Pain in axial spondyloarthritis: role of the JAK/STAT pathway.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that is characterized by new bone formation in the axial musculoskeletal system, with X-ray discriminating between radiographic and non-radiographic forms. Current therapeutic options include non-steroidal anti-inflammatory drugs in addition to biological disease-modifying anti-rheumatic drugs that specifically target tumor necrosis factor-alpha (TNFα) or interleukin (IL)-17. Pain is the most critical symptom for axSpA patients, significantly contributing to the burden of disease and impacting daily life. While the inflammatory process exerts a major role in determining pain in the early phases of the disease, the symptom may also result from mechanical and neuromuscular causes that require complex, multi-faceted pharmacologic and non-pharmacologic treatment, especially in the later phases. In clinical practice, pain often persists and does not respond further despite the absence of inflammatory disease activity. Cytokines involved in axSpA pathogenesis interact directly/indirectly with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascade, a fundamental component in the origin and development of spondyloarthropathies. The JAK/STAT pathway also plays an important role in nociception, and new-generation JAK inhibitors have demonstrated rapid pain relief. We provide a comprehensive review of the different pain types observed in axSpA and the potential role of JAK/STAT signaling in this context, with specific focus on data from preclinical studies and data from clinical trials with JAK inhibitors.

Effects of upadacitinib on enthesitis in patients with psoriatic arthritis: a post hoc analysis of SELECT-PsA 1 and 2.

OBJECTIVES: To characterize the effect of upadacitinib 15 mg once daily (UPA15) on enthesitis in patients with psoriatic arthritis from the SELECT-PsA Phase 3 trials. METHODS: Patients with an inadequate response/intolerance to ≥ 1 non-biologic DMARD (SELECT-PsA 1) or ≥ 1 biologic DMARD (SELECT-PsA 2) received UPA15, adalimumab 40 mg every other week or placebo (weeks 0-24) switched to UPA15 (week 24 onward). The Leeds Enthesitis Index (LEI) and Spondyloarthritis Research Consortium of Canada (SPARCC) index were used to assess improvement in enthesitis, enthesitis resolution, maintenance of enthesitis resolution, and protection from enthesitis development through week 56. RESULTS: Data from 639 patients receiving UPA15 and 635 patients receiving placebo (including 317 patients who switched from placebo to UPA15) were analysed. UPA15 led to higher rates of enthesitis resolution vs placebo at week 24 (LEI: 59.8% vs 38.0%; SPARCC index: 50.6% vs 31.5%, respectively) and greater improvements in the LEI (-1.7 vs -1.0) and SPARCC index (-3.4 vs -1.9); improvements were maintained through week 56. Improvements were observed after 12 weeks of UPA15 treatment. Over 90% of patients without enthesitis (LEI = 0) at baseline receiving UPA15 were enthesitis-free at week 56, and UPA15 prevented recurrence of enthesitis at week 56 in > 80% of patients with enthesitis at baseline who achieved resolution (LEI = 0) at week 24. CONCLUSIONS: UPA15 is associated with a comprehensive improvement in enthesitis, with improvements observed after 12 weeks of treatment. Additionally, treatment with UPA15 was associated with maintaining an enthesitis-free state after resolution and protection against new-onset enthesitis. CLINICALTRIALS.GOV IDENTIFIERS: NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).

Large-scale DNA sequencing identifies rare variants associated with Systemic Lupus Erythematosus susceptibility in known risk genes.

The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the disease. In this study we have analyzed a cohort of 200 Italian SLE patients in order to explore the rare protein-coding variants in five genes (TNFAIP3, STAT4, IL10, TRAF3IP2, and HCP5) already investigated for commons variants found associated in our previous studies. Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing. The identified variants were filtered by frequency and evaluated by in silico predictions. Allelic association analysis was performed with standard Fisher's exact test. Introducing a cutoff at MAF < 0.01, a total of 19 rare variants were identified. Seven of these variants were ultra-rare (MAF < 0.001) and six were absent in the GnomAD database. For TNFAIP3 gene, the variant c.A1939C was observed in 4 SLE patients and it is located in a region enriched in phosphorylation sites and affects the predict affinity of specific kinases. In TRAF3IP2 gene, we observed 5 different rare variants, including the novel variant c.G410A, located in the region that mediates interaction with TRAF6, and therefore a possible risk factor for SLE development. In STAT4 gene, we identified 6 different rare variants. Among these, three missense variants decrease the stability of this protein. Moreover, 3 novel rare variants were detected in 3 SLE patients. In particular, c.A767T variant was predicted as damaging by six prediction tools. Concluding, we have observed that even in genes whose common variability is associated with SLE susceptibility, it is possible to identify rare variants that could have a strong effect in the disease development and could therefore allow a better understanding of the functional domain involved.

