Contemporary imaging of rheumatoid arthritis: Clinical role of ultrasound and MRI.

Magnetic resonance imaging (MRI) and musculoskeletal ultrasound (MSUS) are sensitive imaging modalities used by clinicians to assist in decision-making in the management of rheumatoid arthritis (RA). This review will examine the utility of MRI and MSUS in diagnosing RA, predicting RA flares, tapering therapy, assessing remission, and examining difficult periarticular features. We will also outline the strengths and weaknesses of utilizing MRI and MSUS as outcome measures in the management of RA.

Changes in clinical disease activity are weakly linked to changes in MRI inflammation on treat-to-target escalation of therapy in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) treat-to-target (T2T) regimens often use the disease activity score (28 joints) incorporating C-reactive protein (DAS28CRP) as an outcome measure. We compared changes in the DAS28CRP with changes in magnetic resonance imaging (MRI) inflammation on treatment escalation. METHODS: Eighty seropositive RA patients with active disease were enrolled. Group A (N = 57) escalated to another conventional disease-modifying therapy (cDMARD) combination, and Group B (N = 23) to anti-TNF therapy/cDMARDs. Contrast-enhanced 3T-MRI wrist scans were obtained before and 4 months after regimen change. Scan pairs were scored for inflammation (MRI(i)) and damage. Disease activity was assessed using the DAS28CRP. RESULTS: Eighty patients were enrolled and 66 MRI scan pairs were available for analysis. Intra-reader reliability was high: intraclass correlation coefficient (average) 0.89 (0.56-0.97). ΔDAS28CRP did not differ between groups: Group A, -0.94 (-3.30, 1.61); Group B, -1.53 (-3.59, 0.56) (p = 0.45). ΔMRI(i) also did not differ: Group A, 0 (-25, 10); Group B, -1 (-15, 28) (p = 0.12). Combining groups, ΔMRI(i) correlated weakly with ΔDAS28CRP (Spearman's 0.36, p = 0.003). Using multiple linear regression analysis adjusting for confounders, ΔDAS28CRP was associated with ΔMRI(i) (p = 0.056). Of the individual MRI measures, only Δtenosynovitis correlated with ΔDAS28CRP (Spearman's 0.33, p = 0.007). ΔMRI(i) was negatively associated with the MRI erosion score at entry (p = 0.0052). CONCLUSIONS: We report the first study investigating the link between changes in clinical and imaging inflammation in a real-world RA cohort escalating to conventional and biologic DMARDs. The association was significant but relatively weak, suggesting that MRI targets cannot yet be advocated as outcomes for T2T escalation. TRIAL REGISTRATION: ANZCTR 12614000895684 . Registered 22 August 2014.

Qualitative study: the experience and impact of living with Behcet's syndrome.

AIM: Behcet's syndrome is a rare chronic multisystemic vasculitis of unknown aetiology, is unpredictable and can cause life-threatening complications. This qualitative study aims to explore the experiences of patients living with Behcet's syndrome in New Zealand. METHODS: Eight English-speaking patients participated in in-depth semi-structured interviews about their experiences of living with Behcet's syndrome. Interviews were recorded and transcribed. Data were analysed using a general inductive thematic approach. RESULTS: Five themes related to the experience of Behcet's syndrome emerged from the interviews: diagnosis (diagnostic challenge and closure), impact of disease (pain, fatigue, reduced vision, fear and uncertainty), loneliness and isolation (lack of support and information, invisible illness), acquiring resilience (coping, gaining sense of control, support group) and ongoing interactions with health system (specialist care, primary care, need for multidisciplinary care, doctor-patient relationship). CONCLUSIONS: Behcet's syndrome patients experience difficulties in obtaining a timely and correct diagnosis and contend numerous physical and emotional challenges, often experiencing loneliness and isolation. Establishing trusting doctor-patient relationships, allowing timely access to specialist care and recruiting psychosocial supports will help patients better cope with their illness. Diagnosis and management of Behcet's syndrome requires close collaboration and communication among specialists and general practitioners and improved education on Behcet's syndrome.

Rheumatology around the world: perspectives from Australia and New Zealand.

