Subclinical joint inflammation in rheumatoid arthritis: comparing thermal and ultrasound imaging at the metacarpophalangeal joint.

BACKGROUND: While ultrasound and MRI are both superior to clinical examination in the detection of joint inflammation, there is presently a lack of data whether thermography may be similarly useful in the assessment of joint inflammation in patients with RA. Our study aims to evaluate the use of thermography in detecting subclinical joint inflammation at clinically quiescent (non-tender and non-swollen) metacarpophalangeal joints (MCPJs) in patients with rheumatoid arthritis (RA). The outcomes from thermography in our study will be compared with ultrasonography (which is a more established imaging tool used for joint inflammation assessment in RA). METHODS: The minimum (Tmin), average (Tavg) and maximum (Tmax) temperatures at the 10 MCPJs of each patient were summed to obtain the Total Tmin, Total Tavg and Total Tmax, respectively. Ultrasound grey-scale (GS) and power Doppler (PD) joint inflammation (scored semi-quantitatively, 0-3) at the 10 MCPJs were summed up to derive the respective TGS and TPD scores per patient. Pearson's correlation and simple linear regression were respectively used to assess correlation and characterize relationships between thermographic parameters (Total Tmin, Total Tavg and Total Tmax) and ultrasound imaging parameters (TGS, TPD and the number of joint(s) with PD ≥ 1 or GS ≥ 2). RESULTS: In this cross-sectional study, 420 clinically non-swollen and non-tender MCPJs from 42 RA patients were examined. All thermographic parameters (Total Tmin, Total Tavg and Total Tmax) correlated significantly (P-values ranging from 0.001 to 0.0012) with TGS score (correlation coefficient ranging from 0.421 to 0.430), TPD score (correlation coefficient ranging from 0.383 to 0.424), and the number of joint(s) with PD ≥ 1 or GS ≥ 2 (correlation coefficient ranging from 0.447 to 0.465). Similarly, simple linear regression demonstrated a statistically significant relationship (P-values ranging from 0.001 to 0.005) between all thermographic parameters (Total Tmin, Total Tavg and Total Tmax) and ultrasound imaging parameters (TPD and TGS). CONCLUSION: For the first time, thermographic temperatures were shown to correlate with ultrasound-detected joint inflammation at clinically quiescent MCPJs. The use of thermography in the detection of subclinical joint inflammation in RA appears promising and warrants further investigation.

Optical imaging (HandScan) can identify ultrasound remission in rheumatoid arthritis.

BACKGROUND: Identifying remission is of high importance in rheumatoid arthritis (RA) because remission is associated with less structural progression. We investigated the efficacy of a new optical imaging device, HandScan, to identify RA remission, as defined by ultrasound (US). METHODS: 61 RA patients were included. Disease activity was evaluated by clinical assessment and US, using gray-scale (GS) and Power Doppler (PD). HandScan determined unitary optical spectral transmission (OST) values for wrists, metacarpophalangeal and proximal interphalangeal joints. At the patient level, three composite HandScan (HS) scores were calculated: total HS score; disease activity score OST (DAS-OST) and DAS-OST without patient global assessment (PtGA). Using ROC curves, we determined HS cut-offs to identify US-defined remission. RESULTS: At the joint level, unitary OST values significantly correlated with GS synovitis [odds ratio (OR) 2.43, p < 0.0001] and PD positivity (OR 3.72, p = 0.0002 ). At the patient level, total HS score and DAS-OST were significantly associated with all gray-scale US (GSUS) and power doppler US (PDUS) parameters evaluated (synovitis number and grade, synovial thickness, PD grade) (p < 0.05). The cut-off to identify US-defined remission at the joint level was of 0.92, giving an 81% sensitivity and a 96% positive predictive value (PPV). At the patient level, ROC-curves failed to identify a robust cut-off for the total HS score, but did identify a cut-off (3.68) for DAS-OST to identify US-defined remission, but with lower sensitivity (75%), specificity (56%) and PPV (67%). CONCLUSIONS: HandScan is a non-invasive optical imaging technique providing OST values that correlate with GSUS and PDUS parameters. In addition, HandScan is able to reliably identify US-defined remission in RA at the joint level, with a good sensitivity and high PPV. At the patient level, HandScan DAS-OST can also determine US remission (while total HS score failed to do so), but with lower performance.

