Tender to touch-Prevalence and impact of concomitant fibromyalgia and enthesitis in spondyloarthritis: An ancillary analysis of the ASAS PerSpA study.

OBJECTIVES: The primary objective was to evaluate the co-existence of fibromyalgia (FM) & enthesitis in individuals with spondyloarthritis (SpA). Secondary objectives were to identify clinical features associated with the presence of FM in enthesitis and analyse sex-specific differences. METHODS: This was an ancillary analysis of the Assessment of SpondyloArthritis International Society Peripheral Involvement in SpA (PerSpA) study. Enthesitis was defined as the presence of enthesitis ever. Clinical FM was defined as the rheumatologist's confirmation of the presence of FM. A score of≥5/6 on the Fibromyalgia Rapid Screening Test (FiRST) defined a positive screening test for FM. RESULTS: Enthesitis ever and FM (EFM) co-existed in 10.3% (n=425) of the cohort using FiRST criteria and 5.3% using clinical diagnosis of FM. More individuals with FM by clinical diagnosis had imaging-confirmed enthesitis ever than by FiRST criteria. More females had EFM than males, defined clinically (76.9% vs 23.1%) or by FiRST criteria (62.6% vs 37.4%). Individuals with EFM had more severe disease across all measures compared to those with enthesitis only, with no significant difference between sexes. EFM was significantly associated with age, female sex, BMI, BASDAI and region. CONCLUSION: FM is an important comorbidity in the setting of enthesitis in SpA. While EFM is more common in females, it is not a rare condition in males. EFM is associated with worse disease severity measures in SpA in both males and females. Recognition of FM in the setting of enthesitis is essential to prevent overtreatment and optimise patient outcomes.

Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells.

Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4+ mECs are enriched in red oxidative muscle areas while ATF3/4low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4+ mECs are more angiogenic when compared with white ATF3/4low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4+) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.

Endothelial Lactate Controls Muscle Regeneration from Ischemia by Inducing M2-like Macrophage Polarization.

Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.

Pharmacological treatment for managing bone health in axial spondyloarthropathy: systematic review and meta-analysis.

Axial spondyloarthropathy (axSpA) is associated with an increased prevalence of osteoporosis, but no recommendations exist to guide management. This systematic review and meta-analysis aim to assess the efficacy of pharmacological and non-pharmacological interventions on bone mineral density (BMD) in axSpA. Electronic databases were searched from inception to June 2019 for randomised controlled trials (RCTs) and quasi (q)-RCTs with pharmacological and non-pharmacological interventions. Independent reviewers undertook screening, and risk of bias and quality assessments. Primary outcomes of interest were BMD at spine and hip. Eight studies (two RCTs and six qRCTs) were included (602 participants). Moderate level evidence favoured alendronate over placebo at femoral neck [mean difference (MD) 2.01, 95% CI 0.67 to 3.35], but there was low-level evidence showing no effect at the spine. There was moderate level evidence showing no effect of tumour necrosis factor inhibitors (TNFi) on BMD at total hip (MD - 0.01, 95% CI - 0.06 to 0.04). Very low-level evidence demonstrated no effect of TNFi on spine or femoral neck. Moderate level evidence favoured neridronate over infliximab at the spine (MD 3.26, 95% CI 1.14 to 5.38), but low-level evidence showed no effect at the total hip (MD 2.75, 95% CI - 0.21 to 5.71). There were no eligible studies investigating the efficacy of non-pharmacological interventions. We conditionally recommend alendronate for management of low BMD in axSpA. The balance of evidence does not recommend the use of TNF-inhibitors for treating low BMD. There is a lack of high-quality evidence guiding clinicians treating osteoporosis in axSpA.

The Warburg Effect in Endothelial Cells and its Potential as an Anti-angiogenic Target in Cancer.

Endothelial cells (ECs) make up the lining of our blood vessels and they ensure optimal nutrient and oxygen delivery to the parenchymal tissue. In response to oxygen and/or nutrient deprivation, ECs become activated and sprout into hypo-vascularized tissues forming new vascular networks in a process termed angiogenesis. New sprouts are led by migratory tip cells and extended through the proliferation of trailing stalk cells. Activated ECs rewire their metabolism to cope with the increased energetic and biosynthetic demands associated with migration and proliferation. Moreover, metabolic signaling pathways interact and integrate with angiogenic signaling events. These metabolic adaptations play essential roles in determining EC fate and function, and are perturbed during pathological angiogenesis, as occurs in cancer. The angiogenic switch, or the growth of new blood vessels into an expanding tumor, increases tumor growth and malignancy. Limiting tumor angiogenesis has therefore long been a goal for anticancer therapy but the traditional growth factor targeted anti-angiogenic treatments have met with limited success. In recent years however, it has become increasingly recognized that focusing on altered tumor EC metabolism provides an attractive alternative anti-angiogenic strategy. In this review, we will describe the EC metabolic signature and how changes in EC metabolism affect EC fate during physiological sprouting, as well as in the cancer setting. Then, we will discuss the potential of targeting EC metabolism as a promising approach to develop new anti-cancer therapies.