Blocking of LFA-1 enhances expansion of Th17 cells induced by human CD14(+) CD16(++) nonclassical monocytes.

Among human peripheral blood (PB) monocyte (Mo) subsets, the classical CD14(++) CD16(-) (cMo) and intermediate CD14(++) CD16(+) (iMo) Mos are known to activate pathogenic Th17 responses, whereas the impact of nonclassical CD14(+) CD16(++) Mo (nMo) on T-cell activation has been largely neglected. The aim of this study was to obtain new mechanistic insights on the capacity of Mo subsets from healthy donors (HDs) to activate IL-17(+) T-cell responses in vitro, and assess whether this function was maintained or lost in states of chronic inflammation. When cocultured with autologous CD4(+) T cells in the absence of TLR-2/NOD2 agonists, PB nMos from HDs were more efficient stimulators of IL-17-producing T cells, as compared to cMo. These results could not be explained by differences in Mo lifespan and cytokine profiles. Notably, however, the blocking of LFA-1/ICAM-1 interaction resulted in a significant increase in the percentage of IL-17(+) T cells expanded in nMo/T-cell cocultures. As compared to HD, PB Mo subsets of patients with rheumatoid arthritis were hampered in their T-cell stimulatory capacity. Our new insights highlight the role of Mo subsets in modulating inflammatory T-cell responses and suggest that nMo could become a critical therapeutic target against IL-17-mediated inflammatory diseases.

Molecular maps of synovial cells in inflammatory arthritis using an optimized synovial tissue dissociation protocol.

In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis.

OBJECTIVES: Adalimumab, etanercept and infliximab are effective TNF inhibitors (TNFis) in the treatment of RA, but no randomized clinical trials have compared the three agents. Prior observational data are not consistent. We compared their effectiveness over 1 year in a prospective cohort. METHODS: Analyses were performed on subjects' first episode of TNFi use in the Rheumatic Diseases Portuguese Register, Reuma.pt. The primary outcome was the proportion of patients with European League Against Rheumatism good response sustained at two consecutive observations separated by 3 months during the first year of TNFi use. Comparisons were performed using conventional adjusted logistic regression, as well as matching subjects across the three agents using a propensity score. In addition, baseline predictors of treatment response to TNFi were identified. RESULTS: The study cohort included 617 RA patients, 250 starting etanercept, 206 infliximab and 161 adalimumab. Good response was achieved by 59.6% for adalimumab, 59.2% for etanercept and 51.9% for infliximab (P = 0.21). The modelled probability of good response did not significantly differ across agents (etanercept vs adalimumab OR = 0.97, 95% CI 0.55, 1.71; etanercept vs infliximab OR = 1.25, 95% CI 0.74, 2.12; infliximab vs adalimumab OR = 0.80, 95% CI 0.47, 1.36). Matched propensity score analyses also showed no significant treatment response differences. Greater educational attainment was a predictor of better response, while smoking, presence of ACPA, glucocorticoid use and worse physician assessment of disease activity at baseline each predicted a reduced likelihood of treatment response. CONCLUSION: Over 1 year, we found no difference in effectiveness between adalimumab, etanercept and infliximab.

Smoking is a predictor of worse trabecular mechanical performance in hip fragility fracture patients.