Rheumatoid arthritis disease activity significantly impacts on the severity of interstitial lung disease.

OBJECTIVES: Rheumatoid arthritis (RA) related interstitial lung disease (ILD) impacts on the treatment strategy and its prognosis in patients with RA. However, the relationship between RA disease activity and the severity of comorbid ILD has not been fully investigated. This study aimed to investigate the impact of RA disease activity on the severity of comorbid ILD in detail based on currently established visual scoring method along with physiological severity. METHODS: Consecutive patients with RA visiting to our Rheumatology Centre between December 2020 and December 2023 were analysed. The radiological severity of ILD was evaluated by averaging the extent of the combined lesion of ground glass opacity, reticulation and honeycombing in 5% increments in six representative high-resolution computed tomography slices ranging from 0% (no involvement) to 100% (all lung fields affected) according to Goh and Walsh's method. Associations between the radiological and physiological severity of ILD and patients' features were investigated using linear regression analysis. RESULTS: Among 124 patients (32 men, 92 women), the median age was 70 years, and the median disease duration was 2.92 years. Radiological severity of ILD was 0% (without ILD) in 107 (86.2%), ILD with extent < 10% in nine (7.2%), ILD with extent ≥10% and < 20% in three (2.4%), ILD with extent ≥20% in five (4.0%). Both disease activity score (DAS)28-erythrocyte sedimentation rate (ESR) (standardized coefficient = 0.199, P = 0.03) and rheumatoid factor titre (standardized coefficient = 0.247, P = 0.01) were significantly associated with the radiological quantitative severity of ILD in multivariate analysis adjusted for age, sex, disease duration, smoking status and anti-citrullinated peptide antibody titre. DAS28-ESR was significantly associated with forced vital capacity% predicted (standardized coefficient = -0.230, P = 0.047). CONCLUSIONS: Disease activity of RA was significantly associated with the severity of RA-ILD both radiologically and physiologically.

Polymerized Network-Based Artificial Peroxisome Reprogramming Macrophages for Photoacoustic Imaging-Guided Treatment of Rheumatoid Arthritis.

Artificial peroxisomes (AP) with enzyme-mimetic catalytic activity and recruitment ability have drawn a great deal of attention in fabricating protocell systems for scavenging reactive oxygen species (ROS), modulating the inflammatory microenvironment, and reprogramming macrophages, which is of great potential in treating inflammatory diseases such as rheumatoid arthritis (RA). Herein, a macrophage membrane-cloaked Cu-coordinated polyphthalocyanine-based AP (CuAP) is prepared with a macrocyclic conjugated polymerized network and embedded Cu-single atomic active center, which mimics the catalytic activity and coordination environment of natural superoxide dismutase and catalase, possesses the inflammatory recruitment ability of macrophages, and performs photoacoustic imaging (PAI)-guided treatment. The results of both in vitro cellular and in vivo animal experiments demonstrated that the CuAP under ultrasound and microbubbles could efficiently scavenge excess ROS in cells and tissues, modulate microenvironmental inflammatory cytokines such as interleukin-1ß, tumor necrosis factor-α, and arginase-1, and reprogram macrophages by polarization of M1 (proinflammatory phenotype) to M2 (anti-inflammatory phenotype). We believe this study offers a proof of concept for engineering multifaceted AP and a promising approach for a PAI-guided treatment platform for RA.

Correlation of US-7 and US-9 Scores with Disease Activity Score using 28 Joint Counts (DAS28) in Patients with Rheumatoid Arthritis.

Background: The attentive management of rheumatoid arthritis (RA) has attracted particular attention. The German 7-joint Ultrasound (US-7) is the first scoring system that combines bone erosions and soft tissue lesions in a single composite scoring system. This study aimed to assess the correlation between US-7 and Disease Activity Score Using 28 Joint Counts (DAS28) in clinically active RA patients. The efficacy of a novel ultrasound score-based system, the US-9 score (joints assessed with US-7 plus knees), was also compared with the standard US-7 score. Methods: All the RA patients referred to the outpatient rheumatology clinic of Ghaem Hospital, Mashhad, Iran, during 2019-2020 were included. 28 joints were clinically examined to calculate DAS28. Nine joints were assessed comprising the German US-7 plus knees using grayscale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS). Retrieved data were analyzed by SPSS software, version 22. The Spearman Correlation test was used to find the correlation between DAS28 and ultrasonographic findings. The statistical significance level was set at P<0.05. Results: This study was composed of thirty-five RA patients with a mean age of 49.1±12.0 years. US-7 synovitis scores in GSUS and PDUS were significantly correlated with DAS28 (P=0.02, r=0.38 and P=0.003, r=0.48, respectively). US-9 synovitis scores in GSUS and PDUS were also significantly correlated with DAS28 (P=0.003, r=0.49 and P=0.006, r=0.45, respectively). The synovitis score measured by GSUS was significantly correlated with the GSUS knee synovial score (P=0.01, r=0.42). Conclusion: Ultrasound assessment of large joints such as knees can be an effective approach to determining RA severity. However, it can be proposed that adding more involved joints into the sonographic assessment does not necessarily provide a better clinical correlation.

