised 73% women and 56% were aged <65 years. The mean number of painful joint sites was 3.8: 84% reported pain at ≥2 sites, and 45% at ≥4 sites. Age, BMI, education and smoking were not associated with the number of joint sites. Significant associations were found with being female [rate ratio (RR) = 1.23, 95% CI 1.09, 1.39], having more comorbidities (RR = 1.11, 95% CI 1.07, 1.15) and longer symptom duration (RR = 1.16, 95% CI 1.09, 1.24), although the increase in joint sites with duration was small. Similar regression results were found with the clinical OA sample. CONCLUSION: The lack of an association of age and BMI (obesity) with number of painful joint sites in OA raises questions about the role of these risk factors and our understanding of OA as a multi-joint disease. Filling this knowledge gap is critical to making progress with defining OA phenotypes and identifying potential aetiological mechanisms.

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.

Patellar tendon enthesis abnormalities and their association with knee pain and structural abnormalities in older adults.

OBJECTIVE: To describe associations between presence of patellar tendon enthesis (PTE) abnormalities and symptoms, structural abnormalities, and total knee replacement (TKR) in older adult cohort. METHODS: PTE abnormalities (presence of abnormal bone signal and/or bone erosion), were measured on T2-weighted magnetic resonance (MR) images at baseline in 961 community-dwelling older adults. Knee pain and function limitation were assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Bone marrow lesions (BMLs), cartilage volume and defects score, and infrapatellar fat pad (IPFP) area were measured using validated methods. Incidence of TKR was determined by data linkage. RESULTS: Participants with abnormal PTE bone signal and/or erosion was 20%. Cross-sectionally, presence of PTE abnormalities was associated with greater pain intensity while going up and down stairs (ß = 0.22 (95% confidence interval (CI); 0.03, 0.41)), greater risk of femoral BMLs (RR = 1.46 (1.12, 1.90)) and worse tibial cartilage defects score (RR = 1.70 (1.16, 2.47), and smaller IPFP area (ß = -0.27 (-0.47, -0.06) cm2), after adjustment of confounders. Longitudinally, presence of baseline PTE abnormalities was associated with a deleterious increase in tibial BML size (RR = 1.52 (1.12, 2.05)) over 10.7 years but not symptoms, other structural changes, or TKR. CONCLUSION: PTE abnormalities are common in older adults. Presence of cross-sectional but not longitudinal associations suggests they are commonly co-exist with other knee structural abnormalities but may not play a major role in symptom development or structural change, excepting tibial BMLs.

Is joint pain in patients with arthralgia suspicious for progression to rheumatoid arthritis explained by subclinical inflammation? A cross-sectional MRI study.

Objectives: The development of RA includes a phase of arthralgia preceding clinical arthritis. The aetiology of symptoms of arthralgia is unclear. Since subclinical joint inflammation is expected to be causally related to pain, we aimed to study associations between subclinical MRI-detected inflammation and pain in patients with arthralgia suspicious for progression to RA. Methods: Unilateral MRIs of the wrist, MCP (2-5) and MTP (1-5) joints of 325 patients who fulfilled the EULAR definition of arthralgia suspicious for progression to RA were scored by two readers on subclinical inflammation (synovitis, bone marrow oedema and tenosynovitis). Associations between MRI-detected inflammation and overall pain severity at patient level (measured using the visual analogue scale), as well as with local joint tenderness, were studied. Analyses were stratified for ACPA. Results: At patient level, synovitis (ß = 0.10, P = 0.048) and tenosynovitis (ß = 0.11, P = 0.026) associated with the visual analogue scale pain. Of the 1620 imaged joints, 447 (28%) were tender. MRI-detected synovitis associated independently with joint tenderness in all patients (odds ratio 1.74, P < 0.001), and in the ACPA-negative stratum (odds ratio 1.96, P < 0.001). In the ACPA-positive stratum only bone marrow oedema (osteitis) was independently associated with tenderness (odds ratio 2.39, P = 0.005). Sensitivity analyses in patients who developed inflammatory arthritis during follow-up (n = 61) revealed similar associations. Subclinical inflammation was present in 51% of tender joints and 39% of non-tender joints. Conclusion: In patients with arthralgia suspicious for progression to RA, MRI-detected subclinical inflammation is associated with overall pain and local joint tenderness. However, the association is partial, indicating that subclinical inflammation is not the sole explanation of the arthralgia.

PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia.

Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.

