Search

Background: To date, no studies have investigated the potential reactivation of human endogenous retroviruses (HERVs) in the pathogenesis of antiphospholipid syndrome (APS). HERV-derived syncytin-1 and syncytin-2 are localized in the plasma membrane of cells and physiologically expressed during pregnancy. The current study aimed to determine whether the epitopes of syncytins can trigger an immune response leading to APS in genetically predisposed individuals., Methods: The TepiTool, ABCpred, and DiscoTope servers were utilized to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of syncytin-1, syncytin-2, and β2-glycoprotein I (β2GPI), which served as a reference antigen for APS. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) class II alleles associated with APS according to the literature. Epitope predictions for the different proteins were statistically compared using GraphPad Prism., Results: For syncytin-1, we identified a total of 721 T-cell epitopes, 51 linear B-cell epitopes, and up to 40 conformational epitopes. For syncytin-2, we predicted 705 T-cell epitopes and 28 linear B-cell epitopes, but a lower number of conformational epitopes, which also exhibited lower B-cell receptor (BCR)-binding scores. The predicted T-cell and B-cell conformational epitopes of both syncytin-1 and syncytin-2 demonstrated significantly higher binding affinity to selected HLA alleles and BCR compared with β2GPI. Furthermore, syncytin-1 exhibited significantly higher immunogenicity than syncytin-2., Conclusions: Both syncytin-1 and syncytin-2 are computationally endowed with potential epitopes that may activate either T cells or B cells in individuals genetically predisposed to APS. While these findings may illuminate the possible role of HERVs in the development of APS, they warrant validation in further laboratory studies.

Introduction: Fibromyalgia (FM) is a multifaceted disease that is often associated with neuropsychiatric disorders and is burdened by a high degree of psychological distress. Non-pharmacological interventions, including physical exercise and complementary therapies, have shown satisfactory results for either physical or psychological FM symptoms., Methods: In this narrative review, we analyzed scientific evidence of moderate to high quality regarding the psychological and neurocognitive effects of physical therapies for FM. A total of 29 studies were selected after searching the PubMed and Google Scholar databases using the combination of terms « fibromyalgia», «psychological distress», «fibrofog», mental disorder», «aerobic exercise», «strength exercise», «Pilates», «Tai chi» and «Yoga»., Results: Aerobic exercise can improve depression, anxiety, stress, mental function and mood, thanks to the remodulation of neurotransmitters and hormones. Strength training, on the other hand, has been shown to alleviate mental confusion, anger and depression. Finally, mind-body disciplines appear to be effective for depression, anxiety, catastrophizing, memory and coping strategies. Based on these findings, we devised an ideal exercise program that could relieve the psychological distress of FM patients, thus interrupting the pathogenic neuroendocrine circuits that lead to the exacerbation of pain and other FM-related symptoms., Conclusions: Thanks to neuroendocrine remodulation, physical exercise may simultaneously improve the physical and mental health of FM patients. This narrative review collects current evidence on the effects of specific physical interventions on psychological and neurocognitive domains of FM patients and additionally provides an evidence-based training program that could be prescribed to FM patients with high psychological distress or neuropsychiatric symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Enthesitis is a common feature of spondyloarthritis and can severely impair the patient's quality of life. International guidelines recommend multidisciplinary management of this condition, combining physical and pharmacological interventions. In this case report, we demonstrate clinical and ultrasonographic improvements by prescribing local cryotherapy and therapeutic exercise alone in an adult woman with non-radiographic axial SpA (nRX-AxSpA) complaining of heel enthesitis., Methodology: A personalized program was prescribed that focused on reducing pain, joint stiffness, and muscle tightness, improving strength and endurance. Pain, function, and degree of disability were assessed using the Numerical Rating Scale, the Victorian Institute of Sport Assessment-Achilles, the single-leg heel lift test, and the Foot Function Index. In addition, lower limb muscle strength was measured using a dynamometer and enthesitis was assessed ultrasonographically using the Glasgow Ultrasound Enthesitis Score System., Results: Benefits were evident as early as week 5 and persisted at 3 months on ultrasound assessment. No side effects were reported., Discussion: To the best of our knowledge, this is the first report of prescribing such a strategy in a patient with nRX-AxSpA. Given the good tolerability, this intervention could be considered in patients with contraindications to pharmacologic approaches.

Background: This computational analysis investigated sequence complementarities between the TRIM33 gene and human noncoding (nc)RNAs and characterized their interactions in the context of paraneoplastic dermatomyositis., Methods: TRIM33 FASTA sequence (NCBI Reference Sequence: NC_000001.11) was used for BLASTN analysis against Human GRCh38 in the Ensembl.org database. Retrieved ncRNAs showing hits to TRIM33 were searched in the GeneCards.org database and further analyzed through RNAInter, QmRLFS-finder, Spliceator, and NcPath enrichment analysis., Results: A total of 100 hits were found, involving the lncRNAs NNT-AS1, MKLN1-AS, LINC01206, and PAXBP1-AS1, whose dysregulation has been reported in either cancer or dermatomyositis. Additionally, the lncRNAs NNT-AS1 and PAXBP1-AS1 may interact with microRNA-142-3p, reducing its expression and increasing that of TRIM33 . Sequence complementarity affected only TRIM33 intron 1, possibly resulting in alternatively spliced isoforms of TIF1γ with increased immunogenicity. The results also revealed nucleotide alignment between TRIM33 and the gene regulatory elements of 28 ncRNA genes involved in immune pathways., Conclusions: This pivotal study demonstrates sequence complementarity between TRIM33 and human ncRNAs dysregulated in cancer and dermatomyositis. This scenario may lead to the overproduction of more immunogenic TIF1γ variants in tumors and the stimulation of autoimmunity. Further experimental analyses using targeted methods such as Western blot or Chip-Seq are required to confirm these data.