Low Hounsfield unit values on computed tomography as a potential predictor of vertebral fracture in patients with rheumatoid arthritis: The KURAMA cohort study.

OBJECTIVE: Hounsfield units (HU) measured using computed tomography (CT) have gained considerable attention for the detection of osteoporosis. This study aimed to investigate whether opportunistic CT could predict vertebral fractures in patients with rheumatoid arthritis (RA). METHODS: A total of 233 patients with RA who underwent chest CT were included in this study. The HU values of the anterior 1/3 of the vertebral bodies based on the sagittal plane at T11-L2 after reconstruction were measured. The incidence of vertebral fractures was investigated with respect to the HU value. RESULTS: Vertebral fractures were identified in 32 patients during a mean follow-up period of 3.8 years. In patients who experienced vertebral fractures within 2 years of CT imaging, the HU values of the vertebral bodies (T11-L2) were lower than those in patients who did not experience fractures. Receiver operating characteristic curve analysis identified that a T11 HU value of <125 was a risk factor for vertebral fracture within 2 years. Multivariate analysis showed that a T11 HU value of <125 and the existence of prevalent vertebral fractures were significant risk factors for fracture. CONCLUSION: HU measurements of the anterior 1/3 of the vertebral body are a potential predictor for vertebral fractures in patients with RA.

Long-term clinical and radiological effectiveness and safety of ultralow doses of rituximab in rheumatoid arthritis: observational extension of the REDO trial.

BACKGROUND: The REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness. METHODS: Patients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed. FINDINGS: Data from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13).Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684-1413) per year, and no association was found between RTX dose and adverse events or radiological damage. INTERPRETATION: Long-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.

Adding ultrasound to treat-to-target shows no benefit in achieving clinical remission nor in slowing radiographic progression in rheumatoid arthritis: results from a multicenter prospective cohort.

OBJECTIVE: To assess whether using ultrasound (US) in addition to clinical information versus only clinical information in a treat-to-target (T2T) strategy leads to more clinical remission and to less radiographic progression in RA. METHODS: Patients with RA from the 2-year prospective BIODAM cohort were included. Clinical and US data (US7-score) were collected every 3 months and hands and feet radiographs every 6 months. At each visit, it was decided whether patients were treated according to the clinical definition of T2T with DAS44 remission as benchmark (T2T-DAS44). T2T-DAS44 was correctly applied if: (i) DAS44 remission had been achieved or (ii) if not, treatment was intensified. A T2T strategy also considering US data (T2T-DAS44-US) was correctly applied if: (i) both DAS44 and US remission (synovitis-score < 2, Doppler-score = 0) were present; or (ii) if not, treatment was intensified. The effect of T2T-DAS44-US on attaining clinical remission and on change in Sharp-van der Heijde score compared to T2T-DAS44 was analysed. RESULTS: A total of 1016 visits of 128 patients were included. T2T-DAS44 was correctly followed in 24% of visits and T2T-DAS44-US in 41%. DAS44 < 1.6 was achieved in 39% of visits. Compared to T2T-DAS44, using the T2T-DAS44-US strategy resulted in a 41% lower likelihood of DAS44 remission [OR (95% CI): 0.59 (0.40;0.87)] and had no effect on radiographic progression [ß(95% CI): 0.11 (- 0.16;0.39)] assessed at various intervals up to 12 months later. CONCLUSION: Our results do not suggest a benefit of using the US7-score in addition to clinical information as a T2T benchmark compared to clinical information alone. Key Points • Ultrasound has a valuable role in diagnostic evaluation of rheumatoid arthritis, but it is unclear whether adding ultrasound to the clinical assessment in a treat-to-target (T2T) strategy leads to more patients achieving remission and reduction in radiographic progression. • Our data from a real-world study demonstrated that adding information from ultrasound to the clinical assessment in a T2T strategy led to a lower rather than a higher likelihood of obtaining clinical remission as compared to using only clinical assessment. • Our data demonstrated that adding ultrasound data to a T2T strategy based only on clinical assessment did not offer additional protection against radiographic progression in patients with RA. • Adding US to a T2T strategy based on clinical assessment led to far more treatment intensifications (with consequences for costs and exposure to adverse events) without yielding a meaningful clinical benefit.