Rheumatology continues to be an exciting and vibrant specialty for specialists practising in New Zealand and Australia. Clinicians follow treat-to-target regimens to manage peripheral and axial inflammatory arthritides using conventional and biological agents, which have revolutionised management of rheumatic disease over the past two decades. However, optimal clinical practice has significant pharmacoeconomic implications which impact on health funding at a national level, and the advent of biosimilars is keenly awaited. The management of non-inflammatory rheumatic disease and the lack of effective disease-suppressing pharmacologic therapy for osteoarthritis continue to challenge clinicians. We are fortunate in having world-class rheumatology research in our region with basic scientists and clinical rheumatologists spearheading investigations, the ultimate aim of which is to improve the quality of life for our patients.

Dual-Energy CT of Urate Deposits in Costal Cartilage and Intervertebral Disks of Patients With Tophaceous Gout and Age-Matched Controls.

OBJECTIVE: The purpose of this study was to investigate whether monosodium urate (MSU) deposits could be identified within the abdomen and axial skeleton of patients with tophaceous gout using dual-energy CT (DECT). CONCLUSION: DECT of the abdomen, chest wall, and spine revealed extensive MSU deposits in costal cartilages and, to a lesser extent, intervertebral disks in the male patients with gout in our study. These were quantified volumetrically. However, age-matched control subjects showed similar deposits, indicating this was not a disease-specific finding. Thus, MSU deposition in the axial skeleton may be physiologic in middle-aged men.

Path Analysis Identifies Receptor Activator of Nuclear Factor-κB Ligand, Osteoprotegerin, and Sclerostin as Potential Mediators of the Tophus-bone Erosion Relationship in Gout.

OBJECTIVE: To determine the relationship between tophus, erosion and bone remodeling factors in gout. METHODS: Computed tomography bone erosion and circulating bone factors were measured in adults with tophaceous gout. Multiple regression modeling and path analysis were used to determine predictors of erosion. RESULTS: Tophus number, Maori or Pacific ethnicity, creatinine, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin were independently associated with erosion. Path analysis showed a direct effect of tophus number on erosion, partially mediated through OPG, RANKL, and sclerostin. CONCLUSION: Tophus number is strongly associated with bone erosion in gout. Circulating RANKL, OPG, and sclerostin are potential mediators of tophus-related erosion.

A comparative MRI study of cartilage damage in gout versus rheumatoid arthritis.

INTRODUCTION: Magnetic resonance imaging (MRI) is useful for detecting joint inflammation and damage in the inflammatory arthropathies. This study aimed to investigate MRI cartilage damage and its associations with joint inflammation in patients with gout compared with a group with rheumatoid arthritis (RA). METHODS: Forty patients with gout and 38 with seropositive RA underwent 3T-MRI of the wrist with assessment of cartilage damage at six carpal sites, using established scoring systems. Synovitis and bone oedema (BME) were graded according to Rheumatoid Arthritis MRI Scoring System criteria. Cartilage damage was compared between the groups adjusting for synovitis and disease duration using logistic regression analysis. RESULTS: Compared with RA, there were fewer sites of cartilage damage and lower total damage scores in the gout group (P = 0.02 and 0.003), adjusting for their longer disease duration and lesser degree of synovitis. Cartilage damage was strongly associated with synovitis in both conditions (R = 0.59, P < 0.0001 and R = 0.52, P = 0.0045 respectively) and highly correlated with BME in RA (R = 0.69, P < 0.0001) but not in gout (R = 0.095, P = 0.56). CONCLUSIONS: Cartilage damage is less severe in gout than in RA, with fewer sites affected and lower overall scores. It is associated with synovitis in both diseases, likely indicating an effect of pro-inflammatory cytokine production on cartilage integrity. However, the strong association between cartilage damage and BME observed in RA was not identified in gout. This emphasizes differences in the underlying pathophysiology of joint damage in these two conditions.

Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study.

BACKGROUND: The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. METHODS: We analysed DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). RESULTS: DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. CONCLUSIONS: Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.

Rituximab in diffuse cutaneous systemic sclerosis: should we be using it today?

There is new evidence that B-cell depletion could be an effective intervention in patients with SSc. Observational case-control study data from the European League Against Rheumatism Scleroderma Trials and Research group has suggested that rituximab therapy may reduce progression of skin thickening and lung fibrosis, especially in a subgroup with early dcSSc. These positive data remain preliminary and need to be viewed with caution, recognizing the spontaneous regression of skin thickening that may occur during early disease. In this review, we summarize the clinical evidence for the therapeutic use of rituximab in SSc as well as the basic science evidence suggesting that B cells and autoantibodies are the primary drivers of fibrosis in skin and lung tissue. We have also reviewed the parallels between SSc and the other CTDs where B-cell depletion therapy is efficacious.