Background and Objective: In this review, we discuss evidence concerning the management of psoriatic arthritis (PsA) patients with non-pharmacological interventions and additionally develop physical training protocols that could be prescribed to these patients., Methods: We selected 110 articles, published on PubMed and Google Scholar databases from 1972 to date, investigating the effects of generic hygienic-dietary recommendations and training programs in PsA or psoriasis (PSO) individuals., Results: Although data in support are limited, aerobic, endurance, and strength exercises as well as complementary techniques may all be useful in preserving or improving residual functional capacity, joint flexibility, and muscle strength. Exercise may reduce systemic inflammation, pain, and fatigue and additionally control PsA comorbidities, like dysmetabolism or obesity., Conclusions: The polyhedral clinical expression of PsA underlines the need for a multidisciplinary approach combining the synergistic effects of pharmacological and non-pharmacological treatments. The latter range from preventive measures, like dietary modifications, weight loss, and cigarette smoking cessation, to personalized training protocols according to disease activity and phenotype, comorbidities, and individual tolerability. In these patients, we strongly encourage the regular practice of motor activity at progressively increasing intensity with combined supervised aerobic, strength, endurance, and stretching exercises.

Objectives: To investigate in silico the occurrence of epigenetic crosstalk by nucleotide sequence complementarity between the BNT162b2 mRNA vaccine and whole human genome, including coding and noncoding (nc)RNA genes. To correlate these results with those obtained with the original spike (S) gene of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2)., Methods: The publicly available FASTA sequence of the BNT162b2 mRNA vaccine and the SARS-CoV-2 isolate Wuhan-Hu-1 S gene (NC_045512.2) were used separately as key input to the Ensembl.org library to evaluate base pair match to human GRCh38 genome. Human coding and noncoding genes harboring hits were assessed for functional activity and health effects using bioinformatics tools and GWAS databases., Results: The BLAT analysis against the human GRCh38 genome revealed a total of 37 hits for BNT162b2 mRNA and no hits for the SARS-CoV-2 S gene. More specifically, BNT162b2 mRNA matched 19 human genes whose protein products are variously involved in enzyme reactions, nucleotide or cation binding, signaling, and carrier functions. In BLASTN analysis of ncRNA genes, BNT162b2 mRNA and SARS-CoV-2 S gene matched 17 and 24 different human genomic regions, respectively. Overall, characterization of the matched noncoding sequences revealed stronger interference with epigenetic pathways for BNT162b2 mRNA compared with the original S gene., Conclusion: This pivotal in silico analysis shows that SARS-CoV-2 S gene and the BNT162b2 mRNA vaccine exhibit Watson-Crick nucleotide complementarity with human coding or noncoding genes. Although they do not share the same complementarity pattern, both may disrupt epigenetic mechanisms in target cells, potentially leading to long-term complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: After the start of the worldwide COVID-19 vaccination campaign, there were increased reports of autoimmune diseases occurring de novo after vaccination. This in silico analysis aimed to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most widely administered COVID-19 vaccines, which could induce autoimmunity in predisposed individuals., Methods: The FASTA sequence of the protein encoded by the BNT-162b2 vaccine served as the key input to the Immune Epitope Database and Analysis Resource. Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC-ligand assays without MHC restriction were searched and analyzed. HLA disease associations were screened on the HLA-SPREAD platform by selecting only positive markers., Results: By 7 May 2023, a total of 5693 epitopes corresponding to 21 viral but also human proteins were found. The latter included CHL1, ENTPD1, MEAF6, SLC35G2, and ZFHX2. Importantly, some autoepitopes may be presented by HLA alleles positively associated with various immunological diseases., Conclusions: The protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals through a molecular mimicry mechanism. Genotyping for HLA alleles may help identify individuals at risk. However, further wet-lab studies are needed to confirm this hypothesis.

Giant cell arteritis (GCA) is the most common primary systemic vasculitis in western countries, prevalently affecting elderly people. Both early diagnosis and regular monitoring are necessary for the correct management of GCA. Following the outbreak of the COVID-19 pandemic, government decisions aiming at reducing the contagion led to reductions in health activities, limiting them to urgent cases. At the same time, remote monitoring activities have been implemented through telephone contacts or video calls carried out by specialists. In line with these deep changes affecting the worldwide healthcare system and in consideration of the high risk of GCA morbidity, we activated the TELEMACOV protocol (TELEmedicine and Management of the patient affected by GCA during the COVID-19 pandemic) in order to remotely monitor patients affected by GCA. The aim of this study was to evaluate the effectiveness of telemedicine in the follow-up of patients already diagnosed with GCA. This was a monocenter observational study. Patients with a previous diagnosis of GCA admitted to the Rheumatology Unit of the University Hospital "Città della Salute e della Scienza" in Turin were monitored every 6-7 weeks by means of video/phone calls from 9 March to 9 June 2020. All patients were asked questions concerning the onset of new symptoms or their recurrence, exams carried out, changes in current therapy, and satisfaction with video/phone calls. We performed 74 remote monitoring visits in 37 GCA patients. Patients were mostly women (77.8%) and had a mean age of 71.85 ± 9.25 years old. The mean disease duration was 5.3 ± 2.3 months. A total of 19 patients received oral glucocorticoids (GC) alone at the time of diagnosis with a daily dose of 0.8-1 mg/kg (52.7 ± 18.3 mg) of prednisone, while 18 patients were treated with a combination of oral steroids (at the time of diagnosis, the prednisone mean dose was 51.7 ± 18.8 mg) and subcutaneous injections of tocilizumab (TCZ). During the follow-up, patients additionally treated with TCZ reduced their GC dose more than patients treated with GC alone ( p = 0.03). Only one patient, who was treated with GC alone, had a cranial flare and needed to increase the dosage of GC, which led to rapid improvement. Furthermore, all patients proved very adherent to the therapies (assessed by Medication Adherence Rating Scale (MARS)) and considered this type of monitoring very satisfactory according to a Likert scale (mean score 4.4 ± 0.2 on a 1-5 range). Our study shows that telemedicine can be safely and effectively used in patients with GCA under control as a possible alternative, at least for a limited period of time, to traditional visits.