Visualization of polarity changes in endoplasmic reticulum (ER) autophagy and rheumatoid arthritis mice with near-infrared ER-targeted fluorescent probe.

The crucial cellular activities for maintaining normal cell functions heavily rely on the polarity of the endoplasmic reticulum (ER). Understanding how the polarity shifts, particularly in the context of ER autophagy (ER-phagy), holds significant promise for advancing knowledge of disorders associated with ER stress. Herein, a polarity-sensitive fluorescent probe CDI was easily synthesized from the condensation reaction of coumarin and dicyanoisophorone. CDI was composed of coumarin as the electron-donating moiety (D), ethylene and phenyl ring as the π-conjugation bridge, and malononitrile as the electron-accepting moiety (A), forming a typical D-π-A molecular configuration that recognition in the near-infrared (NIR) region. The findings suggested that as the polarity increased, the fluorescence intensity of CDI decreased, and it was accompanied by a redshift of emission wavelength at the excitation wavelength of 524 nm, shifting from 641 nm to 721 nm. Significantly, CDI exhibited a notable ability to effectively target ER and enabled real-time monitoring of ER-phagy induced by starvation or drugs. Most importantly, alterations in polarity can be discerned through in vivo imaging in mice model of rheumatoid arthritis (RA). CDI has been proven effective in evaluating the therapeutic efficacy of drugs for RA. ER fluorescent probe CDI can be optically activated in lysosomes, providing a sensitive tool for studying ER-phagy in biology and diseases.

Microstructural abnormality of white matter tracts in rheumatoid arthritis.

BACKGROUND: Structural and functional brain imaging studies have reported abnormalities of gray matter morphology and functional activities in patients with rheumatoid arthritis (RA). However, it is largely unknown whether patients with RA show alterations of white matter microstructural organization. OBJECTIVES: To automatically identify alteration of white matter microstructure in patients with RA and further examine how this alteration associates with clinical characteristics. METHODS: This single-institutional prospective study included 66 participants (33 patients with RA [52 ± 9 years, 29 women] and 33 sex/age-matched healthy controls [53 ± 12 years, 27 women]), who underwent diffusion MRI scan from January 2021 to December 2021. The white matter microstructure was assessed using fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Voxelwise analyses were conducted on white matter skeleton using an automated, observer-independent tract-based spatial statistics analysis. The relationship between white matter microstructural alterations and clinical and neuropsychological variables was evaluated using correlation analysis. RESULTS: Compared with healthy controls, patients with RA exhibited lower fractional anisotropy in several major white matter tracts (threshold-free cluster enhancement at P < 0.05 for multiple comparison correction, permutation test), involving the forceps minor, bilateral inferior fronto-occipital fasciculus, bilateral anterior thalamic radiation, and bilateral uncinate fasciculus. Lower fractional anisotropy values in the patients with RA were significantly associated with pain-related assessments, including tender joint count (r = -0.43, P = 0.015), Clinical Disease Activity Index score (r = -0.36, P = 0.049), pain severity rated through visual analogue scale (r = -0.45, P = 0.012), and Simplified Disease Activity Index score (r = -0.36, P = 0.045). No significant group difference was found in mean diffusivity, axial diffusivity, and radial diffusivity. CONCLUSIONS: We report the first anatomical evidence for aberrant microstructure organization of several major white matter tracts and its associations with pain processing in patients with rheumatoid arthritis.

Dual-Channel/Localization Single-Molecule Fluorescence Probe for Monitoring ATP and HOCl in Early Diagnosis and Therapy of Rheumatoid Arthritis.

