Molecular Factors in PAD2 (PADI2) and PAD4 (PADI4) Are Associated with Interstitial Lung Disease Susceptibility in Rheumatoid Arthritis Patients.

Around 50% of rheumatoid arthritis (RA) patients show some extra-articular manifestation, with the lung a usually affected organ; in addition, the presence of anti-citrullinated protein antibodies (ACPA) is a common feature, which is caused by protein citrullination modifications, catalyzed by the peptidyl arginine deiminases (PAD) enzymes. We aimed to identify single nucleotide variants (SNV) in PADI2 and PADI4 genes (PAD2 and PAD4 proteins, respectively) associated with susceptibility to interstitial lung disease (ILD) in RA patients and the PAD2 and PAD4 levels. Material and methods: 867 subjects were included: 118 RA-ILD patients, 133 RA patients, and 616 clinically healthy subjects (CHS). Allelic discrimination was performed in eight SNVs using qPCR, four in PADI2 and four in PADI4. The ELISA technique determined PAD2 and PAD4 levels in serum and bronchoalveolar lavage (BAL) samples, and the population structure was evaluated using 14 informative ancestry markers. Results: The rs1005753-GG (OR = 4.9) in PADI2 and rs11203366-AA (OR = 3.08), rs11203367-GG (OR = 2.4) in PADI4 are associated with genetic susceptibility to RA-ILD as well as the ACTC haplotype (OR = 2.64). In addition, the PAD4 protein is increased in RA-ILD individuals harboring the minor allele homozygous genotype in PADI4 SNVs. Moreover, rs1748033 in PADI4, rs2057094, and rs2076615 in PADI2 are associated with RA susceptibility. In conclusion, in RA patients, single nucleotide variants in PADI4 and PADI2 are associated with ILD susceptibility. The rs1748033 in PADI4 and two different SNVs in PADI2 are associated with RA development but not ILD. PAD4 serum levels are increased in RA-ILD patients.

Entheseal Involvement in Spondyloarthritis (SpA) and Gout: An Ultrasound Comparative Study.

Objective: To compare the assessment of entheses in subjects with spondyloarthritis (SpA) with patients with gout by the Madrid Sonographic Enthesis Index (MASEI). Method: This cross-sectional study includes videos of entheses evaluated by ultrasound (US) of 30 patients with SpA diagnosed according to the ASAS criteria and 30 patients with gout established by the presence of monosodium urate crystals. Entheses were evaluated for MASEI in 2 Institutes located in two different countries. Demographic and clinical data were registered. Total MASEI score, MASEI-inflammatory, and MASEI-chronic damage were analyzed. Comparisons between groups were obtained by chi-square test and Student's t-test. An inter-reading US reliability was realized. Results: Patients with gout were older and had significantly more comorbidities than those with SpA. The total MASEI score was not significantly different among diseases (p = 0.07). MASEI-inflammatory was significantly more prevalent at the Achilles tendon in SpA, while the proximal patellar tendon was in gout. Power Doppler was higher in SpA compared to gout (p = 0.005). MASEI-chronic damage related to calcification/enthesophytes predominated in gout (p = 0.043), while calcaneal erosions did in SpA (p = 0.008). The inter-reader concordance was excellent (0.93, CI 95% 0.87-0.96, p = 0.001). Conclusions: SpA and gout similarly involve entheses according to MASE, however, some inflammatory and chronic lesions differ significantly depending on the underlying disease and tendon scanned.

Synovial fluid analysis for the enhanced clinical diagnosis of crystal arthropathies in a tertiary care institution.