Clinical risk factors (CRFs) are established predictors of fracture events. However, the influence of individual CRFs on trabecular mechanical fragility is still a subject of debate. In this study, we aimed to assess differences, adjusted for CRFs, between bone macrostructural parameters measured in ex-vivo specimens from hip fragility fracture patients and osteoarthritis patients, and to determine whether individual CRFs could predict trabecular bone mechanical behavior in hip fragility fractures. Additionally, we also looked for associations between the 10-year risk of major and hip fracture calculated by FRAX and trabecular bone mechanical performance. In this case-control study, a group of fragility fracture patients were compared with a group of osteoarthritis patients, both having undergone hip replacement surgery. A clinical protocol was applied in order to collect CRFs [body mass index (BMI), prior fragility fracture, parental history of hip fracture, long-term use of oral glucocorticoids, rheumatoid arthritis, current smoking, alcohol consumption, age and gender]. The 10-year probability of fracture was calculated. Serum bone turnover markers were determined and dual X-ray absorptiometry performed. Femoral head diameter was evaluated and trabecular bone cylinders were drilled for mechanical testing to determine bone strength, stiffness and toughness. We evaluated 40 hip fragility fracture and 52 osteoarthritis patients. Trabecular bone stiffness was significantly lower (p = 0.042) in hip fragility fracture patients when compared to osteoarthritic individuals, adjusted for age, gender and BMI. No other macrostructural parameter was statistically different between the groups. In hip fragility fracture patients, smoking habits (ß = -0.403; p = 0.018) and female gender (ß = -0.416; p = 0.008) were independently associated with lower stiffness. In addition, smoking was also independently associated with worse trabecular strength (ß = -0.323; p = 0.045), and toughness (ß = -0.403; p = 0.018). In these patients, the 10-year risk of major (r = -0.550; p = 0.012) and hip fracture (r = -0.513; p = 0.021) calculated using only CRFs was strongly correlated with femoral neck bone mineral density but not with mechanical performance. Our data showed that among fragility fracture patients active smoking is a predictor of worse intrinsic trabecular mechanical performance, and female gender is also independently associated with lower stiffness. In this population, the 10-year risk of fracture using CRFs with different weights only reflects bone mass loss but not trabecular mechanical properties.

Cytokine pattern in very early rheumatoid arthritis favours B-cell activation and survival.

OBJECTIVES: B cells play an important role in the perpetuation of RA, particularly as autoantibody-producing cells. The ICs that further develop deposit in the joints and aggravate the inflammatory process. However, B-cell contribution in the very early stage of the disease remains unknown. The main goal of this work was to determine the concentration of cytokines potentially relevant for B-cell activation in serum from very early polyarthritis patients, with <6 weeks of disease duration, who latter on evolved into very early RA (VERA). METHODS: A proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF) and IL-21 levels were measured by ELISA in the serum of VERA, other very early arthritis (VEA), established RA patients and controls. SF samples of established RA were also analysed. RESULTS: VERA patients have higher levels of APRIL and BAFF as compared with VEA, established RA and controls. Furthermore, APRIL and BAFF levels are also significantly elevated in RA-SF when compared with serum. CONCLUSIONS: The increased levels of APRIL and BAFF in VERA patients suggests that B-cell activation and the development of autoreactive B-cell responses might be crucial in early phases of RA. Therefore, APRIL and BAFF could be promising targets for therapy in the early phase of RA.

Gastric Adenocarcinoma Presenting as a Rheumatoid Factor and Anti-cyclic Citrullinated Protein Antibody-Positive Polyarthritis: A Case Report and Review of Literature.

A 64-year-old male presented with a 6-month history of symmetric polyarthritis involving proximal interphalangeal joints and metacarpophalangeal joints of the hands, wrists, and ankles. Associated symptoms included vomiting, progressive fatigue, and weight loss. Laboratory results showed microcytic anemia, leukocytosis, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and rheumatoid factor (RF) and anti-cyclic citrullinated protein (ACPA) antibody positivity. Joints radiographs were normal, without erosions. Upper endoscopy and gastric endoscopic ultrasonography showed a gastric adenocarcinoma with lymphatic involvement. Intraoperatively, peritoneal carcinomatosis was documented, and the patient started palliative chemotherapy. A paraneoplastic seropositive arthritis was assumed, and treatment with low-dose prednisolone and hydroxychloroquine was started. Arthritis remission was achieved and sustained up to 18 months of follow-up, although gastric cancer progression was documented. We describe a unique phenotype of paraneoplastic arthritis (PA) presenting as a seropositive (RF and ACPA positivity) rheumatoid arthritis (RA) with a good response to both low dose corticosteroids and hydroxychloroquine therapy. We also review the literature of PA, mostly the RA-like pattern, and the association between PA and ACPA positivity. This case highlights the importance of considering underlying cancer in elderly male patients, presenting with polyarthritis and systemic symptoms, even in those with ACPA-positive RA-like arthritis.