Background: Patients with systemic lupus erythematosus (SLE) often suffer from obstetric complications not necessarily associated with the antiphospholipid syndrome. These events may potentially result from the reduced placental synthesis of the fusogenic proteins syncytin-1 and syncytin-2, observed in women with pregnancy-related disorders. SLE patients have an aberrant noncoding (nc)RNA signature that may in turn dysregulate the expression of syncytin-1 and syncytin-2 during placentation. The aim of this research is to computationally evaluate and characterize the interaction between syncytin-1 and syncytin-2 genes and human ncRNAs and to discuss the potential implications for SLE pregnancy adverse outcomes., Methods: The FASTA sequences of the syncytin-1 and syncytin-2 genes were used as inputs to the Ensembl.org library to find any alignments with human ncRNA genes and their transcripts, which were characterized for their tissue expression, regulatory activity on adjacent genes, biological pathways, and potential association with human disease., Results: BLASTN analysis revealed a total of 100 hits with human long ncRNAs (lncRNAs) for the syncytin-1 and syncytin-2 genes, with median alignment scores of 151 and 66.7, respectively. Only lncRNAs TP53TG1, TTTY14, and ENSG00000273328 were reported to be expressed in placental tissue. Dysregulated expression of lncRNAs TP53TG1, LINC01239, and LINC01320 found in this analysis has previously been described in SLE patients as well as in women with a high-risk pregnancy. In addition, some of the genes adjacent to lncRNAs aligned with syncytin-1 or syncytin-2 in a regulatory region might increase the risk of pregnancy complications or SLE., Conclusions: This is the first computational study showing alignments between syncytin-1 and syncytin-2 genes and human lncRNAs. Whether this mechanism affects syncytiotrophoblast morphogenesis in SLE females is unknown and requires further investigation.

Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage. A few studies suggest that serum VEGF-A may also be a potential biomarker for long COVID-19, whereas evidence for COVID-19 vaccines is lacking and merits further investigation.

Lipid rafts are nanoscopic compartments of cell membranes that serve a variety of biological functions. They play a crucial role in viral infections, as enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exploit rafts to enter or quit target cells. On the other hand, lipid rafts contribute to the formation of immune synapses and their proper functioning is a prerequisite for adequate immune response and viral clearance. In this narrative review we dissect the panorama focusing on this singular aspect of cell biology in the context of SARS-CoV-2 infection and therapy. A lipid raft-mediated mechanism can be hypothesized for many drugs recommended or considered for the treatment of SARS-CoV-2 infection, such as glucocorticoids, antimalarials, immunosuppressants and antiviral agents. Furthermore, the additional use of lipid-lowering agents, like statins, may affect the lipid composition of membrane rafts and thus influence the processes occurring in these compartments. The combination of drugs acting on lipid rafts may be successful in the treatment of more severe forms of the disease and should be reserved for further investigation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of this narrative review is to discuss the results of studies investigating the role of physical activity in knee osteoarthritis (OA). We also formulated two evidence-based exercise programs that could be prescribed to patients with symptomatic knee OA or after joint replacement. The PubMed and Google Scholar databases were searched for articles related to knee OA and physical activity. A total of 86 papers written in English and published from 1957 to 2021 were selected. Adapted physical activity, even at high intensity, does not appear to trigger or exacerbate knee OA; on the contrary, it may prevent obesity or lower limb muscle weakness, both of which are considered predisposing factors for the disease. In patients already diagnosed with knee OA, scientific evidence suggests that both land-based and aquatic activities combining aerobics, strength, and endurance programs are safe and effective. Physical interventions tailored to the patient may also accelerate recovery time after knee arthroplasty. Knee OA is a painful and disabling rheumatic disease that is very common in the elderly population. Pharmacotherapy has a modest effect in controlling disease progression, possibly due to the still limited understanding of OA pathogenesis. Non-pharmacologic interventions, including dietary and lifestyle changes and physical activity, may be more effective and safer than drugs in preventing or treating knee OA.

Idiopathic inflammatory myopathies (IIM) are rare diseases affecting skeletal muscles and leading to progressive muscle weakness and disability. Thanks to the better understanding of their pathogenesis, the management of IIM has been noteworthily implemented in recent years. Current therapeutic strategies include pharmacological and non-pharmacological interventions, among which physical exercise represents a useful option, able to ameliorate disease activity without worsening muscle inflammation. The aim of this narrative review is therefore to provide an updated overview of the benefits of physical exercise in patients with IIM and to suggest plausible training programs to be applied in patients with dermatomyositis, polymyositis, necrotizing myopathy, and inclusion body myositis. In this regard, a combined strategy mixing aerobic and resistance exercises could positively affect the pro-inflammatory and metabolic pathways occurring in skeletal muscles, while promoting muscle fiber regeneration and repair., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objectives: To investigate in silico the presence of nucleotide sequence complementarity between the RNA genome of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and human non-coding (nc)RNA genes., Methods: The FASTA sequence (NC_045512.2) of each of the 11 SARS-CoV-2 isolate Wuhan-Hu-1 genes was retrieved from NCBI.nlm.nih.gov/gene and the Ensembl.org library interrogated for any base-pair match with human ncRNA genes. SARS-CoV-2 gene-matched human ncRNAs were screened for functional activity using bioinformatic analysis. Finally, associations between identified ncRNAs and human diseases were searched in GWAS databases., Results: A total of 252 matches were found between the nucleotide sequence of SARS-CoV-2 genes and human ncRNAs. With the exception of two small nuclear RNAs, all of them were long non-coding (lnc)RNAs expressed mainly in testis and central nervous system under physiological conditions. The percentage of alignment ranged from 91.30% to 100% with a mean nucleotide alignment length of 17.5 ± 2.4. Thirty-three (13.09%) of them contained predicted R-loop forming sequences, but none of these intersected the complementary sequences of SARS-CoV-2. However, in 31 cases matches fell on ncRNA regulatory sites, whose adjacent coding genes are mostly involved in cancer, immunological and neurological pathways. Similarly, several polymorphic variants of detected non-coding genes have been associated with neuropsychiatric and proliferative disorders., Conclusion: This pivotal in silico study shows that SARS-CoV-2 genes have Watson-Crick nucleotide complementarity to human ncRNA sequences, potentially disrupting ncRNA epigenetic control of target genes. It remains to be elucidated whether this could result in the development of human disease in the long term., (Copyright © 2021. Published by Elsevier B.V.)

