Explore the vast range of titles available.

Morphological and functional analysis of the microcirculation are objective outcome measures that are recommended for use in the presence of clinical signs of altered peripheral blood flow (such as Raynaud phenomenon), which can occur in systemic sclerosis (SSc) and other autoimmune rheumatic diseases. Several advanced non-invasive tools are available for monitoring the microcirculation, including nailfold videocapillaroscopy, which is the best-studied and most commonly used method for distinguishing and quantifying microvascular morphological alterations in SSc. Nailfold videocapillaroscopy can also be used alongside laser Doppler techniques to assist in the early diagnosis and follow-up of patients with dermatomyositis or mixed connective tissue disease. Power Doppler ultrasonography, which has been used for many years to evaluate the vascularity of synovial tissue in rheumatoid arthritis, is another promising tool for the analysis of skin and nailbed capillary perfusion in other autoimmune rheumatic diseases. Other emerging methods include raster-scanning optoacoustic mesoscopy, which offers non-invasive high-resolution 3D visualization of capillaries and has been tested in psoriatic arthritis and SSc. The principle functions and operative characteristics of several non-invasive tools for analysing microvascular changes are outlined in this Review, and the clinical roles of validated or tested imaging methods are discussed for autoimmune rheumatic diseases.Analysis of the microcirculation is useful in the differential diagnosis of primary and secondary Raynaud phenomenon and in the diagnosis and monitoring of several rheumatic diseases, including systemic sclerosis. This Review provides an overview of techniques for microvascular analysis.

In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.The effects of sex steroids (oestrogens, androgens and progesterone) on immune responses contribute to the sex bias in autoimmune rheumatic diseases in complex ways. Targeting these effects could hold potential for treating patients with autoimmune rheumatic diseases.

Alfonse T. Masi (born October 1930) passed away peacefully and comfortably in his home in March 2025 at the age of 94 years after a prestigious career...

Rheumatoid arthritis (RA) is an invalidating chronic autoimmune disorder characterized by joint inflammation and progressive bone damage. Dietary intervention is an important component in the treatment of RA to mitigate oxidative stress, a major pathogenic driver of the disease. Alongside traditional sources of antioxidants, microalgae—a diverse group of photosynthetic prokaryotes and eukaryotes—are emerging as anti-inflammatory and immunomodulatory food supplements. Several species accumulate therapeutic metabolites—mainly lipids and pigments—which interfere in the pro-inflammatory pathways involved in RA and other chronic inflammatory conditions. The advancement of the clinical uses of microalgae requires the continuous exploration of phytoplankton biodiversity and chemodiversity, followed by the domestication of wild strains into reliable producers of said metabolites. In addition, the tractability of microalgal genomes offers unprecedented possibilities to establish photosynthetic microbes as light-driven biofactories of heterologous immunotherapeutics. Here, we review the evidence-based anti-inflammatory mechanisms of microalgal metabolites and provide a detailed coverage of the genetic engineering strategies to enhance the yields of endogenous compounds and to develop innovative bioproducts.