Efficacy, Safety, and Sample Quality of Ultrasound-Guided Synovial Needle Biopsy in Clinical Practice and Research: A Prospective Observational Study.

OBJECTIVE: To study the efficacy, tolerability, safety, and sampling variation of ultrasound (US)-guided synovial biopsies performed in clinical practice and research. METHODS: We included all patients who had a US-guided synovial needle biopsy from November 2013 to January 2018. Patients were evaluated for procedure safety and tolerability. Usefulness of synovial biopsy was considered based on contribution for achieving the proposed aims. We analyzed samples for presence and quality of synovial tissue, synovitis score/grade, and pathotype. Variation across patients, samples, section levels, and sampling order was assessed. RESULTS: A total of 64 US-guided synovial biopsies were performed (n = 52 in clinical practice, n = 12 in research). Patient tolerability (70% no/mild discomfort) was remarkably high. There was no significant aggravation of symptoms or US synovitis in the biopsied joint. Procedures were overall safe, with few minor, 2 moderate, and no major adverse events. Usefulness of US-guided synovial biopsies was high, both in clinical practice (37% direct diagnostic impact, 100% positive/95% negative predictive values for infection) and in research (92% success). Synovial tissue was retrieved in 88% of biopsies, with a median of 75% gradable samples. There was significant variation in sample quality and synovitis features across patients and samples, but not between different section levels. Samples collected later in the procedure had a lower frequency of synovial tissue and were poorly concordant in pathotype with those collected earlier. CONCLUSION: US-guided synovial needle biopsy is an effective, safe, and well-tolerated means to collect good quality synovial tissue for clinical and research purposes. Samples collected for different aims should be retrieved in parallel, rather than sequentially.

Considerations for improving quality of care of patients with rheumatoid arthritis and associated comorbidities.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a global prevalence of approximately 0.5-1%. Patients with RA are at an increased risk of developing comorbidities (eg, cardiovascular disease, pulmonary disease, diabetes and depression). Despite this, there are limited recommendations for the management and implementation of associated comorbidities. This study aimed to identify good practice interventions in the care of RA and associated comorbidities. METHODS: A combination of primary research (180+ interviews with specialists across 12 European rheumatology centres) and secondary research (literature review of existing publications and guidelines/recommendations) were used to identify challenges in management and corresponding good practice interventions. Findings were prioritised and reviewed by a group of 18 rheumatology experts including rheumatologists, comorbidity experts, a patient representative and a highly specialised nurse. RESULTS: Challenges throughout the patient pathway (including delays in diagnosis and referral, shortage of rheumatologists, limited awareness of primary care professionals) and 18 good practice interventions were identified in the study. The expert group segmented and prioritised interventions according to three distinct stages of the disease: (1) suspected RA, (2) recent diagnosis of RA and (3) established RA. Examples of good practice interventions included enabling self-management (self-monitoring and disease management support, for example, lifestyle adaptations); early arthritis clinic; rapid access to care (online referral, triage, ultrasound-guided diagnosis); dedicated comorbidity specialists; enhanced communication with primary care (hotline, education sessions); and integrating patient registries into daily clinical practice. CONCLUSION: Learning from implementation of good practice interventions in centres across Europe provides an opportunity to more widely improved care for patients with RA and associated comorbidities.

Ultrasound-Guided Biopsies: Medium and Large Joints.