Antiphospholipid antibodies (aPLs), present in 1-5 % of healthy individuals, are associated with the risk of antiphospholipid syndrome (APS), which is the most common form of acquired thrombophilia. APLs may appear following infections or vaccinations and have been reported in patients with COronaVIrus Disease-2019 (COVID-19). However, their association with COVID-19 vaccination is unclear. Notably, a few cases of thrombocytopenia and thrombotic events resembling APS have been reported to develop in recipients of either adenoviral vector- or mRNA-based COVID-19 vaccines. The aim of this review is therefore to speculate on the plausible role of aPLs in the pathogenesis of these rare adverse events. Adenoviral vector-based vaccines can bind platelets and induce their destruction in the reticuloendothelial organs. Liposomal mRNA-based vaccines may instead favour activation of coagulation factors and confer a pro-thrombotic phenotype to endothelial cells and platelets. Furthermore, both formulations may trigger a type I interferon response associated with the generation of aPLs. In turn, aPLs may lead to aberrant activation of the immune response with participation of innate immune cells, cytokines and the complement cascade. NETosis, monocyte recruitment and cytokine release may further support endothelial dysfunction and promote platelet aggregation. These considerations suggest that aPLs may represent a risk factor for thrombotic events following COVID-19 vaccination, and deserve further investigations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There is a lack of real-life clinical data for biosimilar etanercept, an anti-TNF blocking fusion protein. We describe the comparable efficacy and safety of originator and biosimilar etanercept in rheumatoid arthritis (RA) patients in a real-life clinical setting. Our data confirm that a biosimilar etanercept can be safely used as first-line treatment as well as in patients switched from a previous originator compound., Objectives: To compare the efficacy and safety of originator and biosimilar etanercept in a cohort of RA patients attending two Italian hospitals., Methods: The study involved 81 consecutive adult RA patients treated for at least 6 months with originator or biosimilar etanercept and considered their clinical and laboratory data, concomitant medications, and adverse events at baseline, and after 3 and 6 months of treatment., Results: Group 1 included 51 patients taking originator etanercept; group 2 included 30 taking biosimilar etanercept, including 19 who had been switched from the reference product. Despite a significant baseline difference in clinical disease activity, one-way analysis of variance showed that the two groups were clinically comparable after 6 months of treatment, and the same was true when only those receiving etanercept as first-line biological treatment were considered. Nine patients discontinued the treatment due to inefficacy or adverse events, which were never serious and were only reported in group 1., Conclusions: The efficacy and safety profiles of originator and biosimilar etanercept are comparable in RA patients in a real-life clinical setting. Further studies are needed to confirm these preliminary findings.

Objectives: Hepatitis B (HBV) is a common comorbidity among rheumatic patients. The prevalence of HBV infection and the rate of reactivation remain unclear. The literature data suggested a higher risk in chronic than in past infection. Currently, the literature data are mostly focused on anti-TNF and rituximab. This retrospective observational study aimed to analyse the prevalence of HBV infection and the risk of viral reactivation in a population of rheumatic patients undergoing anti-TNF and non-anti-TNF agents., Methods: We analysed 1216 rheumatic patients, treated with both csDMARDs and bDMARDs between 2006 and 2017. Serologic markers for HBV (HBsAg, anti-HBs, anti-HBc) were performed prior and during biologic treatment. Patients with chronic or resolved infection were monitored every 3 months., Results: The prevalence of HBV in our cohort was 15.7% (chronic infection: 0.4%, resolved infection: 12.6%, anti-HBc positivity alone: 2.6%). 12 (6.2%) out of 191 HBV infected patients experienced a reactivation. All of them showed markers of past infection. One patient experienced HBV reactivation despite lamivudine. Only one patient experienced acute hepatitis, probably due to the interruption of immunosuppressors in anticipation of surgery, not preceded by any HBV prophylactic treatment., Conclusions: HBV reactivation is a rare event in patients treated with a bDMARD and it can also occur while taking lamivudine, not only in chronic carriers (as per the literature data) but also in inactive ones. Regular screening followed by prompt treatment can prevent symptoms or complications. Due to the risk of hepatitis following the immune reconstitution, an antiviral therapy should be considered in the case of sudden discontinuation of csDMARDs or bDMARD.

The etiopathogenesis of systemic sclerosis (SSc)-associated interstitial lung disease (ILD) is still debated and no therapeutic options have proved fully effective to date. The intracellular Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is highly conserved among either immune or nonimmune cells and involved in inflammation and fibrosis. Evidence from preclinical studies shows that the JAK/STAT signaling cascade has a crucial role in the differentiation of autoreactive cells as well as in the extracellular matrix remodeling that occurs in SSc. Therefore, it is likely that the use of oral small molecule JAK-inhibitors, especially if prescribed early, may prevent or slow the progression of SSc-associated ILD, but few clinical studies currently support this hypothesis.

Objective: ACE2 is crucially involved in the infection sustained by SARS-CoV-2, as it allows the entry of the virus into target cells while counteracting local inflammation, oxidative stress, and fibrosis. In this narrative review, we aim to discuss the usefulness of ACE2-derived peptides in the infection sustained by SARS-CoV-2., Methods: A total of 49 papers pertinent to the purpose of the review were selected from the PubMed and Google Scholar databases. Clinical trials registered at ClinicalTrials.gov and dealing with the use of ACE2-derived medications in COVID-19 were also searched and discussed., Results: Preclinical and clinical evidence shows that drugs mimicking or potentiating the effects of ACE2 may reduce the viral load and dampen the inflammatory and fibrotic pathways leading to respiratory distress. ACE2-derived therapeutic peptides may have a better pharmacokinetic and pharmacodynamic profile than other ACE2-based medications. They could be easily screened through peptide libraries and chemically modified in order to ameliorate the pharmacological properties. Furthermore, their local administration via an intranasal delivery or inhalation may reduce the risk of systemic side effects, thus conferring a good safety profile., Conclusion: ACE2-derived peptides may play a dual beneficial role in COVID-19, by either preventing virus spread or inhibiting the secretion of pro-inflammatory mediators in airways. Viral, host, and environmental factors may affect the effectiveness of this therapeutic approach to a various extent and represent therefore a matter of investigation for future studies., Competing Interests: None., (AJCEI Copyright © 2020.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can give rise to different clinical manifestations that are directly related to viral tissue damage or indirectly induced by the antiviral immune response. Hyper-activation of the immune system in an attempt to eradicate the infection may trigger autoimmunity. Several immune-mediated disorders have been described in SARS-CoV-2-infected individuals. These include cutaneous rashes and vasculitis, autoimmune cytopenia, anti-phospholipid syndrome, central or peripheral neuropathy, myositis and myocarditis. On the other hand, rheumatic patients were reported to have similar coronavirus disease 2019 (COVID-19) incidence, morbidity and mortality rates compared to general population. This opinion review will summarize the crucial immunologic steps which occur during SARS-CoV-2-infection that may link autoimmunity to COVID-19 and provides an opportunity for further discussion regarding this association., Competing Interests: Conflict-of-interest statement: The author declares no conflict of interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Studies in vitro and in vivo have identified several peptides that are potentially useful in treating systemic lupus erythematosus (SLE). The rationale for their use lies in the cost-effective production, high potency, target selectivity, low toxicity, and a peculiar mechanism of action that is mainly based on the induction of immune tolerance. Three therapeutic peptides have entered clinical development, but they have yielded disappointing results. However, some subsets of patients, such as those with the positivity of anti-dsDNA antibodies, appear more likely to respond to these medications., Areas Covered: This review evaluates the potential use of therapeutic peptides for SLE and gives an opinion on how they may offer advantages for SLE treatment., Expert Opinion: Given their acceptable safety profile, therapeutic peptides could be added to agents traditionally used to treat SLE and this may offer a synergistic and drug-sparing effect, especially in selected patient populations. Moreover, they could temporarily be utilized to manage SLE flares, or be administered as a vaccine in subjects at risk. Efforts to ameliorate bioavailability, increase the half-life and prevent immunogenicity are ongoing. The formulation of hybrid compounds, like peptibodies or peptidomimetic small molecules, is expected to yield renewed treatments with a better pharmacologic profile and increased efficacy.