Overexpression of miR-595 and miR-1246 in the sera of patients with active forms of inflammatory bowel disease.

BACKGROUND: MicroRNAs (miRNAs) are dysregulated in the inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), which arise due to dysfunctional host-microbe interactions and impairment of the barrier function of the intestine. Here, we sought to determine whether circulating miRNAs are biomarkers of active colonic CD and UC and can provide insights into disease pathogenesis. Comparison was made with serum miRNAs in patients with rheumatoid arthritis (RA). METHODS: Total serum RNA from patients with colonic CD, UC, and RA, and normal healthy adults was screened for disease-associated miRNAs by microarray analysis, with subsequent validation by quantitative reverse-transcription polymerase chain reaction. MiRNA targets were identified by luciferase reporter assays. RESULTS: MiR-595 and miR-1246 were significantly upregulated in the sera of active colonic CD, UC, and RA patients, compared with healthy subjects; and in active colonic CD and UC compared with inactive disease. Luciferase reporter assays indicated that miR-595 inhibits the expression of neural cell adhesion molecule-1 and fibroblast growth factor receptor 2. CONCLUSIONS: Serum miR-595 and miR-1246 are biomarkers of active CD, UC, and RA. These findings gain significance from reports that miR-595 impairs epithelial tight junctions, whereas miR-1246 indirectly activates the proinflammatory nuclear factor of activated T cells. miR-595 targets the cell adhesion molecule neural cell adhesion molecule-1, and fibroblast growth factor receptor 2, which plays a key role in the differentiation, protection, and repair of colonic epithelium, and maintenance of tight junctions. miR-595 and miR-1246 warrant testing as potential targets for therapeutic intervention in the treatment of inflammatory bowel disease.

Relationship between structural joint damage and urate deposition in gout: a plain radiography and dual-energy CT study.

OBJECTIVES: The aim of this work was to examine the relationship between joint damage and monosodium urate (MSU) crystal deposition in gout. METHODS: Plain radiographs and dual-energy CT (DECT) scans of the feet were prospectively obtained from 92 people with tophaceous gout. Subcutaneous tophus count was recorded. The ten metatarsophalangeal joints were scored on plain radiography for Sharp-van der Heijde erosion and joint space narrowing (JSN) scores, and presence of spur, osteophyte, periosteal new bone and sclerosis (920 total joints). DECT scans were analysed for the presence of MSU crystal deposition at the same joints. RESULTS: DECT MSU crystal deposition was more frequently observed in joints with erosion (OR (95% CI) 8.5 (5.5 to 13.1)), JSN (4.2 (2.7 to 6.7%)), spur (7.9 (4.9 to 12.8)), osteophyte (3.9 (2.5 to 6.0)), periosteal new bone (7.0 (4.0 to 12.2)) and sclerosis (6.9 (4.6 to 10.2)), p<0.0001 for all. A strong linear relationship was observed in the frequency of joints affected by MSU crystals with radiographic erosion score (p<0.0001). The number of joints at each site with MSU crystal deposition correlated with all features of radiographic joint damage (r>0.88, p<0.05 for all). In linear regression models, the relationship between MSU crystal deposition and all radiographic changes except JSN and osteophytes persisted after adjusting for subcutaneous tophus count, serum urate concentration and disease duration. CONCLUSIONS: MSU crystals are frequently present in joints affected by radiographic damage in gout. These findings support the concept that MSU crystals interact with articular tissues to influence the development of structural joint damage in this disease.

Interactions between tenocytes and monosodium urate monohydrate crystals: implications for tendon involvement in gout.

OBJECTIVES: Advanced imaging studies have demonstrated that urate deposition in periarticular structures, such as tendons, is common in gout. The aim of this study was to investigate the effects of monosodium urate monohydrate (MSU) crystals on tenocyte viability and function. METHODS: The histological appearance of tendons in joints affected by advanced gout was examined using light microscopy. In vitro, colorimetric assays and flow cytometry were used to assess cell viability in primary rat and primary human tenocytes cultured with MSU crystals. Real-time PCR was used to determine changes in the relative mRNA expression levels of tendon-related genes, and Sirius red staining was used to measure changes in collagen deposition in primary rat tenocytes. RESULTS: In joint samples from patients with gout, MSU crystals were identified within the tendon, adjacent to and invading into tendon, and at the enthesis. MSU crystals reduced tenocyte viability in a dose-dependent manner. MSU crystals decreased the mRNA expression of tendon collagens, matrix proteins and degradative enzymes and reduced collagen protein deposition by tenocytes. CONCLUSIONS: These data indicate that MSU crystals directly interact with tenocytes to reduce cell viability and function. These interactions may contribute to tendon damage in people with advanced gout.