Rheumatoid arthritis (RA), a common chronic inflammatory illness, is still incurable, reducing the sufferers' quality of life significantly. Adenosine 5'-triphosphate (ATP) and hypochlorous acid (HOCl) are key indicators in RA, but their precise mechanisms in RA pathophysiology are unknown. As a result, in order to detect ATP and HOCl simultaneously, we created two new dual-channel/localization single-molecule fluorescence probes, RhTNMB and RhFNMB. Furthermore, RhFNMB outperformed RhTNMB in terms of detection performance. ATP and HOCl produce independent fluorescence responses in the light red channel (λex = 520 nm, λem = 586 nm) and deep red channel (λex = 620 nm, λem = 688 nm), respectively, without spectral crosstalk. It should be noted that the probe RhFNMB successfully imaged ATP in mitochondria and HOCl in cells. Surprisingly, the probe RhFNMB demonstrated remarkable detection ability in the diagnosis and treatment of Pseudomonas aeruginosa-induced abdominal inflammation in mice. We continued to apply the probe RhFNMB to track ATP and HOCl in RA and discovered that ATP and HOCl concentrations were considerably greater in RA joints than in normal joints. We also confirmed the therapeutic effect of methotrexate on RA. This study is the first to achieve dual-channel imaging of ATP and HOCl, which is of great value for the early diagnosis and therapy of RA.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Evento cardiovascular en una cohorte de pacientes con artritis reumatoide en Castilla-La Mancha, utilidad de la ecografía carotídea / Cardiovascular event in a cohort of rheumatoid arthritis patients in Castilla-La Mancha: Utility of carotid ultrasound

La artritis reumatoide (AR) presenta una mortalidad de 1,3-3 veces superior a la población general donde destaca la mortalidad de origen cardiovascular con un 40-50%. Actualmente se considera la enfermedad cardiovascular como una manifestación extraarticular de la AR, siendo un factor de riesgo independiente de los tradicionales, con un riesgo elevado de enfermedad cardiovascular (OR: 1,5-4,0). La medición ecográfica del grosor íntimo medial (GIM) de la arteria carótida común y la presencia de placas ateromatosas es un método no invasivo y marcador subrogado de arterioesclerosis subclínica. Objetivo: Establecer si los hallazgos de arterioesclerosis subclínica por ecografía carotídea pueden ser un buen predictor del desarrollo de eventos cardiovasculares (ECV) en una cohorte de pacientes con AR a 10 años. Metodología: Se evaluó una cohorte de pacientes con AR atendidos en consulta externa de Reumatología de una hospital de Castilla-La Mancha durante el año 2013. Se realizó una evaluación para el desarrollo de ECV a los 10 años siguientes de comenzado el estudio y se analizó su correlación con los hallazgos ecográficos previos de GIM y placas ateromatosas. Resultados: Ocho (24%) pacientes presentaron un ECV. Tres (9%), episodio de fallo cardiaco; 3 (9%) accidente cerebrovascular y 2 (6%) episodio de infarto agudo al miocardio. Los pacientes con AR que desarrollaron un ECV habían presentado un GIM mayor (0,97±0,08mm) en comparación con los pacientes con AR que no tuvieron complicaciones cardiovasculares (0,74±0,15mm) (p=0,003). La presencia de un GIM≥0,9mm y placas ateromatosas representó un riesgo relativo de 12,25 (p=0,012) y 18,66 (p=0,003), respectivamente, para el desarrollo de un ECV. Conclusiones: La ecografía carotídea en pacientes con AR nos podría permitir la detección precoz de aterosclerosis subclínica antes del desarrollo de ECV, siendo fundamentalmente el GIM≥0,9mm el hallazgo más asociado a ECV y no influenciado por la edad.(AU)