INTRODUCTION/OBJECTIVES: Few studies have addressed the detection and clinical impact of different crystals in patients with diverse rheumatologic diagnoses in Latin America. The aim of this study was to assess the consistency between the clinical referring diagnosis and the identification of crystals, such as monosodium urate (MSU) and calcium pyrophosphate (CPP), in the synovial fluid (SF) of patients from a Mexican tertiary care institution. METHODS: We reviewed the results of 264 SF analyses to identify any changes in diagnosis upon SF analysis. We reported patient medical file data on sex, age, diagnosis, and microscopic SF analysis results. We performed consistency analyses between referring diagnoses and SF findings with McNemar's test. RESULTS: The prevalence of MSU crystals in SF was noted in 89.1% of gout cases and 9.09% of cases of calcium pyrophosphate disease (CPPD). CPP crystals were present in 54.5% of CPPD cases, 42.9% of osteoarthritis (OA) cases, and 7.27% of gout cases. Calcium hydroxyapatite (HA) crystals were identified in 5.45% of gout cases, 33.3% of rheumatoid arthritis (RA) cases, 57.1% of OA cases, and 63.6% of CPPD cases. Cholesterol and lipid crystals were present in small proportions in RA cases. Glucocorticoid crystals were observed in 1.85% of gout cases, 44.4% of RA cases, and 42.9% of OA cases. We observed an association of MSU identification with clinical suspicion of gout (P = 0.08), CPP with OA (P = 0.26) and CPPD (P = 0.50). An association was noted between HA and the diagnosis of CPPD (P = 0.84) and OA (P > 0.99). The number of initial diagnoses that changed upon SF analysis was 14.3%. CONCLUSIONS: SF analysis has major diagnostic value regarding MSU crystals and gout. Our findings underscore the importance of SF crystal analysis in identifying the prevalence of crystals in the Mexican population. SF analysis provides for better diagnosis of crystal arthropathies and improves the quality of the medical care that the patient receives. Key Points • Synovial fluid analysis in laboratories from developing countries has been scarce. • In some cases, the initial diagnosis is modified after of synovial fluid analysis. • This study confirmed that synovial fluid analysis exhibits major diagnostic value for urate crystals and gout.

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

Correction to: Serum substance P: an indicator of disease activity and subclinical inflammation in rheumatoid arthritis.

Following publication, it was brought to the authors' attention by Dr. Julia Toscano-Garibay that she did not participate as a reviewer of the final version of this manuscript prior to its submission and publication in Clinical Rheumatology.

Plasma let-7i, miR-16, and miR-221 levels as candidate biomarkers for the assessment of ankylosing spondylitis in Mexican patients naïve to anti-TNF therapy.

Novel biomarkers are needed for the diagnosis and clinical assessment of ankylosing spondylitis (AS). Our objective was to investigate plasma microRNAs differentially expressed between AS patients and controls and to evaluate their potential as biomarkers in Mexican subjects. A cross-sectional study including 15 AS patients naïve to anti-TNF therapy and 13 controls was performed. Disease activity, physical function, and global well-being were evaluated by the AS Disease Activity Score (ASDAS-CRP), the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), and the AS Quality of Life Questionnaire (ASQoL), respectively. Total RNA was isolated from plasma of participants and relative expression of let-7i, miR-16, and miR-221 was evaluated. Serum levels of C-reactive protein (CRP), matrix metalloproteinase-1 (MMP-1), MMP-9, and intercellular adhesion molecule-1 (ICAM-1) were also measured. Expression of let-7i was higher in patients than in controls (1.8, 0.9 to 3.4 versus 0.6, 0.4 to 1.2; P = 0.033) with an AUC/ROC of 0.74 (0.54 to 0.93; P = 0.032). Levels of miR-16 and miR-221 were unable to discriminate between patients and controls. Notably, plasma miR-16 levels were inversely correlated with the ASDAS-CRP score (rho - 64, - 0.87 to - 0.18; P = 0.011), the BASFI score (rho - 0.78, - 0.93 to - 0.43; P = 0.001), and serum MMP-1 levels (rho - 0.59, - 0.85 to - 0.09; P = 0.022). No other associations were found. Plasma let-7i levels may serve as a biomarker for the diagnosis of AS in Mexican individuals. Additionally, plasma miR-16 levels are associated with disease activity and physical functionality in patients naïve to anti-TNF therapy.