Imaging in the crystal arthropathies.

Imaging in the crystal arthropathies has undergone great advances in the past decade, with newer techniques having additional benefits for assisting diagnosis, predicting prognosis, and monitoring the treatment of these conditions. Three-dimensional digitized modalities such as computed tomography, dual-energy computed tomography, and magnetic resonance imaging (MRI) offer a multislice view of any anatomic region. Both ultrasonography and MRI reveal features of inflammation and joint damage in all crystal arthropathies, and can be used to monitor the inflammatory response to therapy. The type of imaging used needs to be adapted to the clinical question of relevance.

MRI in rheumatoid arthritis: a useful tool for the clinician?

Over the last two decades, MRI has emerged as an important clinical tool to assist in the diagnosis and management of rheumatic disease. In rheumatoid arthritis (RA), MRI has improved our understanding of the pathological basis of disease and has provided new information about imaging features that reflect joint inflammation and damage. Using MRI, we can now directly observe inflammation involving the synovial membrane and tenosynovium, plus joint damage including bone erosion and cartilage thinning. Inflammation of bone beneath the joint (osteitis) appears as bone oedema which is a feature unique to MRI and yields important diagnostic and prognostic information in patients with inflammatory arthritis. With the introduction of biologics to rheumatology clinical practice, sensitive tools are required to monitor disease activity and progression, so that the disease suppressing effect of these new agents can be measured. MRI fits the bill for this role as it can inform the clinician about the development of bone erosions well before plain radiography, and its ability to reveal cartilage damage is emerging. The use of MRI as a marker of outcome in clinical trials is being paralleled by its increasing role in the clinic. Both extremity and high field MRI have clinical applications in RA and need to be considered along with other advanced imaging techniques as useful tools to add to the clinician's armamentarium. This review will summarise recent advances in this field and will apply current knowledge to specific clinical scenarios relevant to modern rheumatology practice.

MRI osteitis predicts cartilage damage at the wrist in RA: a three-year prospective 3T MRI study examining cartilage damage.

INTRODUCTION: Cartilage damage impacts on patient disability in rheumatoid arthritis (RA). The aims of this magnetic resonance imaging (MRI) study were to investigate cartilage damage over three years and determine predictive factors. METHODS: A total of 38 RA patients and 22 controls were enrolled at t = 0 (2009). After 3 years, clinical and MRI data were available in 28 patients and 15 controls. 3T MRI scans were scored for cartilage damage, bone erosion, synovitis and osteitis. A model was developed to predict cartilage damage from baseline parameters. RESULTS: Inter-reader reliability for the Auckland MRI cartilage score (AMRICS) was high for status scores; intraclass correlation coefficient (ICC), 0.90 (0.81 to 0.95) and moderate for change scores (ICC 0.58 (0.24 to 0.77)). AMRICS scores correlated with the Outcome MEasures in Rheumatoid Arthritis Clinical Trials (OMERACT) MRI joint space narrowing (jsn) and X-Ray (XR) jsn scores (r =0.96, P < 0.0001 and 0.80, P < 0.0001, respectively). AMRICS change scores were greater for RA patients than controls (P = 0.06 and P = 0.04 for the two readers). Using linear regression, baseline MRI cartilage, synovitis and osteitis scores predicted the three-year AMRICS (R² = 0.67, 0.37 and 0.39, respectively). A multiple linear regression model predicted the three-year AMRICS (R² = 0.78). Baseline radial osteitis predicted increased cartilage scores at the radiolunate and radioscaphoid joints, P = 0.0001 and 0.0012, respectively and synovitis at radioulnar, radiocarpal and intercarpal-carpometacarpal joints also influenced three-year cartilage scores (P-values of 0.001, 0.04 and 0.01, respectively). CONCLUSIONS: MRI cartilage damage progression is preceded by osteitis and synovitis but is most influenced by pre-existing cartilage damage suggesting primacy of the cartilage damage pathway in certain patients.

Is rheumatoid arthritis a B-cell haematological disease with a predilection for the joints? Following the B cell thread to its logical conclusion.