Rheumatoid arthritis (RA) has a mortality rate 1.3–3 times higher than the general population, with cardiovascular mortality accounting for 40%–50% of cases. Currently, cardiovascular disease is considered an extra-articular manifestation of RA (OR: 1.5–4.0). Ultrasound measurement of the intima-media thickness (IMT) of the common carotid artery and the presence of atherosclerotic plaques is a non-invasive method and a surrogate marker of subclinical arteriosclerosis. Objective: To determine if subclinical arteriosclerosis findings through carotid ultrasound can serve as a good predictor of cardiovascular events (CVE) development in a cohort of RA patients over a 10-year period. Methodology: A cohort of RA patients seen in the rheumatology outpatient clinic of a hospital in Castilla-La Mancha in 2013 was evaluated. A prospective evaluation for the development of CVE over the following 10 years was conducted, and its correlation with previous ultrasound findings of IMT and atherosclerotic plaques was analyzed. Results: Eight (24%) patients experienced a CVE. Three (9%) had heart failure, three (9%) had a stroke, and two (6%) experienced acute myocardial infarction. RA patients who developed a CVE had a higher IMT (0.97±0.08mm) compared to the RA patients without cardiovascular complications (0.74±0.15mm) (P=.003). The presence of IMT≥0.9mm and atherosclerotic plaques had a relative risk of 12.25 (P=.012) and 18.66 (P=.003), respectively, for the development of a CVE. Conclusions: Carotid ultrasound in RA patients may allow for early detection of subclinical atherosclerosis before the development of CVE, with IMT≥0.9mm being the most closely associated finding with CVE, unaffected by age.(AU)

Cardiovascular event in a cohort of rheumatoid arthritis patients in Castilla-La Mancha: Utility of carotid ultrasound.

Rheumatoid Arthritis (RA) has a mortality rate 1,3 to 3 times higher than the general population, with cardiovascular mortality accounting for 40-50% of cases. Currently, cardiovascular disease is considered an extraarticular manifestation of RA (OR: 1,5-4,0). Ultrasound measurement of the intima-media thickness (IMT) of the common carotid artery and the presence of atherosclerotic plaques (AP) is a non-invasive method and a surrogate marker of subclinical arteriosclerosis. OBJECTIVE: To determine if subclinical arteriosclerosis findings through carotid ultrasound can serve as a good predictor of cardiovascular events (CVE) development in a cohort of RA patients over a 10-year period. METHODOLOGY: A cohort of RA patients seen in the Rheumatology outpatient clinic of a hospital in Castilla La Mancha in 2013 was evaluated. A prospective evaluation for the development of CVE over the following 10 years was conducted, and its correlation with previous ultrasound findings of IMT and AP was analyzed. RESULTS: Eight (24%) patients experienced a CVE. Three (9%) had heart failure, three (9%) had a stroke, and two (6%) experienced acute myocardial infarction. RA patients who developed a CVE had a higher IMT (0,97 +/- 0.08 mm) compared to the RA patients without CV complications (0,74 +/- 0.15 mm) (p = 0,003). The presence of IMT ≥ 0.9 mm and AP had a relative risk of 12,25 (p = 0,012) and 18,66 (p = 0,003), respectively, for the development of a CVE. CONCLUSIONS: Carotid ultrasound in RA patients may allow for early detection of subclinical atherosclerosis before the development of CVE, with IMT ≥ 0.9 mm being the most closely associated finding with CVE, unaffected by age.

Long-term efficacy of a 2-year MRI treat-to-target strategy on disease activity and radiographic progression in patients with rheumatoid arthritis in clinical remission: 5-year follow-up of the IMAGINE-RA randomised trial.

OBJECTIVE: To investigate whether a 2-year MRI treat-to-target strategy targeting the absence of osteitis combined with clinical remission, compared with a conventional treat-to-target strategy targeting clinical remission only (IMAGINE-rheumatoid arthritis (RA) trial) improves clinical and radiographic outcomes over 5 years in patients with RA in clinical remission. METHODS: IMAGINE-more was an observational extension study of the original 2-year IMAGINE-RA randomised trial (NCT01656278). Clinical examinations and radiographs (hands and feet) were obtained yearly. Prespecified coprimary outcomes at year 5 were Disease Activity Score in 28 joints C reactive protein (DAS28-CRP) remission rate (DAS28-CRP<2.6) and no radiographic progression (van der Heijde-modified Sharp score (vdHSS) ≤0) from baseline. Secondary outcomes included 5-year changes in radiographic, MRI and clinical measures of disease activity and physical function. RESULTS: In total 131 patients, 86 women (67%), mean age 61.2, disease duration 9.5 years, median baseline DAS28-CRP 1.9 (IQR 1.6-2.2) and vdHSS 16.0 (IQR 7.0-36.0) were included in the study; 59 (59%) patients from the original MRI treat-to-target group and 72 (72%) from the conventional group. At year 5, 47 patients (80%) in the MRI treat-to-target group vs 54 patients (75%) in the conventional treat-to-target group were in DAS28-CRP remission (OR 2.00 (95% CI 0.76 to 5.28); p=0.16) while 14 patients (24%) vs 19 patients (26%) had no radiographic progression (OR 0.70, (95% CI 0.28 to 1.71); p=0.43). CONCLUSION: A 2-year combined MRI and clinical treat-to-target strategy, compared with a conventional clinical treat-to-target strategy alone, had no effect on the long-term probability of achieving DAS28-CRP remission and of avoiding radiographic progression.