Longitudinal validity of using digital hand photographs for assessing hand osteoarthritis progression over 7 years in community-dwelling older adults with hand pain.

BACKGROUND: To determine the longitudinal construct validity of assessing hand OA progression on digital photographs over 7 years compared with progression determined from radiographs, clinical features and change in symptoms. METHODS: Participants were community-dwelling older adults (≥50 years) in North Staffordshire, UK. Standardized digital hand photographs were taken at baseline and 7 years, and hand joints graded for OA severity using an established photographic atlas. Radiographic hand OA was assessed using the Kellgren and Lawrence grading system. Hand examination determined the presence of nodes, bony enlargement and deformity. Symptoms were reported in self-complete questionnaires. Radiographic and clinical progression and change in symptoms were compared to photographic progression. Differences were examined using analysis of covariance and Chi-Square tests. RESULTS: Of 253 individuals (61% women, mean age 63 years) the proportion with photographic progression at the joint and joint group-level was higher in individuals with radiographic or clinical progression compared to those without, although differences were not statistically significant. At the person-level, those with moderate photographic progression over 7 years had significantly higher summed radiographic and clinical scores (adjusted for baseline scores) compared to those with no or mild photographic progression. Similar findings were observed for change in symptoms, although differences were small and not statistically significant. CONCLUSION: Assessing hand OA on photographs shows modest longitudinal construct validity over 7 years compared with change in radiographic and clinical hand OA at the person-level. Using photographs to assess overall long-term change in a person with hand OA may be a reasonable alternative when hand examinations and radiographs are not feasible.

Transforming growth factor-ß stimulates nerve growth factor production in osteoarthritic synovium.

BACKGROUND: Nerve growth factor (NGF) contributes to pain in knee osteoarthritis (KOA) patients. Transforming growth factor-beta (TGF-ß) stimulates NGF expression in chondrocytes from KOA patients. However, the correlation between synovial TGF-ß and NGF levels has not been sufficiently studied in human KOA patients. Further, the mechanism governing NGF regulation by TGF-ß in synovial cells is unclear. METHODS: During total knee arthroplasty, we extracted the synovial tissue (SYT) of 107 subjects with unilateral Kellgren/Lawrence grade 3-4 KOA confirmed by radiography. We examined the distribution of TGF-ß and NGF using immunohistochemistry, and analyzed the relationship between NGF and TGFB mRNA levels. Cultured synovial cells extracted from SYT were exposed to culture medium (control), human recombinant TGF-ß (rhTGF-ß), rhTGF-ß + ALK5 inhibitor SB505124, rhTGF-ß + transforming growth factor activating kinase 1 (TAK1) inhibitor (5Z)-7-oxozeaenol, or rhTGF-ß + p38 inhibitor SB203580 for 30 min, 6 h and 24 h. NGF mRNA expressed by the cultured cells and NGF protein levels in the cell supernatant were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Phosphorylation of p38 was evaluated by western blotting. RESULTS: NGF mRNA levels were positively correlated with those of TGFB. Cells expressing TGF-ß and NGF protein were observed in the lining layer of SYT. TGF-ß stimulated increased NGF mRNA expression and NGF protein production. The ALK5 inhibitor completely suppressed the TGF-ß-mediated increase in NGF expression and NGF production in synovial cells. ALK5, TAK1 and p38 inhibitors inhibited the TGF-ß-induced phosphorylation of p38, and TAK1 and p38 inhibitors partially inhibited the TGF-ß-mediated increase in NGF expression and NGF production in synovial cells. CONCLUSION: TGF-ß regulates NGF production via the TGF-ß/ALK5 signaling pathway in osteoarthritic synovium. This effect may partially occur through inhibition of the TAK1/p38 pathway in the SYT of KOA patients.

Time course analyses of structural changes in the infrapatellar fat pad and synovial membrane during inflammation-induced persistent pain development in rat knee joint.