B-cell depleting therapy (BCDT) is effective in suppressing synovitis and erosions in rheumatoid arthritis suggesting that a cell of the B-lymphocyte lineage is critical in the pathogenesis of this disease. Non-Hodgkins lymphoma (NHL) also responds to BCDT but multiple myeloma (MM), does not as cells have differentiated beyond the CD20-bearing stage. However, there are similarities between B-NHL, MM and RA that suggest all 3 conditions could be initiated and perpetuated by the same cellular players. Numerous plasma cells and B cells are present within rheumatoid synovial membrane, and subarticular bone where they contribute to osteitis. On MRI scans this appears as bone oedema, which has been demonstrated to precede the development of bone erosions. Plasma cell clonality has been detected within RA synovial membrane and bone marrow. It is proposed that RA could represent a "forme fruste" of a B cell neoplastic condition, with production of autoantibodies that target a self-antigen within the joint. The activation of rheumatoid bone osteoclasts by anticitrullinated protein antibodies supports this theory. The erosions of RA would have parallels with the lytic lesions of MM but autoantigen targeting dictates that erosions occur at joint margins. This theory is discussed from rheumatologic and haematologic perspectives.

Zoledronate for prevention of bone erosion in tophaceous gout: a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: The osteoclast has been implicated in development of bone erosion in gout. The aim of this study was to determine whether zoledronate, a potent antiosteoclast drug, influences bone erosion in people with tophaceous gout. METHODS: This was a 2-year, randomised, double-blind, placebo-controlled trial of 100 people with tophaceous gout. Participants were randomised to annual administration of 5 mg intravenous zoledronate or placebo. The primary endpoint was change in the foot CT bone erosion score from baseline. Secondary endpoint was change in plain radiographic damage scores. Other endpoints were change in bone mineral density (BMD), bone turnover markers and the OMERACT-endorsed core domains for chronic gout studies. RESULTS: There was no change in CT erosion scores over 2 years, and no difference between the two treatment groups at Year 1 or 2 (p(treat)=0.10, p(time)=0.47, p(treat*time)=0.23). Similarly, there was no change in plain radiographic scores over 2 years, and no difference between the two groups at Year 1 or 2. By contrast, zoledronate increased spine, neck of femur, total hip and total body BMD. Zoledronate therapy also reduced the bone turnover markers P1NP and ß-CTX compared with placebo. There was no difference between treatment groups in OMERACT-endorsed core domains. CONCLUSIONS: Despite improvements in BMD and suppression of bone turnover markers, antiosteoclast therapy with zoledronate did not influence bone erosion in people with tophaceous gout. These findings suggest a disconnect between responses in the healthy skeleton and at sites of focal bone erosion in tophaceous gout.

Determining a magnetic resonance imaging inflammatory activity acceptable state without subsequent radiographic progression in rheumatoid arthritis: results from a followup MRI study of 254 patients in clinical remission or low disease activity.

OBJECTIVE: To assess the predictive value of magnetic resonance imaging (MRI)-detected subclinical inflammation for subsequent radiographic progression in a longitudinal study of patients with rheumatoid arthritis (RA) in clinical remission or low disease activity (LDA), and to determine cutoffs for an MRI inflammatory activity acceptable state in RA in which radiographic progression rarely occurs. METHODS: Patients with RA in clinical remission [28-joint Disease Activity Score-C-reactive protein (DAS28-CRP) < 2.6, n = 185] or LDA state (2.6 ≤ DAS28-CRP < 3.2, n = 69) with longitudinal MRI and radiographic data were included from 5 cohorts (4 international centers). MRI were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS). Statistical analyses included an underlying conditional logistic regression model stratified per cohort, with radiographic progression as dependent variable. RESULTS: A total of 254 patients were included in the multivariate analyses. At baseline, synovitis was observed in 95% and osteitis in 49% of patients. Radiographic progression was observed in 60 patients (24%). RAMRIS synovitis was the only independent predictive factor in multivariate analysis. ROC analysis identified a cutoff value for baseline RAMRIS synovitis score of 5 (maximum possible score 21). Rheumatoid factor (RF) status yielded a significant interaction with synovitis (p value = 0.044). RF-positive patients with a RAMRIS synovitis score of > 5 vs ≤ 5, had an OR of 4.4 (95% CI 1.72-11.4) for radiographic progression. CONCLUSION: High MRI synovitis score predicts radiographic progression in patients in clinical remission/LDA. A cutoff point for determining an MRI inflammatory activity acceptable state based on the RAMRIS synovitis score was established. Incorporating MRI in future remission criteria should be considered.