Osteopontin, osteoprotegerin and musculoskeletal ultrasound findings in first-degree relatives of rheumatoid arthritis: potential markers of preclinical disease.

BACKGROUND: First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients are known to have increased risk of developing the disease. The detection of altered bone metabolism in FDRs could be a predictor of the disease. Musculoskeletal ultrasound (MSUS) is known for its ability to detect subclinical joint inflammation in RA, but changes in FDRs are not yet described. We aimed to study serum Osteopontin (OPN) and Osteoprotegerin (OPG) levels in FDRs of RA patients as markers of altered bone metabolism in relation to clinical, laboratory and musculoskeletal ultrasound (MSUS) findings. METHODS: Fifty-five individuals were included, 20 had definite RA, 25 were first degree relatives (FDRs) of RA patients, and 10 healthy controls. Clinical evaluation for joint swelling/tenderness was performed for all. ESR, CRP, rheumatoid factor (RF), anti-citrullinated antibodies (ACPA), OPN, OPG, and Musculoskeletal ultrasound (MSUS) by the US7 score were evaluated. RESULTS: Osteoprotegerin was significantly higher in RA (143.89 pg/ml ± 365.47) than in FDRs (22.23 pg/ml ± 65.73; p = 0.009) and controls (6.20 pg/ml ± 12.43; p = 0.003). OPN was also higher in RA (3.66 ng/ml ± 4.20) than in FDRs (1.97 ng/ml ± 1.04) and controls (2.81 ng/ml ± 1.31), though not significant (p = 0.102). Eight of 25 FDRs (32%) had arthralgia without clinical arthritis and 17/25 (68%) were asymptomatic. FDRs with arthralgia had significantly higher ESR and CRP levels than asymptomatic FDRs (9.82 mm/h ± 4.13; p = 0.003, and 3.93 mg/l ± 3.58; p = 0.003). Osteoprotegerin was higher in FDRs than in controls, and also in those with arthralgia (51.55 pg/ml ± 114.68) than in those without (8.44 pg/ml ± 9.67), though without significant difference. OPN was higher in FDRs with arthralgia (2.09 ng/ml ± 1.19) than in asymptomatic (1.70 ng/ml ± 0.55), also without significant difference. Pathologic findings by US7 were detected in 10/25 (40%) FDRs, of which three (12%) had arthralgia and seven (28%) were asymptomatic. CONCLUSIONS: The raised OPG and lower OPN in FDRs than in controls reflect an altered bone metabolism which could precede clinical disease phase. OPN and OPG could serve as markers of altered preclinical bone metabolism in FDRs of RA. US7 score might be a useful screening tool to identify 'at-risk' individuals.

A Novel Activatable Nanoradiosensitizer for Second Near-Infrared Fluorescence Imaging-Guided Safe-Dose Synergetic Chemo-Radiotherapy of Rheumatoid Arthritis.

The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo-radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer-40 (denoted as IRnR-40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near-infrared fluorescence (NIR-II FL) imaging-guided safe-dose synergetic chemo-radiotherapy. The high concentration of matrix metalloproteinase-9 (MMP-9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR-40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real-time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)-mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR-40 is believed to be the first attempt to achieve efficient NIR-II FL imaging-guided safe-dose chemo-radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases.

Bony proliferations in rheumatoid arthritis, psoriatic arthritis and osteoarthritis using high-resolution peripheral quantitative computed tomography-A systematic literature review.

