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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 naive 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 naive to anti-TNF therapy.

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.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.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 (P0.99). The number of initial diagnoses that changed upon SF analysis was 14.3%.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.

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-1β (IL-1β), 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.

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.

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.

Background: Golimumab is a human anti-TNF monoclonal antibody that has shown efficacy in RA. In the RA pathophysiology, the elevation of TNF modulates the cellular immune response, which leads to a sustained activation of T-cell response; however, it is unknown whether anti-TNF interferes with the immunophenotype of T-cell. Objectives: To evaluate activation (CD25, CD69) and exhausted (PD-1, TIM-3, LAG-3, CTLA-4) markers of T-cells in RA patients treated with Golimumab. Methods: We included 14 patients with RA diagnosis (Criteria ACR/EULAR 2010), with moderate to severe activity; 11 non-responders to synthetic DMARDs (NR-DMARDs) and 3 responders to synthetic DMARDs with pharmacological toxicity (R-DMARDs). All patients were treated with Golimumab during 24 weeks. The questionnaire SF-36, DAS28-CRP, power Doppler signal and expression of CD25, CD69, PD-1, TIM-3, LAG-3 and CTLA-4, in T-cell were evaluated at 0 and 24 weeks. Results: Clinical variables evaluated in patients with Rheumatoid Arthritis are shown in tables 1 and 2. The frequency of LAG-3+ on CD4+ T-cells increased after 24 weeks of treatment with Golimumab (p = 0.013) (figure 1). The expression of LAG-3 in CD4+ T-cells (r = -0.586, p = 0.028) (Figure 2) and CD8+ T-cells (r = -0.617, p = 0.019) (Figure 3) inversely correlated with DAS28-CRP after treatment. At the beginning of treatment NR-DMARDs patients showed higher expression of CD25 in CD8+ T-cells and lower expression of TIM-3 in CD4+ and CD8+ T-cells with respect to R-DMARDs. After 24 weeks of treatment, a lower frequency of CD69+ and LAG-3+ T-cells was found and increased of CD25+ T-cells compared to R-DMARDs. Conclusion: Golimumab treatment increased the expression of LAG-3 in T-cells, suggesting a negative regulator of antigen presentation of T-cells. References [1] Tahir Z, Kavanaugh A. The role of golimumab in inflammatory arthritis. A review of the evidence. Ther Adv Musculoskel Dis2018;9:181–194. [2] Cuda C, Pope R, Perlman H. The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Nat rev Rheumatol2016;12: 543-555. [3] Wherry E, Kurachi M. Molecular and celular insights into T cell exhaustion. Nat rev Inmunol 2015;15: 486-496. [4] Burmester G, Feist E, Dorner T. Emerging cell and cytokine targets in rheumatoid arthritis. Nat rev Inmunol2013;15:1-10. [5] McKinney E, Lee J, Jayne D, Lyons P. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nat rev Inmunol2015;523: 612-616. Disclosure of Interests: None declared

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.

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

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.

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.

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.

Primary Sjogren’s syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration leading to destruction of acinar and ductal cells and loss of glandular parenchyma. Although sicca symptoms are pivotal manifestations of pSS, extraglandular involvement also occurs. Pulmonary involvement in pSS consists of interstitial lung disease, obstructive small airway disease, pulmonary arterial hypertension (PAH), bullous disease, and lymphoma1. Recent evidence suggests that cytokine-mediated mechanisms are critical in pSS, but the precise cytokine pattern driving lung injury remains unclear2–4. Because of current availability of therapies that modulate selected cytokines, in-depth knowledge of the cytokine profile associated to specific tissue damage is necessary. We analyzed circulating concentrations of several prototypical TH1 [interferon-γ (IFN-γ)], TH2 [interleukin 4 (IL-4), IL-6, IL-10], and TH17 (IL-17) cytokines in patients with pSS according to the presence or absence of pulmonary involvement. From an outpatient cohort with pSS according to the preliminary classification criteria5 we selected patients who had pulmonary involvement demonstrated by high-resolution computed tomography scans of the lungs, and at least one of the following: pulmonary function test, spirometry, or lung biopsy. For comparisons, we selected age and gender-matched pSS patients without pulmonary manifestations and normal chest radiograph. We excluded … Address correspondence to Dr. L.M. Amezcua-Guerra; E-mail: lmamezcuag{at}gmail.com

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.