PCSK3 Overexpression in Sjögren's Syndrome Patients May Be Regulated by rs4932178 SNP in Its Promoter Region and Correlates with IFN-γ Gene Expression.

BACKGROUND: The PCSK3 gene encodes for the protease enzyme Furin, which promotes proteolytic maturation of important regulators of the immune response, and also enhances the secretion of interferon-γ (IFN). Several studies have suggested its possible involvement in the pathogenesis of chronic inflammatory diseases. METHODS: We investigated the PCSK3 gene expression level in peripheral blood mononuclear cells isolated from Sjögren's Syndrome (SS) patients and healthy controls and we evaluated a possible correlation with IFN-γ gene expression. Moreover, we also explored the variability of two PCSK3 genetic polymorphisms (rs4932178 and rs4702) to evaluate a possible association between these polymorphisms and the expression levels of this gene. RESULTS: We observed, by RT-qPCR, that the PCSK3 expression level was significantly higher in SS patients compared to the controls (p = 0.028), and we confirmed a positive correlation between PCSK3 and IFN-γ expression levels (p < 0.001). Moreover, we reported that the variant homozygous genotype of rs4932178 SNP is associated with a higher expression of the PCSK3 gene (p = 0.038) and with the SS susceptibility (p = 0.016). CONCLUSIONS: Our data suggest that Furin could play a role in SS development, also promoting IFN-γ secretion.

KLRG1 is reduced on NK cells in SLE patients, inversely correlates with disease activity and is modulated by hydroxychloroquine in vitro.

OBJECTIVES: Killer cell lectin-like receptor G 1 (KLRG1), a transmembrane receptor with inhibitory capacity expressed in human immune cells, emerged as a novel susceptibility gene for systemic lupus erythematosus (SLE). The aim of this study was to investigate the expression of KLRG1 in SLE patients compared to healthy controls (HC) on both NK and T cells and to evaluate its possible involvement in SLE pathogenesis. METHODS: Eighteen SLE patients and twelve healthy controls were enrolled. Peripheral blood mononuclear cells (PBMCs) from these patients were phenotypically characterized by immunofluorescence and flow cytometry. The effect of the hydroxychloroquine (HCQ) in vitro on KLRG1 expression and its signaling mediated functions in NK cells were analyzed. RESULTS: KLRG1 expression was significantly reduced on the analyzed immune cell populations in SLE patients compared to HC, especially on total NK cells. Moreover, expression of KLRG1 on total NK cells inversely correlated with the SLEDAI-2K. A direct association between KLRG1 expression on NK cells and patients' treatment with HCQ was observed. In vitro treatment with HCQ increased KLRG1 expression on NK cells. In HC, KLRG1+ NK cells showed reduced degranulation and IFNγ production, while in SLE patient, this inhibition occurred only for the IFNγ production. CONCLUSION: With this study we revealed a reduced expression and an impaired function of KLRG1 on NK cells in SLE patients. These results suggest a possible role of KLRG1 in the pathogenesis of SLE and as a novel biomarker of this disease.

How Has Molecular Biology Enhanced Our Undertaking of axSpA and Its Management.

PURPOSE: This review aims at investigating pathophysiological mechanisms in spondyloarthritis (SpA). Analysis of genetic factors, immunological pathways, and abnormalities of bone metabolism lay the foundations for a better understanding of development of the axial clinical manifestations in patients, allowing physician to choose the most appropriate therapeutic strategy in a more targeted manner. RECENT FINDINGS: In addition to the contribution of MHC system, findings emerged about the role of non-HLA genes (as ERAP1 and 2, whose inhibition could represent a new therapeutic approach) and of epigenetic mechanisms that regulate the expression of genes involved in SpA pathogenesis. Increasing evidence of bone metabolism abnormalities secondary to the activation of immunological pathways suggests the development of various bone anomalies that are present in axSpA patients. SpA are a group of inflammatory diseases with a multifactorial origin, whose pathogenesis is linked to the genetic predisposition, the action of environmental risk factors, and the activation of immune response. It is now well known how bone metabolism leads to long-term structural damage via increased bone turnover, bone loss and osteoporosis, osteitis, erosions, osteosclerosis, and osteoproliferation. These effects can exist in the same patient over time or even simultaneously. Evidence suggests a cross relationship among innate immunity, autoimmunity, and bone remodeling in SpA, making treatment approach a challenge for rheumatologists. Specifically, treatment targets are consistently increasing as new drugs are upcoming. Both biological and targeted synthetic drugs are promising in terms of their efficacy and safety profile in patients affected by SpA.