Ultrasound-guided needle synovial biopsies are useful for clinical practice and research in rheumatology. With the emergence of personalized medicine for the treatment of inflammatory rheumatic diseases, it is predicted that this technique will be increasingly used in the near future. Standardized characterization of the technical aspects of ultrasound-guided needle synovial biopsies is needed in order to produce solid evidence on the safety and effectiveness of the technique.

Treatment of Persistent Cutaneous Atrophy After Corticosteroid Injection With Fat Graft.

Subcutaneous fat atrophy and hypopigmentation are potential adverse side effects of local corticosteroid injection that may resolve spontaneously within 1-2 years. This report shows that fat grafting provides a simple, effective and safe correction of corticosteroid induced cutaneous atrophy with very satisfying esthetic and functional results.

Portuguese recommendations for the use of ultrasound in rheumatology.

INTRODUCTION: Ultrasound (US) is a relatively cheap, easily available and reliable method to improve the care of rheumatic patients. However, its use in rheumatology practice is very heterogeneous and needs to be standardized. OBJECTIVES: To develop recommendations for the use of US in rheumatic diseases endorsed by the Portuguese Society of Rheumatology. METHODS: A systematic literature review of the available recommendations on the use of ultrasound in rheumatic diseases was performed and presented in a Portuguese Society of Rheumatology meeting to a subgroup of rheumatologists and rheumatology trainees with special interest in the subject. The most important topics to be addressed were selected and assigned to subgroups for literature review and draft recommendations. Following an iterative process of consensus, the final recommendations were developed, and their level of agreement voted anonymously online. A recommendation was approved when the average level of agreement was ≥ 7.5 in a 10-point Likert scale. RESULTS: Fourteen recommendations were produced regarding nine rheumatology topics: rheumatoid arthritis, spondyloarthritis, connective tissue diseases, polymyalgia rheumatica, vasculitis, crystal-deposition diseases, soft tissue rheumatism, osteoarthritis and ultrasound-guided procedures. CONCLUSION: We developed an up-to-date guidance in the form of recommendations for the use of US in nine different areas of rheumatology. As ultrasound is an important imaging modality with increasing use in the rheumatology setting, and there are frequent technological advances in the ultrasound machines and probes, in parallel with continuous associated research, these recommendations should be regularly updated.

Ultrasound and its clinical use in rheumatoid arthritis: where do we stand?

High-resolution musculoskeletal ultrasound (MSUS) has been increasingly employed in daily rheumatological practice and in clinical research. In rheumatoid arthritis (RA), MSUS can be now considered a complement to physical examination. This method evaluates synovitis through gray-scale and power Doppler and it is also able to identify bone erosions. The utilization of MSUS as a marker of RA activity has received attention in recent literature. Current data account for good correlation of MSUS with classical measures of clinical activity; in some instances, MSUS appears to perform even better. Diagnosis of subclinical synovitis by MSUS might help the physician in RA management. With some variation, interobserver MSUS agreement seems excellent for erosion and good for synovitis. However, lack of MSUS score standardization is still an unmet need. In this review, we describe several MSUS scores, as well as their correlation with clinical RA activity and response to therapy. Finally, we look at the relationship of MSUS with synovial tissue inflammation and discuss future perspectives for a better interpretation and integration of this imaging method into clinical practice.

B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizumab treatment in rheumatoid arthritis.