Correspondence to Professor Maurizio Cutolo; mcutolo@unige.it Introduction In their original article, Park et al investigated the differences in terms of clinical outcomes between early menopause (EM) (<45 years) and usual menopause (UM) (≥45 years) in a large nationwide cohort of patients with rheumatoid arthritis (RA), highlighting the impact of EM on longitudinal changes in RA activity and patient-reported outcomes (PROs).1 As a result, the EM group demonstrated a higher disease activity and worse PROs for global assessment, fatigue, sleep disturbance and health-related quality of life than UM group in a 5-year follow-up period. [...]for the first time, the study investigated the association between age at menopause and clinical impact in patients with RA using validated disease activity indices and PROs during their follow-up.1 The clinical results of the analysis suggest possible pathophysiological interpretations based on the complex role played by oestrogens in immune response and in particular in the higher risk and severity of RA disease activity during menopause. [...]onset and progression of chronic autoimmune rheumatic diseases such as RA are more commonly observed in women rather than men and are correlated with ageing and menopause, the last characterised by the permanent cessation of ovulation with subsequent hypo-oestrogenaemia.2 The partial loss of the immunomodulatory effects exerted by oestrogens is an important factor responsible for the negative clinical outcomes observed in patients with RA during menopause.3 Consequently, the decrease in oestrogen concentrations after menopause could contribute to the reported negative effects on disease progression and severity in patients affected by RA.4 Dichotomous effects of oestrogens on immune response Male and female gonadal hormones have important proinflammatory and anti-inflammatory effects on the immune system, as clearly demonstrated by in vitro and in vivo (both animal and human) studies of different pathological conditions.3 Androgens have direct and indirect anti-inflammatory effects on immune system with a significant lower risk of developing autoimmune rheumatic diseases in men than women.5 By contrast, oestrogens exert both complex proinflammatory and anti-inflammatory effects that may differ depending on the cell type mainly involved in the specific autoimmune disease onset and progression (ie, T or B cells) and on the doses or concentrations involved (exogenous and/or endogenous sources).6 Usually, oestrogens exert proinflammatory effects on B cells and anti-inflammatory effects on T cells, especially at high concentrations, by inhibiting T helper 1 (TH1) cells, TH17 cells via oestrogen receptor-α (nevertheless, an opposite effect can be observed via oestrogen receptor-β) and on macrophages.3 7 8 Additionally, oestrogens seem to support regulatory T cells and TH2 cell-associated cytokines production (interleukin (IL)-4, IL-10 and transforming growth factor-β).3 7 8 However, low endogenous oestrogen concentrations may increase the risk of developing autoimmune rheumatic diseases mainly driven by T cells. [...]the immune modulatory activities exerted by oestrogens play essential roles and may address the clinical outcomes during pregnancy or menopause in women affected by the most diffuse autoimmune rheumatic diseases.10 Modifications of the maternal immune system during pregnancy enable both the tolerance towards the fetus and the defence against infections, and these modifications induce almost a natural improvement in disease activity as observed in patients with RA. [...]pregnancy and its related increase of oestrogen levels are commonly considered protective elements against disease flares in patients with RA, as shown by a lower disease activity at the beginning of pregnancy (table 1).11 However, gravidity did not show to be a potential risk factor for RA development in healthy women (table 1).12 On the other hand, post partum and breast feeding are linked to disease flares in almost all rheumatic diseases, including RA.13 The immunomodulatory action exerted by the steroidal hormones produced by the placenta during pregnancy expires in the post partum leading to disease flares, as commonly observed in patients with RA. [...]HRT increases the risk of worsening SLE disease activity, according to the HRT-SELENA trial.23 Moreover, HRT was found to induce mild-to-moderate flares in this disease.23 By contrast, HRT in menopause might have generally protective effects in RA that is mainly driven by T cells, with a small but significant increased risk of disease worsening in patients with seropositive RA that are accordingly characterised by prevalent B cell activation (table 1).24–26 In conclusion, in the study of Park et al, no significant differences were observed between menopausal groups regarding previous or current use of HRT, even if it was found employed more frequently in EM, as expected.1 Oestrogens, menopause and cancer risk Oestrogens not only modulate immune responses but are also involved in the development and spread of malignant tumours enhancing the progression of a range of hormonally responsive tumours, including in female breast and other gynaecological cancers.27 For example, in patients with breast cancer, the inhibition of androgen-to-oestrogen conversion by aromatase inhibitors has been found associated with an increased risk of RA.28 Same results were found from literature review of case reports that reported positive associations between aromatase inhibitor use and RA.29 Remarkably, the use of aromatase inhibitors does not induce a

ObjectivesTo determine the causes of death and risk factors in systemic sclerosis (SSc).MethodsBetween 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.ResultsWe identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.ConclusionCombining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Background Systemic sclerosis (SSc) is a disorder characterized by immune system alterations, vasculopathy and fibrosis. SSc-related interstitial lung disease (ILD) represents a common and early complication, being the leading cause of mortality. Monocytes/macrophages seem to have a key role in SSc-related ILD. Interestingly, the classically (M1) and alternatively (M2) activated monocyte/macrophage phenotype categorization is currently under revision. Our aim was to evaluate if circulating monocyte/macrophage phenotype could be used as biomarker for lung involvement in SSc. To this purpose we developed a wide phenotype characterization of circulating monocyte/macrophage subsets in SSc patients and we evaluated possible relations with lung involvement parameter values. Methods A single centre cross-sectional study was performed in fifty-five consecutive SSc patients, during the year 2017. All clinical and instrumental tests requested for SSc follow up and in particular, lung computed tomography (CT) scan, pulmonary function tests (PFTs), Doppler echocardiography with systolic pulmonary artery pressure (sPAP) measurement, blood pro-hormone of brain natriuretic peptide (pro-BNP) evaluation, were performed in each patient in a maximum one-month period. Flow cytometry characterization of circulating cells belonging to the monocyte/macrophage lineage was performed using specific M1 (CD80, CD86, TLR2 and TLR4) and M2 surface markers (CD204, CD163 and CD206). Non-parametric tests were used for statistical analysis. Results A higher percentage of circulating CD204 + CD163 + CD206 + TLR4 + CD80 + CD86 + and CD14 + CD206 + CD163 + CD204 + TLR4 + CD80 + CD86 + mixed M1/M2 monocyte/macrophage subsets, was identified to characterize patients affected by SSc-related ILD and higher systolic pulmonary artery pressure. Mixed M1/M2 monocyte/macrophage subset showed higher percentages in patients positive for anti-topoisomerase antibody, a known lung involvement predictor. Conclusions The present study shows for the first time, through a wide flow cytometry surface marker analysis, that higher circulating mixed M1/M2 monocyte/macrophage cell percentages are associated with ILD, sPAP and anti-topoisomerase antibody positivity in SSc, opening the path for research on their possible role as pathogenic or biomarker elements for SSc lung involvement.