Low-energy Pulsed Electromagnetic Field Therapy Reduces Pain in Fibromyalgia: A Randomized Single-blind Controlled Pilot Study.

Objectives: Fibromyalgia symptoms have a significant impact on the quality of life and respond poorly to medications. It has been hypothesized that the use of low-energy pulsed electromagnetic field (PEMF) induces neuroprotective effects that may interfere with pain perception. We explored the efficacy of PEMF in patients affected by fibromyalgia. Methods: Twenty-one females (median age 59 years, interquartile range [IQR] 16.5) affected by fibromyalgia were randomized to receive pulsed electromagnetic field-triple energy pain treatment (PEMF-TEPT) or placebo at T0 and at 4 weeks and 8 weeks. Fibromyalgia impact questionnaire (FIQ), widespread pain index (WPI), visual analog score (VAS) pain, symptom severity (SS) scale, and short form 36 (SF-36) health survey questionnaire have been evaluated. Results: Patients in the PEMF-TEPT group had a significantly higher reduction of WPI compared to placebo (mean difference -12.90 ± standard deviation [SD] 5.32 vs. -1.91 ± 4.55, difference in difference [DD] of -10.99; P < 0.001), of SS score (-4.10 ± 4.85 vs. -2.00 ± 2.32; DD = -2.1; P < 0.05), of VAS pain (-48 ± 30.75 vs. -16.82 ± 23.69; DD = -31.18; P < 0.01). They also reported a higher improvement of FIQ and SF-36, albeit not reaching statistical significance. Conclusion: In our pilot controlled study, PEMF-TEPT appeared to be safe and improved fibromyalgia symptoms.

Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role in inflammatory and immune processes. Since the mitochondrial DNA (mtDNA) copy number could change in response to physiological or environmental stimuli, this study aimed to evaluate possible alterations in the mtDNA copy number in SS. We have analyzed the amount of mtDNA in the peripheral blood of 74 SS patients and 61 healthy controls by qPCR. Then, since mitochondrial fusion and fission play a crucial role in maintaining the number of mitochondria, we investigated the expression variability of the genes most commonly involved in mitochondrial dynamics in a subgroup of SS patients and healthy controls. Interestingly, we observed a highly significant decrease in mtDNA copies in the SS patients compared to healthy controls (p = 1.44 × 10-12). Expression levels of mitochondrial fission factor (MFF), mitofusin-1 (MFN1), and mitochondrial transcription factor A (TFAM) genes were analyzed, showing a statistically significant increase in the expression of MFF (p = 0.003) and TFAM (p = 0.022) in the SS patients compared to healthy controls. These results give further insight into the possible involvement of mitochondrial dysfunctions in SS disease.

Impact of TRAF3IP2, IL10 and HCP5 Genetic Polymorphisms in the Response to TNF-i Treatment in Patients with Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory rheumatic disease. The introduction of therapy with biological drugs is promising, even if the efficacy is very variable. Since the response to drugs is a complex trait, identifying genetic factors associated to treatment response could help define new biomarkers for a more effective and personalized therapy. This study aimed to evaluate the potential role of polymorphisms in genes involved in PsA susceptibility as predictors of therapy efficacy. Nine polymorphisms were analyzed in a cohort of 163 PsA patients treated with TNF-i. To evaluate the treatment response, the DAPsA score was estimated for each patient. The possible association between the selected SNPs and mean values of DAPsA differences, at 22 and 54 weeks from the beginning of the treatment, were evaluated by t-test. Patients carrying the variant allele of TRAF3IP2 seemed to respond better to treatment, both at 22 and 54 weeks. This variant allele was also associated with an improvement in joint involvement. In contrast, patients carrying the IL10 variant allele showed an improvement lower than patients with the wild-type genotype at 54 weeks. Our results suggest that polymorphisms in genes associated with PsA susceptibility could also play a role in TNF-i treatment response.