Levels of Cytokines and MicroRNAs in Individuals With Asymptomatic Hyperuricemia and Ultrasonographic Findings of Gout: A Bench-to-Bedside Approach.

OBJECTIVE: To assess potential associations among serum cytokines and microRNA (miR) levels with ultrasound (US) findings suggestive of urate deposits in chronic asymptomatic hyperuricemia and gout. METHODS: All participants underwent musculoskeletal US and measurements of serum interleukin-1ß (IL-1ß), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, interferon-γ, tumor necrosis factor, monocyte chemoattractant protein 1, and epithelial neutrophil-activating peptide 78, as well as miR-146a, miR-155, and miR-223 levels. RESULTS: Thirty individuals with asymptomatic hyperuricemia, 31 normouricemic controls, and 30 patients with gout were included. The frequency of synovitis and double contour sign using US was similar between asymptomatic hyperuricemia (67% and 27%, respectively) and patients with gout (77% and 27%, respectively), and each had a higher frequency than controls (45% and 0%, respectively). Serum IL-6 and IL-8 levels were similar between patients with asymptomatic hyperuricemia (mean ± SD 69.7 ± 73.4 and 18.5 ± 25.6 pg/ml, respectively) and gout (mean ± SD 75.8 ± 47.6 and 24.4 ± 31.7 pg/ml, respectively), and higher than controls (mean ± SD 28.2 ± 17.6 and 7.4 ± 6.0 pg/ml, respectively). A similar distribution was observed for miR-155 levels in asymptomatic hyperuricemia, patients with gout, and controls (mean ± SD 0.22 ± 0.18, 0.20 ± 0.14, and 0.08 ± 0.04, respectively). Associations between morphostructural abnormalities suggestive of urate deposits (regardless of clinical diagnosis) and serum markers were assessed. Subjects with urate deposits had higher IL-6 (257.2 versus 47.0 pg/ml; P = 0.005), IL-8 (73.2 versus 12.0 pg/ml; P = 0.026), and miR-155 (0.21 versus 0.16; P = 0.015) levels than those without deposition findings. CONCLUSION: In individuals with chronic asymptomatic hyperuricemia, the presence of synovitis and double contour sign by US may represent a subclinical manifestation of monosodium urate crystal nucleation, capable of triggering inflammatory pathways (IL-6 and IL-8) and mechanisms of intercellular communication (miR-155), similar to what is observed in patients with gout.

Serum substance P: an indicator of disease activity and subclinical inflammation in rheumatoid arthritis.

The aim of the is study is to examine the role of serum substance P (SP) levels as a simple biomarker for rheumatoid arthritis (RA) disease activity, its correlation with other markers of disease activity, and with selected clinical parameters. The study comprised 90 RA patients and 24 healthy controls. RA activity was assessed by means of the disease activity 28-C-reactive protein (DAS28-CRP) index and ultrasound power Doppler (USPD) by the German ultrasound score based on seven joints. SP serum values were obtained by means of an ELISA commercial kit. Statistics were achieved by the Student's t test and Spearman correlation analysis with Bonferroni correction. As a group, RA patients had significantly increased levels of SP compared with healthy controls (p < 0.0001). SP levels correlated with DAS28-CRP (r = 0.5050, p < 0.0001), number of tender joints (NTJ, r = 0.4668, p < 0.0001), number of swollen joints (NSJ, r = 0.4439, p < 0.0001), visual analogue scale (VAS, r = 0.5131, p < 0.0001). However, SP did not correlate with CRP levels (r = 0.0468, p = 0.6613), nor with the USPD (r = 0.1740, p = 0.1009). Elevated serum SP is a common feature of RA patients, which also appears to correlate with clinical measurements of disease activity and with subjective clinical data (NTJ and VAS). Thus, although SP is higher in RA patients with high disease activity, it also detects subtle RA disease activity even in patients in apparent remission, which suggests its usefulness for therapeutic decisions.