PURPOSE: Osteoarthritis (OA), rheumatoid arthritis (RA), and psoriatic arthritis (PsA) can all lead to the formation of bony proliferations (BP). This systematic review aimed to examine the characteristics of BPs in patients with RA, PsA, OA, and healthy controls (HC) using high-resolution peripheral quantitative computed tomography (HR-pQCT). Secondarily, we examined any treatment-related effect on BP number and size. METHODS: A systematic literature search was conducted in PubMed and Embase, and a total of 15 studies were included. RESULTS: Seven studies demonstrated a disease-specific variation in BP location. One study showed no difference in the number of BPs between patients with PsA and OA. The number of BPs was greater in patients with PsA compared to RA in one study, and to HC in another study, while one study documented no difference in the number of BPs between patients with RA and HC. Five studies showed larger BPs in patients with PsA compared to HC, and one study larger BPs in patients with PsA compared to RA. One study showed no difference in BP size between patients with PsA and OA. Secukinumab may have a potential effect on arresting BP progression. Otherwise, no other treatment was reported to influence BP size and progression. No standard definitions or measurement techniques for BPs using HR-pQCT have been identified. CONCLUSION: BPs showed disease-specific variations in location, size, and number. Results regarding treatment-related effects are sparse. An agreement on the definition and measurement technique for BPs using HR-pQCT is warranted for diagnostic accuracy, disease comparability, and monitoring potential.

Patient-reported outcomes and radiographic progression in patients with rheumatoid arthritis in sustained remission versus low disease activity.

OBJECTIVE: To compare clinical and patient-reported outcomes (PROs) over 5 years between patients with rheumatoid arthritis (RA) in sustained remission (sREM), sustained low disease activity (sLDA) or active disease (AD) in the first year after diagnosis. METHODS: All patients with RA from the treatment in the Rotterdam Early Arthritis CoHort trial, a multicentre, stratified, single-blinded trial with a treat-to-target approach, aiming for LDA (Disease Activity Score (DAS) ≤2.4), were studied. Patients were categorised into: (1) sREM (mean DAS from 6 to 12 months <1.6) (n=173); (2) sLDA (mean DAS from 6 to 12 months 1.6-2.4) (n=142); and (3) AD (mean DAS from 6 to 12 months >2.4) (n=59). Pain, fatigue, functional impairment, health-related quality of life (HRQoL), health status and productivity loss during 5 years were compared between groups. Radiographic progression (modified Total Sharp Score (mTSS)) was compared over 2 years. RESULTS: Patients in sLDA in the first year had worse PROs during follow-up, compared with patients in sREM: pain (0-10 Likert) was 0.90 units higher (95% CI 0.52 to 1.27), fatigue (Visual Analogue Scale) was 12.10 units higher (95% CI 7.27 to 16.92), functional impairment (Health Assessment Questionnaire-Disability Index) was 0.28 units higher (95% CI 0.17 to 0.39), physical HRQoL (36-item Short Form Health Survey (SF-36) Physical Component Summary score) was 4.42 units lower (95% CI -6.39 to -2.45), mental HRQoL (SF-36 Mental Component Summary score (MCS)) was 2.95 units lower (95% CI -4.83 to -1.07), health status (European Quality of life 5-Dimensions 3-Levels (EQ-5D-3L)) was 0.06 units lower (95% CI -0.09 to -0.03) and productivity loss (0%-100%) was 7.76% higher (95% CI 2.76 to 12.75). Differences between the AD and sREM group were even larger, except for the SF-36 MCS and EQ-5D-3L. No differences in mTSS were found between groups. CONCLUSION: Patients with RA who reach sREM in the first year have better HRQoL and function, and less pain, fatigue and productivity loss in the years thereafter, compared with patients with RA who are in sLDA or AD in the first year.

Precision Medicine in Rheumatology: The Promise of Ultrasound-Guided Synovial Biopsy, Barriers to Its Implementation in the United States, and Proposed Solutions.

PURPOSE OF REVIEW: In the clinical evaluation of inflammatory arthritis and the research into its pathogenesis, there is a growing role for the direct analysis of synovial tissue. Over the years, various biopsy techniques have been used to obtain human synovial tissue samples, and there have been progressive improvements in the safety, tolerability, and utility of the procedure. RECENT FINDINGS: The latest advancement in synovial tissue biopsy techniques is the use of ultrasound imaging to guide the biopsy device, along with evolution in the characteristics of the device itself. While ultrasound guided synovial biopsy (UGSB) has taken a strong foothold in Europe, the procedure is still relatively new to the United States of America (USA). In this paper, we describe the expansion of UGSB in the USA, elucidate the challenges faced by rheumatologists developing UGSB programs in the USA, and describe several strategies for overcoming these challenges.