Residual Disease in Patients with Axial Spondyloarthritis: A Post-Hoc Analysis of the QUASAR Study.

In this study, we evaluated the presence of residual disease in patients with axial spondyloarthritis (axSpA) in remission/low disease activity (LDA) status. This cross-sectional post-hoc analysis of the QUASAR study involving 23 rheumatology centres across Italy included adults with axSpA classified according to the Assessment of SpondyloArthritis International Society criteria. Patients with inactive disease (score < 1.3) or at least LDA status (score < 2.1) at baseline visit according to Ankylosing Spondylitis Disease Activity Score were investigated to evaluate how residual disease activity impacts patients' quality of life. They were assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) questionnaires. This study included 480 patients with axSpA (mean age, 47.5 ± 12.9 years, 64% male). In total, 123 patients (25.6%) had inactive disease and 262 (54.6%) had at least LDA. Using the ASQoL, ranges of 10−25% and 20−40% of patients with inactive disease and with LDA status, respectively, experienced tiredness/fatigue. Despite being classified with inactive disease, 48.8% of patients reported light pain/discomfort according to the EQ-5D-5L, with 4.1% reporting moderate pain/discomfort, whereas 55.7% of patients with LDA reported light pain/discomfort and 13% had moderate pain/discomfort. Using the ASQoL questionnaire, in patients with at least LDA, a higher proportion of women compared with males and a higher proportion of patients > 48 years of age (vs. patients ≤ 48 years) experienced tiredness. In this post-hoc analysis, ≥25% of axSpA patients in remission/LDA status were still burdened by residual disease, mainly characterised by pain and fatigue.

A multilocus genetic study evidences the association of autoimmune-related genes with Psoriatic Arthritis in Italian patients.

Psoriatic Arthritis (PsA) is an immune-mediated rheumatic disease caused by the interaction between environmental factors and genetic predisposition. Many of the risk loci associated with PsA susceptibility are shared with other autoimmune diseases, suggesting an involvement of the same pathways in these diseases. We investigated the association between nine selected polymorphisms and PsA susceptibility and their possible role in the modulation of the disease activity. We analysed 163 patients with PsA and 298 age and sex-matched healthy subjects. Our results showed the associations of five polymorphisms with the disease development: rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3), rs27524 (ERAP1), rs7574865 (STAT4) and rs1800872 (IL10). Patients carrying the variant allele of TRAF3IP2 polymorphism had a higher number of tender/swollen joints and a higher Disease Activity Index for PsA score. The multilocus genetic risk profile showed a higher probability to develop the disease in subjects with at least four risk alleles.

Extra-Articular Manifestations and Comorbidities in Psoriatic Disease: A Journey Into the Immunologic Crosstalk.

Psoriatic arthritis (PsA) is a chronic inflammatory disease primarily affecting peripheral and axial joints, with the possible presence of extra-articular manifestations (EAMs), such as psoriasis, uveitis, and inflammatory bowel disease. Recently, the concept of psoriatic disease (PsD) has been proposed to define a systemic condition encompassing, in addition to joints and EAMs, some comorbidities (e.g., metabolic syndrome, type II diabetes, hypertension) that can affect the disease outcome and the achievement of remission. EAMs and comorbidities in PsA share common immunopathogenic pathways linked to the systemic inflammation of this disease; these involve a broad variety of immune cells and cytokines. Currently, various therapeutics are available targeting different cytokines and molecules implicated in the inflammatory response of this condition; however, despite an improvement in the management of PsA, comprehensive disease control is often not achievable. There is, therefore, a big gap to fill especially in terms of comorbidities and EAMs management. In this review, we summarize the clinical aspects of the main comorbidities and EAMs in PsA, and we focus on the immunopathologic features they share with the articular manifestations. Moreover, we discuss the effect of a diverse immunomodulation and the current unmet needs in PsD.

Emerging Role of microRNAs and Long Non-Coding RNAs in Sjögren's Syndrome.