Background: The role of nutrition in the pathogenesis of rheumatic diseases, including rheumatoid arthritis (RA), has gained increasing attention in recent years. A growing number of studies have focussed on the diverse nutritional contents of beverages, and their possible role in the development and progression of RA. Main body: We aimed to summarise the current knowledge on the role of a range of beverages in the context of RA. Beverages have a key role within the mosaic of autoimmunity in RA and potential to alter the microbiome, leading to downstream effects on inflammatory pathways. The molecular contents of beverages, including coffee, tea, and wine, have similarly been found to interfere with immune signalling pathways, some beneficial for disease progression and others less so. Finally, we consider beverages in the context of wider dietary patterns, and how this growing body of evidence may be harnessed by the multidisciplinary team in patient management. Conclusions: While there is increasing work focussing on the role of beverages in RA, integration of discussions around diet and lifestyle in our management of patients remains sparse. Nutrition in RA remains a controversial topic, but future studies, especially on the role of beverages, are likely to shed further light on this in coming years.

Correspondence to Professor Maurizio Cutolo; mcutolo@unige.it Introduction Vitamin D and COVID-19 A growing number of concordant reports support a protective role for vitamin D in reducing at least the risk/severity of respiratory tract infections (RTIs), especially in the influenza and COVID-19 context.1–5 Major clinical reports show that vitamin D deficiency contribute to acute respiratory distress syndrome (ARDS) SARS-CoV-2 and that case-fatality rates increase with age and the highest SARS-CoV-2 serum concentrations.6 7 In addition, the outbreak of COVID-19 seems to occur mainly in the cold winter time, when serum 25-hydroxyvitamin D (25(OH)D—calcidiol or calcifediol) concentrations are the lowest, as well as the ultraviolet B (UVB) doses, whereas the number of cases in the Southern Hemisphere near the end of summer are lower.8- Targeted 25(OH)D serum concentration measurements and vitamin D supplementation is strongly suggested have important patient and public health benefits.9 The positive role of vitamin D replacement therapy (vDRT) in reducing risk and severity in COVID-19 patients is supported by several clinical evidences and RCTs are undergoing, however, previous experiences of RCT related to vDRT are available from other lung viral infection studies and even in mechanically ventilated adult intensive care unit (ICU) patients.10–14 These important observations are corroborated by several biological/molecular mechanisms through vitamin D can generally reduce risk of infections and downregulate the immune/inflammatory reaction. The discovered presence of the VDR in activated T cells and monocytes, first suggested in 1983 that vitamin D may have a role in the function of the immune system.19 As matter of fact, vitamin D has received increased worldwide attention for its involvement in reducing risk for several chronic diseases, besides infectious diseases, including type 1 diabetes and notably autoimmune rheumatic diseases for the reason that may interfere with the immune system.20 The biological/molecular evidence for the interactions of vitamin D with the immune response is that its final active metabolite, namely calcitriol (1,25(OH)2D3), due to its structural origin from cholesterol, is molecularly considered a steroid hormone (D-hormone) like others (ie, sex hormones, cortisol) and analogously to glucocorticoids (and sex hormones) can exerts immunomodulatory/antinflammatory activities through functional cell steroid receptors21–23 (figure 1). Furthermore, the intensity and quality of the host immune/inflammatory response seems to influence the clinical severity and mortality risk associated with viral diseases (such as influenza and COVID-19) rather than the viral pathogen itself.24 25 Consequently, it is biologically plausible that 1,25(OH)2D3 may exert immunomodulatory effects also in COVID-19 patients, playing a role in the regulation of both innate and adaptive immunity.26 The intracellular conversion of 25(OH)D (calcidiol or calcifediol) into the active metabolite 1,25(OH)2D3, (calcitriol), through the intracrine actions of the enzyme 1-alpha-hydroxylase (CYP27B1), is distinct from the 1,25(OH)2D3 produced in kidneys and released into the systemic circulation; however, both have autocrine and paracrine functions that enhance host immunity, for example, by upregulating the antimicrobial peptides cathelicidin and alpha-defensin26 (figure 1). Conclusion, vitamin D deficiency seems a prevalent and further risk factor for severe COVID-19 male patients.39 Vitamin D and RTIs: lesson from the recent experience The seasonality of viral RTIs such as those caused by influenza virus and rhinovirus has been recognised from long time and is even considered to be one of the major contributor to seasonal variations in human mortality.40 As matter of fact, a recent large study found that sunlight UV radiation dose is negatively correlated with the percent positive patients for SARS-CoV-2 and for four other common human coronaviruses in the USA, and this association is season-related with lowest vitamin D serum concentrations.41 In a large population survey (6789 participants), the prevalence of RTIs and altered lung function showed a strong seasonal pattern and linear association in the opposite direction to the vitamin D serum concentrations.42 A more detailed study evaluating the link between vitamin D concentrations and ARDS, patients with 25(OH)D3 <20 ng/mL showed a significantly higher odds of ARDS compared with patients with 25(OH)D >20 ng/mL after adjustment for age, gender, diagnostic category, staging and degree of cigarette consumption, (p=0.032).7 Interestingly, when 25(OH)D concentrations were analysed with logistic regression as a continuous exposure in 0.4 ng/mL increments, the odds of ARDS decreased by 17% for every 0.4 ng/mL increase in 25(OH)D (OR 0.83 (95% CI 0.69 to 0.98; p=0.033).7 In another study, it was found that each 4 ng/mL increase in 25(OH)D was associated with a 7% lower risk of lung infection (95 % CI 3% to 11 %) after adjustment for lifestyle, socioeconomic factors and adiposity.42 Therefore, it has been argued that vitamin D status should be taken into account as an important contributor in determining the population susceptibility to seasonal epidemic outbreaks, together with the effects of augmented indoor confinement in wintertime (ie, school) and increased circulating reservoirs of respiratory viruses.43 Furthermore, another large observational study evaluating healthy adults during the fall and winter of 2009–2010, investigated the relationship between serum 25(OH)D concentrations and incidence of acute RTIs (ARTIs).44 The result was that only 17% of patients showing serum 25(OH)D concentrations over 38