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use.

The pathogenesis of systemic lupus erythematosus (SLE) is characterised by the hyper-activation of immunologic pathways related to the antiviral response. Exogenous and endogenous retroviruses, by integrating their DNA templates in the host cell genome, may epigenetically control the transcription of genes involved in the immune response. Furthermore, their nucleic acids or neo-synthesized proteins could stimulate the sensor molecules placed upstream the inflammatory cascade. Exogenous retroviruses, like human immunodeficiency virus, have been associated to SLE-like manifestations or to a fair SLE diagnosis. In addition, there is some evidence confirming a pathogenic role of human endogenous retroviruses in SLE. In line with these data, the use of antiretroviral agents could represent an attractive opportunity in the future therapeutic algorithms of this disease, but studies are still missing.

Human endogenous retroviruses (HERV)-E consist of a family of more than 1300 elements, stably integrated in the human genome. Some of them are full-length proviruses able to synthesize the viral proteins gag, pol and env. The reactivation of HERV-E elements has been associated to placentation, cancer and autoimmunity. In this narrative review, we aimed to report the status of the art concerning the involvement of HERV-E in rheumatic autoimmune diseases. Following a research on PubMed database, a total of 87 articles were selected. The highest amount of evidence derives from studies on systemic lupus erythematosus (SLE), whereas a few to no data are available on other immune-mediated diseases. In SLE, the hyper-expression of HERV-E clone 4-1 in peripheral blood mononuclear cells or differentiated lymphocytes has been associated with disease activity and autoantibody production. It is likely that HERV-E take part to the pathogenesis of rheumatic autoimmune diseases but additional research is needed., (© 2020 APMIS. Published by John Wiley & Sons Ltd.)

Objectives: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation)., Methods: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc., Results: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features., Conclusions: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

The aim of this review is to describe the metabolism of calcium in ankylosing spondylitis compared to physiologic conditions, and to present the current evidence on the benefits and disadvantages of calcium supplementation in these patients. A narrative review of the literature was conducted using the PubMed database and a total of 65 articles were selected. Calcium is involved in many physiopathological processes, including inflammation, bone loss and bone formation, all of which occur in ankylosing spondylitis. Many ankylosing spondylitis patients suffer from concomitant osteopenia or osteoporosis, which represent indications for calcium supplementation. Conversely, there are still concerns about the use of calcium salts for the prevention of bone fragility in non-osteoporotic or non-osteopenic patients. In these cases, biologic agents may indirectly normalize calcium dysmetabolism by rebalancing the cytokine milieu, in turn associated with bone remodeling. Calcium supplements may be disadvantageous for entheseal calcifications, but so far there are no clear data confirming that such an association exists., Competing Interests: The authors declare no conflict of interest. The authors declare that all the figures presented are prepared by the authors and have not been previously published., (Copyright: © 2020 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie.)

Endogenous retroelements are a class of ancient defective viral insertions contained in the genome of host cells, where they account for up to 40% of all DNA. Centuries of co-existence in host genome have led to the development of immunotolerance to endogenous retroelements, most of which are defective and unable to replicate or transcribe functional proteins. However, given their capacity to move across the nuclear and mitochondrial genome and recombine, they could mix phenotypes and give rise to infections that may trigger innate and adaptive immune responses by sensing receptors capable of recognising foreign nucleic acids and proteins. It has recently been suggested that they play a role in the pathogenesis of autoimmune diseases on the grounds of their partial reactivation or the epigenetic control of host gene transcription. A number of studies have confirmed their contribution to the development of rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, but there is still a lack of data concerning systemic sclerosis (SSc). Their role in the pathogenesis of SSc can be hypothesised on the basis of mitochondrial and nuclear chromatinic damage, and hyper-activation of the immune pathway involved in antiviral defense. SSc is characterised by genetic and immunological evidence of a viral infection but, as no viral agent has yet been isolated from SSc patients, the hypothesis that partial reactivation of endogenous retroviruses may trigger the disease cannot be excluded and deserves further investigation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The pathogenesis of psoriatic arthritis (PSA) is still a matter of debate. A favourable genetic background is interwoven with environmental triggering factors in a complex network. Shared antigens and the recirculation of immune cells may account for the clinical manifestations, involving both cutaneous and articular sites. A favourable genetic background has been demonstrated in many genomic and proteomic studies, being associated to polymorphic variants of the genes coding for Major Histocompatibility Complex I and cytokine pathways. In genetic-predisposed individuals, triggering factors, like infections, dysbiosis or mechanic stress may promote the development of the disease. The subsequent activation of the innate and adaptive immune system, following the stimulation of Toll-like Receptors, culminates in the expansion of dendritic cells, macrophages, CD4+ and CD8+ T cells, neutrophils, monocytes, Natural Killer lymphocytes and other cells with the final inflammation and damage of skin, joint and enthesis. Particularly, the activation of CD4+ T helper 17 lymphocytes represents a crucial point in the pathogenesis of the disease. The participation of the visceral adipose tissue may amplify the inflammatory process by means of the synthesis of pro-inflammatory adipokines. Current therapeutic algorithms address the variety of clinical manifestations with a tailored strategy aiming to achieve the best control of the symptoms with minimal side effects. Conventional immunosuppressive drugs, biologic agents and synthetic small molecules offer different attack routes and may be chosen individually or in combination according to the phenotype of the disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To correlate the expression of microRNAs (miRNAs) 146a/b, 16, the 17-92 cluster and 181a in salivary and plasma samples taken from primary Sjögren's syndrome (pSS) patients with clinical, laboratory and ultrasound findings., Methods: Plasma and salivary samples were collected from 28 patients with pSS according to 2012 ACR and/or 2016 ACR/EULAR criteria (27 females, mean age 64.4±10.1 years, mean disease duration 10.7±6.9 years), and from 23 healthy subjects used as controls. The following patient data were recorded: ESSDAI and ESSPRI scores, anti-SSA and anti-SSB antibody status and laboratory data, Schirmer's test, ultrasound scores of the four major salivary glands according to Cornec et al., and concomitant treatments. The retro-transcribed and quantified miRNAs were: miR16-5p, miR17-5p, miR18a-5p, miR19a-5p, miR19b-1-5p, miR20a, miR92-5p, miR146a-5p, miR146b-5p, miR181a-5p., Results: SS patients had higher expression of salivary miR146a than gender- and age-matched controls (p=0.01). Spearman's regression analysis revealed that salivary miR146b was significantly more expressed in the patients with worse ESSPRI scores (p=0.02), whereas salivary miR17 and 146b and plasma miR17 expression was lower in the patients with higher ultrasound scores (respectively p=0.01, p=0.01 and p=0.04). Salivary miR18a expression was significantly increased in the patients who were anti-La/SSB positive (p=0.04). Neither salivary nor plasma miRNAs correlated with disease duration or concomitant therapies., Conclusions: Our data show that salivary mi146a may represent a marker of the disease, and that the expression of salivary miR17, 18a and 146b may be altered in patients with pSS, and associated with worse ultrasound and ESSPRI scores and anti-La/SSB positivity.