Reliability of ultrasound grading traditional score and new global OMERACT-EULAR score system (GLOESS): results from an inter- and intra-reading exercise by rheumatologists.

This study aims to test the reliability of ultrasound to graduate synovitis in static and video images, evaluating separately grayscale and power Doppler (PD), and combined. Thirteen trained rheumatologist ultrasonographers participated in two separate rounds reading 42 images, 15 static and 27 videos, of the 7-joint count [wrist, 2nd and 3rd metacarpophalangeal (MCP), 2nd and 3rd interphalangeal (IPP), 2nd and 5th metatarsophalangeal (MTP) joints]. The images were from six patients with rheumatoid arthritis, performed by one ultrasonographer. Synovitis definition was according to OMERACT. Scoring system in grayscale, PD separately, and combined (GLOESS-Global OMERACT-EULAR Score System) were reviewed before exercise. Reliability intra- and inter-reading was calculated with Cohen's kappa weighted, according to Landis and Koch. Kappa values for inter-reading were good to excellent. The minor kappa was for GLOESS in static images, and the highest was for the same scoring in videos (k 0.59 and 0.85, respectively). Excellent values were obtained for static PD in 5th MTP joint and for PD video in 2nd MTP joint. Results for GLOESS in general were good to moderate. Poor agreement was observed in 3rd MCP and 3rd IPP in all kinds of images. Intra-reading agreement were greater in grayscale and GLOESS in static images than in videos (k 0.86 vs. 0.77 and k 0.86 vs. 0.71, respectively), but PD was greater in videos than in static images (k 1.0 vs. 0.79). The reliability of the synovitis scoring through static images and videos is in general good to moderate when using grayscale and PD separately or combined.

Ambroxol for fibromyalgia: one group pretest-posttest open-label pilot study.

A consistent line of investigation proposes that fibromyalgia is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia sodium channels may play a major role in fibromyalgia pain transmission. Ambroxol is a secretolytic agent used in the treatment of various airway disorders. Recently, it was discovered that this compound is also an efficient sodium channel blocker with potent anti-neuropathic pain properties. We evaluated the add-on effect of ambroxol to the treatment of fibromyalgia. We studied 25 patients with fibromyalgia. Ambroxol was prescribed at the usual clinical dose of 30 mg PO 3 times a day × 1 month. At the beginning and at the end of the study, all participants filled out the Revised Fibromyalgia Impact Questionnaire (FIQ-R) and the 2010 ACR diagnostic criteria including the widespread pain index (WPI). At the end of the study, FIQ-R decreased from a baseline value of 62 ± 15 to 51 ± 19 (p = 0.013). Pain visual analogue scale decreased from 77 ± 14 to 56 ± 30 (p = 0.018). WPI diminished from 14.6 ± 3.1 to 10.4 ± 5.3 (p = 0.001). Side effects were minor. In this pilot study, the use of ambroxol was associated to decreased fibromyalgia pain and improved fibromyalgia symptoms. The open nature of our study does not allow extracting the placebo effect from the positive results. The drug was well tolerated. Ambroxol newly recognized pharmacological properties could theoretically interfere with fibromyalgia pain pathways. Dose escalating-controlled studies seem warranted.

Exudado en «arcilla blanca» en gota tofácea crónica / White clay drainage in chronic tophaceous gout

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Joint involvement in primary Sjögren's syndrome: an ultrasound "target area approach to arthritis".