Sjögren's Syndrome (SS) is a chronic autoimmune inflammatory disease. It is considered a multifactorial pathology, in which underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to development. The epigenetic regulations represent a link between genetic predisposition and environmental factors. Recent studies suggested a regulatory role for non-coding RNAs in critical biological and disease processes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play a critical role in the post-transcriptional mRNA expression, forming a complex network of gene expression regulation. This review aims to give an overview of the latest studies that have investigated the role of miRNAs and lncRNAs in the SS. We included papers that investigated the expression of non-coding RNAs on different tissues, in particular on peripheral blood mononuclear cells and salivary glands. However, regarding the involvement of non-coding RNAs genetic variability in SS susceptibility very few data are available. Further research could help to elucidate underlying pathogenic processes of SS and provide new opportunities for the development of targeted therapies.

mRNA expression analysis confirms CD44 splicing impairment in systemic lupus erythematosus patients.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a complex chronic autoimmune disease characterized by several immunological alterations. T cells have a peculiar role in SLE pathogenesis, moving from the bloodstream to the peripheral tissues, causing organ damage. This process is possible for their increased adherence and migration capacity mediated by adhesion molecules, such as CD44. Ten different variant isoforms of this molecule have been described, and two of them, CD44v3 and CD44v6 have been found to be increased on SLE T cells compared to healthy controls, being proposed as biomarkers of disease and disease activity. The process of alternative splicing of CD44 transcripts is not fully understood. We investigated the mRNA expression of CD44v3 and CD44v6 and also analyzed possible CD44 splicing regulators (ESRP1 molecule and rs9666607 CD44 polymorphism) in a cohort of SLE patients compared to healthy controls. METHODS: This study involved 18 SLE patients and 18 healthy controls. Total RNA and DNA were extracted by peripheral blood mononuclear cells. The expression study was conducted by quantitative RT-polymerase chain reaction, using SYBR Green protocol. Genotyping of rs9666607 SNP was performed by direct sequencing. RESULTS: CD44v6 mRNA expression was higher in SLE patients compared to healthy controls (p = 0.028). CD44v3/v6 mRNA ratio in healthy controls was strongly unbalanced towards isoform v3 compared to SLE patients (p = 0.002) and decreased progressively from healthy controls to the SLE patients in remission and those with active disease (p = 0.015). The expression levels of CD44v3 and CD44v6 mRNA correlated with the disease duration (p = 0.038, Pearson r = 0.493 and p = 0.038, Pearson r = 0.495, respectively). Splicing regulator ESRP1 expression positively correlated with CD44v6 expression in healthy controls (p = 0.02, Pearson r = 0.532) but not in SLE patients. The variant A allele of rs9666607 of CD44 was associated with higher level of global CD44 mRNA (p = 0.04) but not with the variant isoforms. CONCLUSIONS: In SLE patients, the increase in CD44v6 protein correlates with a higher transcript level of this isoform, confirming an impairment of CD44 splicing in the disease, whose regulatory mechanisms require further investigation.

The JANUS of chronic inflammatory and autoimmune diseases onset during COVID-19 - A systematic review of the literature.

The diverse clinical manifestations of COVID-19 is emerging as a hallmark of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. While the initial target of SARS-CoV-2 is the respiratory tract, it is becoming increasingly clear that there is a complex interaction between the virus and the immune system ranging from mild to controlling responses to exuberant and dysfunctional multi-tissue directed autoimmune responses. The immune system plays a dual role in COVID-19, being implicated in both the anti-viral response and in the acute progression of the disease, with a dysregulated response represented by the marked cytokine release syndrome, macrophage activation, and systemic hyperinflammation. It has been speculated that these immunological changes may induce the loss of tolerance and/or trigger chronic inflammation. In particular, molecular mimicry, bystander activation and epitope spreading are well-established proposed mechanisms to explain this correlation with the likely contribution of HLA alleles. We performed a systematic literature review to evaluate the COVID-19-related autoimmune/rheumatic disorders reported between January and September 2020. In particular, we investigated the cases of incident hematological autoimmune manifestations, connective tissue diseases, antiphospholipid syndrome/antibodies, vasculitis, Kawasaki-like syndromes, acute arthritis, autoimmune-like skin lesions, and neurologic autoimmune conditions such as Guillain-Barré syndrome. We screened 6263 articles and report herein the findings of 382 select reports which allow us to conclude that there are 2 faces of the immune response against SARS-CoV-2, that include a benign virus controlling immune response and a many faceted range of dysregulated multi-tissue and organ directed autoimmune responses that provides a major challenge in the management of this viral disease. The number of cases for each disease varied significantly while there were no reported cases of adult onset Still disease, systemic sclerosis, or inflammatory myositis.

VDR Polymorphisms in Autoimmune Connective Tissue Diseases: Focus on Italian Population.