Klotho is a transmembrane and soluble glycoprotein that governs vascular integrity. Previous studies have demonstrated reduced serum klotho concentrations in patients with systemic sclerosis (SSc), and it is known that klotho deficiency can impair the healing of digital ulcers related to microvessel damage. The aim of this study was to evaluate the association between serum klotho levels and nailfold capillaroscopic abnormalities in SSc patients. We retrospectively enrolled 54 consecutive patients with SSc diagnosed on the basis of the 2013 EULAR/ACR criteria [11 with diffuse SSc; 47 females; median age 68.0 years (IQ 18); median disease duration 11.0 years (IQ 7)]. Serum klotho concentrations were determined by means of an enzyme-linked immunosorbent assay. On the basis of the 2000 classification of Cutolo et al., 14 patients had normal nailfold capillaroscopic findings, 8 had an early scleroderma pattern, 21 an active scleroderma pattern, and 11 a late scleroderma pattern. The median serum klotho concentration was 0.29 ng/mL (IQ 1). Regression analysis of variation showed an inverse correlation between serum klotho concentrations and the severity of the capillaroscopic pattern (p=0.02; t -2.2284), which was not influenced by concomitant treatment. Logistic regression did not reveal any significant association between the risk of developing digital ulcers and nailfold capillaroscopic patterns, serum klotho levels, or concomitant medications. The presence of avascular areas significantly correlated with calcinosis (p=0.006). In line with previous studies, our findings confirm that klotho plays a role in preventing microvascular damage detected with nailfold capillaroscopy.

The aim of this review is to report the current evidence on immunogenicity of monoclonal antibodies (moAbs) used in cancer compared with autoimmune diseases, focusing on local microenvironment. English abstracts were identified in Medline and www.clinicaltrials.gov . A total of 82 papers were selected. The percentage of immunogenicity of moAbs used for cancer therapy, evaluated as the serum concentration of antidrug antibodies, is significantly lower than that of moAbs used for the treatment of autoimmune diseases. This condition may rely on a different immunologic background characterized by a hyperactivation of immune cells in autoimmune diseases. The formation of complexes between antidrug antibodies and non-neutralizing moAbs bound to neoplastic antigens may allow more efficient elimination of cancer cells, but additional studies are needed.

Introduction: Understanding the mechanisms underlying the pathogenesis of Sjögren's syndrome (SS) is crucially important in order to be able to discriminate the steps that lead to B cell transformation and promptly identify the patients at risk of lymphomagenesis. The aim of this narrative review is to describe the evidence concerning the role that infections or dysbiosis plays in the epigenetic control of gene expression in SS patients and their possible involvement in B cell lymphomagenesis., Materials and Methods: We searched the PubMed and Google Scholar databases and selected a total of 92 articles published during the last 25 years that describe experimental and clinical studies of the potential associations of microbiota and epigenetic aberrations with the risk of B cell lymphoma in SS patients., Results and Discussion: The genetic background of SS patients is characterized by the hyperexpression of genes that are mainly involved in regulating the innate and adaptive immune responses and oncogenesis. In addition, salivary gland epithelial cells and lymphocytes both have an altered epigenetic background that enhances the activation of proinflammatory and survival pathways. Dysbiosis or chronic latent infections may tune the immune response and modify the cell epigenetic machinery in such a way as to give B lymphocytes an activated or transformed phenotype. It is also worth noting that transposable integrated retroelements may participate in the pathogenesis of SS and B cell lymphomagenesis by inducing DNA breaks, modulating cell gene expression, or generating aberrant transcripts that chronically stimulate the immune system., Conclusions: Microorganisms may epigenetically modify target cells and induce their transcriptome to generate an activated or transformed phenotype. The occurrence of lymphoma in more than 15% of SS patients may be the end result of a combination of genetics, epigenetics, and dysbiosis or latent infections.

Fibromyalgia is characterised by chronic pain, fatigue and functional symptoms. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings related to the aetiopathogenesis, diagnosis, clinical aspects and treatment of FM published between January 2018 and January 2019.