BACKGROUND: Osteoarthritis (OA) is a common joint disease in aging societies, which is accompanied by chronic inflammation and degeneration of the joint structure. Inflammation of the infrapatellar fat pad (IFP) and synovial membrane (IFP surface) plays essential roles in persistent pain development in patients with OA. To identify the point during the inflammatory process critical for persistent pain development, we performed a time course histological analysis in a rat arthritis model. METHODS: Wistar rats received single intra-articular injection of monoiodoacetic acid (MIA, 0.2 or 1.0 mg/30 µL) in the right knees or phosphate-buffered saline (PBS, 30 µL) as a control in the left knees. Pain avoidance behaviors (weight-bearing asymmetry and tactile hypersensitivity of the plantar surface of the hind paw) were evaluated on days 0, 1, 3, 5, 7, and 14 after injection. Histological assessments of the knee joint were performed on days 0, 1, 3, 5, and 7 after MIA injection. RESULTS: Weight-bearing asymmetry was observed along with the onset of acute inflammation in both the low- (0.2 mg) and high-dose (1.0 mg) groups. In the low-dose group, weight-bearing asymmetry was completely reversed on day 10, indicating that joint pain seemed to alleviate between days 7 and 10. In contrast, we observed persistent joint pain after day 10 in the high-dose group. Histological assessments of the high-dose group indicated that the initial sign of inflammatory responses was observed in the perivascular region inside the IFP. Inflammatory cell infiltration from the perivascular region to the parenchymal region of the IFP was observed on day 3 and reached the IFP surface (synovial membrane) on day 7. Extensive fibrosis throughout the IFP was observed between days 5 and 7 after MIA injection. CONCLUSION: Our data indicated that acute joint pain occurs along with the onset of acute inflammatory process. Irreversible structural changes in the IFP, such as extensive fibrosis, are observed prior to persistent pain development. Thus, we consider that this process may play important roles in persistent pain development.

Anatomical variations related to pathological conditions of the peroneal tendon: evaluation of ankle MRI with a 3D SPACE sequence in symptomatic patients.

OBJECTIVE: To evaluate anatomical variations in the lateral ankle and their relationships with pathological conditions of the peroneal tendon on magnetic resonance imaging (MRI) in symptomatic patients. MATERIALS AND METHODS: Sixty-nine ankles MRIs of 60 adult patients with symptomatic ankles were included. The presence and sizes of peroneal tubercle and retrotrochlear eminence (RTE), the prevalence of peroneus quartus (PQ), os peroneum, and boomerang-shaped peroneus brevis (PB) tendon, the shape of the retromalleolar fibular groove (RMFG), and the location of the PB muscle-tendon junction were evaluated. The relationships of these variations with peroneal tendinopathies were assessed. The correlations between pathological peroneal conditions on MRI and clinical findings were evaluated. RESULTS: Peroneal tubercle (mean size, 3.2 mm) and RTE (mean size, 4.5 mm) were identified in 58 (84%) and 69 (100%) ankles respectively. PQ muscle, os peroneum, and boomerang-shaped PB tendon were found in 9 (13%), 7 (10%), and 24 (34.8%) ankles respectively. The RMFG was concave, flat, convex, and irregular in 14 (20.3%), 40 (58%), 13 (18.8%), and 2 (2.9%) ankles respectively. Sixteen (23.2%) patients had low-lying PB muscle belly. Only boomerang-shaped PB tendons showed a significant relationship with peroneal tendinopathies. MRI and clinical findings had a poor correlation in pathological peroneal conditions and both had low sensitivity in diagnosis. CONCLUSION: Lateral ankle anatomical variations are common and cannot be attributed to pathological conditions of the peroneal tendon, except for boomerang-shaped PB tendons. Both clinical and MRI findings have low sensitivity in the diagnosis of peroneal tendinopathies, which are often incidental findings on MRI.

Patellofemoral pain, body morphology and alignment in female pubertal dancers: One-year follow-up.

The aim of this study was to assess changes in body morphology, anatomical alignment and prevalence of patellofemoral pain (PFP) in young female dancers along one year of pubertal growth, and to identify the risk factors related to PFP in these young dancers. Both legs of 60 dancers were evaluated during grade 7 and again after 1-year. At each of these points in time, the dancers were interviewed concerning their background, and anthropometric measurements, lower-limb physical examinations and knee ultrasound scans were performed. Morphological parameters changed significantly from baseline to follow-up. PFP was found in 53.3% of the dancers' knees at baseline. At follow-up, 55.4% of the asymptomatic knees at baseline developed PFP, and only 9.4% of the symptomatic knees at baseline recovered. Lower BMI was identified among dancers who developed PFP during follow-up compared with dancers with no PFP, either at baseline or at follow-up. A positive grinding and positive Patellar Inhibition Test (PIT) were found to be risk factors for PFP at follow-up. A high prevalence of young dancers suffered PFP, from injuries they sustained mostly during the 1-year of dance practice. Parameters predisposing the dancers to PFP should be identified at early stages of dance class.