BACKGROUND: The use of TNF-inhibitors and/or the IL-6 receptor antagonist, tocilizumab, in rheumatoid arthritis (RA) have pleiotropic effects that also involve circulating B-cells. The main goal of this study was to assess the effect of TNF-inhibitors and tocilizumab on B-cell phenotype and gene expression in RA. METHODS: Blood samples were collected from untreated early RA (ERA) patients, established RA patients under methotrexate treatment, established RA patients before and after treatment with TNF-inhibitors and tocilizumab, and healthy donors. B-cell subpopulations were characterized by flow cytometry and B-cell gene expression was analyzed by real-time PCR on isolated B-cells. Serum levels of BAFF, CXCL13 and sCD23 were determined by ELISA. RESULTS: The frequency of total CD19+ B cells in circulation was similar between controls and all RA groups, irrespective of treatment, but double negative (DN) IgD-CD27- memory B cells were significantly increased in ERA and established RA when compared to controls. Treatment with TNF-inhibitors and tocilizumab restored the frequency of IgD-CD27- B-cells to normal levels, but did not affect other B cell subpopulations. TACI, CD95, CD5, HLA-DR and TLR9 expression on B-cells significantly increased after treatment with either TNF-inhibitors and/ or tocilizumab, but no significant changes were observed in BAFF-R, BCMA, CD69, CD86, CXCR5, CD23, CD38 and IgM expression on B-cells when comparing baseline with post-treatment follow-ups. Alterations in B-cell gene expression of BAFF-R, TACI, TLR9, FcγRIIB, BCL-2, BLIMP-1 and ß2M were found in ERA and established RA patients, but no significant differences were observed after TNF-inhibitors and tocilizumab treatment when comparing baseline and follow-ups. Serum levels of CXCL13, sCD23 and BAFF were not significantly affected by treatment with TNF-inhibitors and tocilizumab. CONCLUSIONS: In RA patients, the use of TNF-inhibitors and/ or tocilizumab treatment affects B-cell phenotype and IgD-CD27- memory B cells in circulation, but not B-cell gene expression levels.

Portuguese Recommendations for the use of biological therapies in patients with rheumatoid arthritis- 2016 update.

OBJECTIVE: To update the recommendations for the treatment of Rheumatoid Arthritis (RA) with biological therapies, endorsed by the Portuguese Society of Rheumatology (SPR). METHODS: These treatment recommendations were formulated by Portuguese rheumatologists based on literature evidence and consensus opinion. At a national meeting the 10 recommendations were discussed and updated. The document resulting from this meeting circulated to all Portuguese rheumatologists, who anonymously voted online on the level of agreement with the recommendations. RESULTS: These recommendations cover general aspects as shared decision, prospective registry in Reuma.pt, assessment of activity and RA impact and treatment objective. Consensus was also achieved regarding specific aspects as initiation of biologic therapy, assessment of response, switching and definition of persistent remission. CONCLUSION: These recommendations may be used for guidance of treatment with biological therapies in patients with RA. As more evidence becomes available and more therapies are licensed, these recommendations will be updated.

Portuguese recommendations for the use of methotrexate in rheumatic diseases - 2016 update.

BACKGROUND: Methotrexate (MTX) is the first-line drug in the treatment of rheumatoid arthritis (RA) and the most commonly prescribed disease modifying anti-rheumatic drug. Moreover, it is also used as an adjuvant drug in patients under biologic therapies, enhancing the efficacy of biologic agents. OBJECTIVES: To review the literature and update the Portuguese recommendations for the use of MTX in rheumatic diseases first published in 2009. METHODS: The first Portuguese guidelines for the use of MTX in rheumatic diseases were published in 2009 and were integrated in the multinational 3E Initiative (Evidence Expertise Exchange) project. The Portuguese rheumatologists based on literature evidence and consensus opinion formulated 13 recommendations. At a national meeting, the recommendations included in this document were further discussed and updated. The document resulting from this meeting circulated to all Portuguese rheumatologists, who anonymously voted online on the level of agreement with the updated recommendations. RESULTS: Results presented in this article are mainly in accordance with previous guidelines, with some new information regarding hepatitis B infection during MTX treatment, pulmonary toxicity monitoring, hepatotoxicity management, association with hematologic neoplasms, combination therapy and tuberculosis screening during treatment. CONCLUSION: The present recommendations combine scientific evidence with expert opinion and attained desirable agreement among Portuguese rheumatologists. The regular update of these recommendations is essential in order to keep them a valid and useful tool in daily practice.