Objectives: Fibromyalgia (FM) is a syndrome of unknown aetiology that is characterised by widespread musculoskeletal pain, fatigue and disordered sleep, and often associated with neuropsychiatric and cognitive symptoms. Current treatment options are only partially effective, but hyperbaric oxygen therapy (HBOT) seems to be capable of relieving some of the symptoms. The aim of this study was to evaluate the efficacy and safety of HBOT after fewer sessions than generally used, chosen on the basis of pre-clinical and clinical data showing its rapid and sustained antinociceptive effect., Methods: Patients with FM underwent HBOT (100% oxygen at 2.5 ata with air breaks) administered on three days per week for a total of twenty 90-minute sessions. Pain, fatigue, the quality of sleep, symptoms of anxiety and depression, and the patients' health-related quality of life were prospectively assessed before and after ten and twenty sessions., Results: Twenty-eight of the 32 study patients completed the 20 HBOT sessions. Pain scores and the symptoms of anxiety (but not those of depression) significantly improved after both 10 and 20 sessions, whereas fatigue and FM symptom severity scores significantly improved only after 20 sessions. There was no significant change in the quality of sleep. The adverse effects were limited., Conclusions: These findings support the view that HBOT is an effective, rapid and safe means of treating various symptoms of FM.

Background: A new class of oral synthetic drugs has been developed for the treatment of rheumatoid arthritis (RA) with the aim of blocking the Janus kinase/signal transducer and activator of transcription (JAK-STAT) system. Tofacitinib and baricitinib have been approved for the treatment RA patients who inadequately respond to methotrexate or anti-tumor necrosis factor drugs. The aim of this narrative review is to summarize the data concerning the drugs' basic mechanisms and clinical trial results in order to inform clinicians about the serious and non-serious adverse events associated with JAK inhibitors. Areas covered: The mechanisms, adverse events, and clinical trial data associated with the use of JAK inhibitors in RA patients were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1999 and April 2018 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: Management of the adverse events of JAK inhibitors is challenging because of the lack of robust treatment data used and the heterogeneity of the events themselves. Treatment decisions are often made clinically on the basis of age and the burden of comorbidities, and require the multidisciplinary collaboration of rheumatologists and other specialists.

Autoimmune diseases and autoinflammatory diseases have a number of similar etiopathogenetic and clinical characteristics, including genetic predisposition and recurrent systemic inflammatory flares. The first phase of ADs involves innate immunity: by means of TLRs, autoantigen presentation, B and T cell recruitment and autoantibody synthesis. The second phase involves adaptive immunity, a self-sustaining process in which immune complexes containing nucleic acids and autoantibodies activate self-directed inflammation. The link between autoimmunity and autoinflammation is IL-1ß, which is crucial in connecting the innate immune response due to NLR activation and the adaptive immune responses of T and B cells. In conclusion, although ADs are still considered adaptive immunity-mediated disorders, there is increasing evidence that innate immunity and inflammasomes are also involved. The aim of this review is to highlight the link between the innate and adaptive immune mechanisms involved in autoimmune diseases.

Background: Aseptic osteonecrosis of the hip is a clinical entity in which the necrotic process of the bone leads to pain and progressive disability., Objective: Pamidronate seems to reduce drastically the activation of the osteoclasts so that it can be useful only in the early stage of the disease, delaying the time of bone collapsing., Method: A 27-years-old male was treated with pamidronate for three consecutive days every four weeks., Results: After three months the patient came back at control showing a marked improvement in clinical condition, referred full recover from pain and dysmotility with improvement of the quality of life, which was confirmed by the result of MRI he had for control., Conclusion: We reported a case of aseptic osteonecrosis of the hip which was successfully treated pamidronate at dosage of 45 mg.

Central nervous system (CNS) involvement is quite unusual in patients with rheumatoid arthritis (RA), although cerebral vasculitis, rheumatoid nodules and meningitis have all been reported, and patients with RA may also have CNS comorbidities such as stroke and neuro-degenerative and demyelinating syndromes. It has been found that biological drugs, especially anti-tumour necrosis factor-alpha (anti-TNF-α) drugs, slightly increase the risk of developing demyelinating diseases, and they are consequently discouraged in patients with multiple sclerosis and related disorders. Furthermore, the risk of opportunistic CNS infections is increased in immunosuppressed patients. To review the current literature concerning CNS involvement in patients with RA (including RA-related forms and comorbidities) and the incidence of new-onset CNS diseases in patients with RA undergoing biological treatment (anti-TNF or non-anti-TNF drugs), the Medline database was searched using the key words 'rheumatoid arthritis', 'central nervous system', 'anti-TNF', 'abatacept', 'tocilizumab', 'rituximab' and 'anakinra'. Abstracts not in English were excluded. We selected 76 articles published between 1989 and 2017, which were divided into four groups on the basis of whether CNS involvement was RA-related or not and according to the type of biological agent used (TNF inhibitors or other agents). The RA-related diseases included aseptic meningitis, vasculitis and cerebral rheumatoid nodules, which benefit from immunosuppressive treatments. CNS comorbidities included stroke, seizures, dementia and neuropsychiatric disorders, which have been frequently described in biological agent-naïve patients with RA, and other rarely reported neurological diseases, such as extra-pyramidal syndromes and demyelinating disorders. CNS comorbidities are relatively frequent among patients with RA and may be related to systemic inflammation or concomitant medications. The use of anti-TNF drugs is associated with the risk of developing demyelinating diseases, and CNS infections have been described in patients treated with anti-TNF and non-anti-TNF agents. Non-anti-TNF drugs may be preferred in the case of demyelinating diseases, cerebral vasculitis or neurolupus. Patients with RA may suffer from CNS involvement as a manifestation of RA or as a comorbidity. The treatment of such medical conditions should be guided on the basis of their etiopathogenesis: steroids and immunosuppressants are useful in the case of RA-related CNS diseases but are often detrimental in other situations. Similarly, the choice of biological agents in patients with RA with CNS complications should be guided by a correct diagnosis in order to prevent further complications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Tocilizumab is a monoclonal antibody directed against the interleukin-6 receptor, which is approved for the treatment of moderate-to-severe rheumatoid arthritis. Authors have found that it prevents lung and subcutaneous nodulosis in patients with rheumatoid arthritis but, to the best of our knowledge, there are no data concerning the acceleration of subcutaneous nodulosis during tocilizumab therapy., Case Presentation: We report for the first time a small case series of five patients with rheumatoid arthritis: a 46-year-old white woman, a 70-year-old white woman, a 63-year-old white woman, a 69-year-old white man, and a 72-year-old white woman (mean age 64 ± 10.6 years); they experienced worsening subcutaneous nodulosis during treatment with intravenously administered tocilizumab. Four of the five patients were positive for rheumatoid factor and five for anti-citrullinated peptide antibodies. All of the patients had previously been treated with various conventional and biological drugs; at the time of our observation, three were taking methotrexate, two hydroxychloroquine, and four were taking prednisone. Tocilizumab 8 mg/kg was administered intravenously every 4 weeks for a mean of 43.4 ± 32.4 months, and led to good disease control in three cases. All of the patients had a history of subcutaneous nodulosis, which considerably worsened during tocilizumab treatment, with the development of new nodules on their fingers, elbows, or in the inframammary fold, tending to ulcerate. The management of this medical event included discontinuation of methotrexate, the administration of steroids, the addition of hydroxychloroquine or colchicine, the use of antibiotics, and surgery. However, neither pharmacological nor surgical treatment was completely effective, as the nodules tended to recur and increased in number and size., Conclusions: To the best of our knowledge, this is the first report describing accelerated subcutaneous nodulosis in a small case series of patients with rheumatoid arthritis treated with tocilizumab.