Vitamin D is an important hormone involved in various physiologic processes, and its activity is linked to binding with vitamin D receptor (VDR). Genetic polymorphisms in the VDR gene could modulate the expression or function of the receptor and, consequently, alter the effects of vitamin D. Variants in VDR gene have been associated with susceptibility to many illnesses sensitive to vitamin D administration and to autoimmune disorders, but no data are available regarding autoimmune connective tissue diseases in Italian population. We analyzed three VDR polymorphisms in 695 Italian patients with autoimmune connective tissue diseases (308 with systemic lupus erythematosus (SLE), 195 with primary Sjogren's syndrome (pSS), and 192 with rheumatoid arthritis (RA)) and in 246 healthy controls with the aim to evaluate a possible association of VDR SNPs with susceptibility to these diseases in the Italian population. Genotyping of rs2228570, rs7975232, and rs731236 in VDR gene was performed by an allelic discrimination assay. A case/control association study and a genotype/phenotype correlation analysis have been performed. We observed a higher risk to develop SLE for rs2228570 TT genotype (P = 0.029, OR = 1.79). No association was observed between susceptibility to pSS or RA and this SNP, although this variant is significantly less present in RA patients producing autoantibodies. For rs7975232 SNP, we observed a significant association of the variant homozygous genotype with SLE (P = 0.009, OR = 1.82), pSS (P = 0.046, OR = 1.66), and RA (P = 0.028, OR = 1.75) susceptibility. Moreover, we reported associations of this genotype with clinical phenotypes of SLE and pSS. Lastly, the GG genotype of rs731236 was associated with a lower RA susceptibility (P = 0.045, OR = 0.55). Our results show that the explored VDR polymorphisms are significantly associated with autoimmune connective tissue disorders and support the hypothesis that the genetic variability of VDR gene may be involved in susceptibility to these diseases in Italian population.

Altered expression of miR-142, miR-155, miR-499a and of their putative common target MDM2 in systemic lupus erythematosus.

Aim: To evaluate genetic and expression variability of three miRNAs potentially involved in systemic lupus erythematosus (SLE) and to identify any miRNA's target gene. Materials & methods: Gene polymorphisms and expression levels of three miRNAs have been evaluated in a cohort of SLE patients and controls. Results: miR-142 and miR-499a were significantly down-expressed in patients (p = 0.005 and p = 0.02, respectively). A trend for down-expression of miR-155 was also observed (p = 0.07). The lower expression of miR-142 was associated with the rs2632516 polymorphism variant allele (p = 0.002). Predictive analyses identified a target gene common to the three miRNAs, MDM2, whose higher expression was seen in patients compared with controls (p = 0.03). Conclusion: The three miRNAs and MDM2 might be involved in SLE.

Increased eryptosis in patients with primary antiphospholipid syndrome (APS): a new actor in the pathogenesis of APS.

OBJECTIVES: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by a hypercoagulable state and the presence of antiphospholipid antibodies (aPL). During the mechanism of red blood cells (RBCs) death, called eryptosis, RBCs can adhere to vascular wall participating in the development of a pro-thrombotic state. It is known that enhanced eryptosis contributes to several pathological conditions but the role of this process in APS has not been investigated yet. We analysed spontaneous eryptosis in a cohort of APS patients and aPL carriers (asymptomatic subjects with positive aPL tests). The effect on eryptosis of antibodies (Abs) purified from serum of APS patients and aPL carriers was also investigated. METHODS: In this study, 30 patients with primary APS (PAPS) and 17 aPL carriers were recruited. Twenty healthy donors (HD) and 13 patients affected by autoimmune haemolytic anaemia (AHIA) were also recruited. RBCs were incubated with PAPS and aPL carriers Abs, purified by ammonium sulfate precipitation. Levels of eryptosis were analysed by flow cytometry. RESULTS: In vitro Abs from APS patients induced eryptosis in RBCs isolated from HD after 4 h of culture. On the contrary, Abs from aPL carriers had no effect on the percentage of phosphatidylserine-exposing RBCs. Ex vivo, APS patients showed higher levels of spontaneous eryptosis compared to HD and aPL carriers. CONCLUSIONS: In this study, we demonstrated a potential new aspect of APS pathogenesis based on the ability of Abs isolated from APS patients, not identified in aPL carriers, to stimulate eryptosis suggesting a possible contribution of this process in the clinical manifestations of APS.

Autoinflammatory and autoimmune conditions at the crossroad of COVID-19.

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.