Background In rheumatoid arthritis (RA), macrophages play an important role in modulating the immunoinflammatory response through their polarisation into “classically” (M1) or “alternatively activated” (M2) phenotypes. In RA, CTLA4-Ig (abatacept) reduces the inflammatory activity of macrophages by interacting with the costimulatory molecule CD86. The study aimed to investigate the efficacy of CTLA4-Ig treatment to induce an M2 phenotype both in M1-polarised monocyte-derived macrophages (MDMs) obtained from healthy subjects (HS) and in cultured MDMs obtained from active RA patients. Methods Cultured MDMs were obtained from peripheral blood mononuclear cells of 7 active RA patients and from 10 HS after stimulation with phorbol myristate acetate (5 ng/mL) for 24 h. HS-MDMs were then stimulated with lipopolysaccharide (LPS, 1 mg/mL) for 4 h to induce M1-MDMs. M1-MDMs and RA-MDMs were treated with CTLA4-Ig (100 μM and 500 μM) for 3, 12, 24, and 48 h. The gene expression of CD80, CD86, and TLR4 (M1 markers); CD163, CD204, and CD206 (surface M2 markers); and MerTK (functional M2 marker) was evaluated by qRT-PCR. The protein synthesis of surface M2 markers was investigated by Western blotting. The statistical analysis was performed by the Wilcoxon t -test. Results In LPS-induced HS-M1-MDMs, CTLA4-Ig 100 μM and 500 μM significantly downregulated the gene expression of M1 markers (3 h p <0.01 for all molecules; 12 h p <0.05 for TLR4 and CD86) and significantly upregulated that of M2 markers, primarily after 12 h of treatment (CD163: p < 0.01 and p < 0.05; CD206: p < 0.05 and p < 0.01; CD204: p < 0.05 by 100 mg/mL). Moreover, in these cells, CTLA4-Ig 500 μM increased the protein synthesis of surface M2 markers ( p < 0.05). Similarly, in RA-MDMs, the CTLA4-Ig treatment significantly downregulated the gene expression of M1 markers at both concentrations primarily after 12 h ( p < 0.05). Furthermore, both concentrations of CTLA4-Ig significantly upregulated the gene expression of CD206 (after 3 h of treatment; p < 0.05), CD163, and MerTK (after 12 h of treatment, p < 0.05), whereas CD204 gene expression was significantly upregulated by the high concentration of CTLA4-Ig ( p < 0.05). The protein synthesis of all surface markers was increased primarily by CTLA4-Ig 500 μM, significantly for CD204 and CD206 after 24 h of treatment ( p < 0.05). Conclusions CTLA4-Ig treatment seems to induce the in vitro shift from M1 to M2 macrophages, of both HS-M1-MDMs and RA-MDMs, as observed by the significant downregulation exerted on selected M1 markers and the upregulation of selected M2 markers suggesting an additional mechanism for its modulation of the RA inflammatory process.