OBJECTIVE: To characterize the ultrasound (US) pattern of joint involvement in primary Sjögren's syndrome (pSS). METHODS: Seventeen patients with pSS, 18 with secondary Sjögren's syndrome (sSS), and 17 healthy controls underwent US examinations of various articular regions. Synovitis (synovial hypertrophy/joint effusion), power Doppler (PD) signals, and erosions were assessed. RESULTS: In patients with pSS, synovitis was found in the metacarpophalangeal joints (MCP, 76%), wrists (76%), and knees (76%), while the proximal interphalangeal joints, elbows, and ankles were mostly unscathed. Intra-articular PD signals were occasionally detected in wrists (12%), elbows (6%), and knees (6%). Erosions were evident in the wrists of three (18%) patients with pSS, one of these also having anti-cyclic citrullinated peptide (anti-CCP) antibodies. While US synovitis does not discriminate between sSS and pSS, demonstration of bone erosions in the 2nd MCP joints showed 28.8% sensitivity and 100% specificity for diagnosing sSS; in comparison, these figures were 72.2 and 94.1% for circulating anti-CCP antibodies. CONCLUSIONS: In pSS, the pattern of joint involvement by US is polyarticular, bilateral, and symmetrical. Synovitis is the US sign most commonly found in patients with pSS, especially in MCP joints, wrists, and knees, and bone erosions also may occur.

Sternoclavicular joint involvement in rheumatoid arthritis: clinical and ultrasound findings of a neglected joint.

OBJECTIVE: To describe the prevalence of sternoclavicular (SC) joint involvement and the relationship between clinical and ultrasound (US) findings in patients with rheumatoid arthritis (RA). METHODS: One hundred three consecutive patients with RA and 103 age- and sex-matched healthy individuals were enrolled. Clinical evaluation and blinded US examinations of the SC joint were performed bilaterally in both groups. The presence of gray-scale synovitis, osteophytes, erosions, and intraarticular power Doppler (PD) was recorded. Interobserver agreement was calculated. RESULTS: A total of 412 SC joints were evaluated: 206 from patients with RA and 206 from healthy controls. In the RA group, 39 joints (19%) were found to be clinically involved (pain/swelling), in contrast to only 4 (1.9%) in the control group (P = 0.0001). In the RA group, US abnormalities were recorded in 89 SC joints (43%) compared with 36 (17%) in the healthy control group (P = 0.0001), comprising osteophytes in 59 (29%) versus 25 (12%; P = 0.0001), synovitis in 31 (15%) versus 5 (2%; P = 0.0001), erosions in 23 (11%) versus none (P = 0.0001), and intraarticular PD in 5 (2%) versus none (P = 0.03). Furthermore, a correlation between the presence of US synovitis (P < 0.001) and intraarticular PD (P < 0.0001) with a higher Disease Activity Score in 28 joints (DAS28) was found. CONCLUSION: In patients with RA, US detected a higher number of involved SC joints than with clinical assessment. Our results indicate that both gray-scale and PD US findings were more prevalent in patients with RA than in healthy controls. US synovitis and synovial hyperperfusion correlated with the DAS28, suggesting that SC joints actively participate in the systemic inflammatory process of RA.

Utilidad del ultrasonido en osteoartritis: un enfoque de su rol diagnóstico y de monitoreo / Ultrasound in osteoarthritis: its role in the diagnosis and the disease monitoring

Ultrasonography (US) has been steadily and progressively gaining ground in the diagnostic approach to different areas of Rheumatology due to a combination of factors ranging from its low cost and portability, advantages related to the characteristics of the method, as the absence of ionizing radiation, the possibility of multiplanar imaging, high resolution real time and dynamic maneuvers to assess musculoskeletal structures with maximum functionality. Its specific role in osteoarthritis (OA) has allowed a detailed evaluation of the degenerative process, quantification of early or pre-radiological OA stages. The superb resolution of high power ultrasound probes can identify minimum alterations in the articular cartilage, bone tissue and other anatomical elements that contribute to OA. The aim of this review is to describe the major ultrasound findings in OA, and its usefulness as a diagnostic and monitoring disease progression in this rheumatic disease.

La ultrasonografía (US) viene ganando espacios, de manera continua y progresiva, en el abordaje diagnóstico de distintas áreas de la Medicina debido a una suma de factores que van desde su bajo costo y su portabilidad hasta ventajas relacionadas con las características propias del método, como la ausencia de radiación ionizante, la posibilidad de obtención de imágenes multiplanares de alta resolución en tiempo real, y de realizar maniobras dinámicas que permiten evaluar las estructuras en su máxima funcionalidad. Su específico rol en la evaluación de la osteoartritis se va afirmando a medida que se van generando métodos de evaluación que permiten una detallada cuantificación del proceso degenerativo, inclusive en las fases precoces o prerradiológicas. El magnífico poder de resolución de las sondas de última generación permite individualizar alteraciones mínimas de los elementos anatómicos frecuentemente comprometidos en la osteoartritis, como el cartílago articular y el tejido óseo. El objetivo de esta revisión es el de describir los hallazgos ultrasonográficos en osteoartritis, y su utilidad como herramienta diagnóstica y de seguimiento.

Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study.

INTRODUCTION: In this study, we aimed to investigate ultrasonographic (US) changes suggestive of gouty arthritis in the hyaline cartilage, joints and tendons from asymptomatic individuals with hyperuricemia. METHODS: We conducted a cross-sectional, controlled study including US examinations of the knees and first metatarsal-phalangeal joints (first MTPJs), as well as of the tendons and enthesis of the lower limbs. Differences were estimated by χ² or unpaired t-tests as appropriate. Associations were calculated using the Spearman's correlation coefficient rank test. RESULTS: Fifty asymptomatic individuals with hyperuricemia and 52 normouricemic subjects were included. Hyperechoic enhancement of the superficial margin of the hyaline cartilage (double contour sign) was found in 25% of the first MTPJs from hyperuricemic individuals, in contrast to none in the control group (P < 0.0001). Similar results were found on the femoral cartilage (17% versus 0; P < 0.0001). Patellar enthesopathy (12% versus 2.9%; P = 0.01) and tophi (6% versus 0; P = 0.01) as well as Achilles enthesopathy (15% versus 1.9%; P = 0.0007) were more frequent in hyperuricemic than in normouricemic individuals. Intra-articular tophi were found in eight hyperuricemic individuals but in none of the normouricemic subjects (P = 0.003). CONCLUSIONS: These data demonstrate that morphostructural changes suggestive of gouty arthritis induced by chronic hyperuricemia frequently occur in both intra- and extra-articular structures of clinically asymptomatic individuals.

Pan-American League of Associations for Rheumatology (PANLAR) recommendations and guidelines for musculoskeletal ultrasound training in the Americas for rheumatologists.

OBJECTIVE: To develop guidelines for Musculoskeletal Ultrasound (MSKUS) training for rheumatologists in the Americas. METHODS: A total of 25 Rheumatologists from 19 countries of the American Continent participated in a consensus-based interactive process (Delphi method) using 2 consecutive electronic questionnaires. The first questionnaire included the following: the relevance of organizing courses to teach MSKUS to Rheumatologists, the determination of the most effective educational course models, the trainee levels, the educational objectives, the requirements for passing the course(s), the course venues, the number of course participants per instructor, and the percentage of time spent in hands-on sessions. The second questionnaire consisted of questions that did not achieve consensus (>65%) in the first questionnaire, topics, and pathologies to be covered at each course MSKUS level. RESULTS: General consensus was obtained for MSKUS courses to be divided into 3 educational levels: basic, intermediate, and advanced. These courses should be taught using a theoretical-didactic and hands-on model. In addition, the group established the minimum requirements for attending and passing each MSKUS course level, the ideal number of course participants per instructor (4 participants/instructor), and the specific topics and musculoskeletal pathologies to be covered. In the same manner, the group concluded that 60% to 70% of course time should be focused on hands-on sessions. CONCLUSION: A multinational group of MSKUS sonographers using a consensus-based questionnaire (Delphi method) established the first recommendations and guidelines for MSKUS course training in the Americas. Pan-American League of Associations for Rheumatology urges that these guidelines and recommendations be adopted in the future by both national and regional institutions in the American continent involved in the training of Rheumatologists for the performance of MSKUS.