The role of pericytes in systemic sclerosis (SSc) is unclear because of the difficulty in phenotyping them. They are mainly distributed in the pre-capillary, capillary and post-capillary abluminal side of non-muscular micro-vessels, express platelet-derived growth factor receptors (PDGFRs), and preside over vascular integrity and regeneration. By establishing close contact with many endothelial cells, a single pericyte can regulate ion influx, mechanical stress, leukocyte diapedesis, and platelet activation. Moreover, under pathological conditions such as SSc, pericytes may acquire a contractile phenotype and respond to various stimuli, including endothelin, angiotensin II and reactive oxygen species. The pericytes of SSc patients share some molecular patterns with myofibroblasts or fibroblasts, including A disintegrin and metalloproteinase domain 12 (ADAM-12), α-smooth muscle actin (α-SMA), the extra domain A (ED-A) variant of fibronectin, and Thy-1. Following stimulation with PDGF-β or transforming growth factor-β (TGF-β), pericytes may acquire a myofibroblast phenotype, and produce extracellular matrix or indirectly promote fibroblast activation. They may also contribute to fibrosis by means of epigenetic regulation. The pericyte plasmalemma is particularly rich in caveolae containing caveolin-1, a deficit of which has been associated with defective vessel tone control and lung fibrosis in mice. Consequently, dysfunctional pericytes may underlie the microangiopathy and fibrosis observed in SSc patients. However, given its variability in biological behaviour and the lack of a pan-pericyte marker, the exact role of these cells in SSc warrants further investigation., Competing Interests: Disclosures: Financial support: No grants or funding have been received for this study. Conflict of interest: None of the authors has financial interest related to this study to disclose., (© The Author(s) 2017.)

Background: The expression of CD70 on T cells is greatly enhanced by antigen-presenting cell (APC)-associated signals, such as tumour necrosis factor(TNF)-α, which is constitutionally high in patients with inflammatory bowel disease (IBD). Experimentally, the chronic activation of CD27 as a result of the constitutive expression of CD70 leads to the demise of B cells in bone marrow (BM) and the secondary lymphoid organs. The aim of this study was to assess the number and phenotype of circulating B cell in untreated IBD patients and their counterparts treated with biological anti-TNF drugs., Methods: The study involved 13 untreated IBD patients, 36 IBD patients treated with biological drugs, and 10 healthy controls. The B cell phenotypes were assessed by means of flow cytometry using monoclonal antibodies specific for CD20, CD19, CD3, CD27 and CD43. In order to evaluate B cell development in bone marrow and peripheral B cell activation, we identified four B cell subsets: hematogones (HBs: CD20 + 19 + 3 - 27 - 43 + ), memory B cells (MBs: CD20 + 19 + 3 - 27 + 43 - ), pre-plasmablasts (PPBs: CD20 + 19 + 3 - 27 + 43 + ), and plasmablasts (PBs: CD20 - 19 + 3 - 27 + 43 + )., Results: The total number of B cells in the untreated patients was three times lower than that in the patients treated with biological drug (p<0.001), and half that in the healthy controls (p=0.03). The between-group differences (including the healthy donors) were statistically significant in the case of HBs and MBs, but not in the case of PPBs and PBs. Only one treated patient showed a transiently large increase in PPBs. There were statistically significant differences in all of the parameters between the untreated patients and those receiving biological therapy, and in some cases between the untreated patients and healthy controls, but never between the controls and the treated patients. Four non-responders to anti-TNF therapy had a smaller number of total circulating B cells than the untreated patients., Conclusions: Anti-TNF drugs disinhibit B cell production in IBD patients, but maintain the constant homeostasis of circulating B cells. The presence of individual variations may allow the activity of anti-TNF drugs to be monitored by studying B cell subgroups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The biological drugs have all been successfully used to treat rheumatoid arthritis (RA) and have led to fair rates of clinical remission; however, the possible occurrence of adverse events such as infectious diseases or cancers means that the patients undergoing treatment need to be closely monitored. Anti-TNF agents, first appeared in the pharmacological algorithm of RA in the early 2000s, seem to lead to a higher risk of reactivated tubercular infection than the biological agents with different mechanism of action (abatacept or rituximab). Although the data on anti-TNF agents and cancer are controversial, their use is currently not recommended in neoplastic patients because of their uncertain effects on immune-surveillance. The safety profile of abatacept is similar to that of other biological agents, while rituximab is used to treat non-Hodgkin lymphomas and is also considered in the case of RA patients with previous hematological or non-hematological malignancies. The risk of infections and new-onset cancers during tocilizumab treatment is similar to that associated with other biological therapies. Finally, under particular circumstances, such as in the presence of infections or malignancies, blocking a specific immunological pathway may be simultaneously successful and detrimental. The only thing that can be done at the moment is to continue to look for adverse events in order to discover these complications as soon as possible, and then develop the most appropriate means of treating (and even preventing) them., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The aim was to evaluate the role of klotho in the pathogenesis of systemic sclerosis (SSc), through the measurement of its serum concentration in SSc patients compared to healthy controls, and to assess the association with cutaneous and visceral involvement. Blood samples obtained from both SSc patients and healthy controls were analysed by an ELISA assay for the detection of human klotho. SSc patients were globally evaluated for disease activity and assessed through the modified Rodnan's Skin Score, Medsger's scale, pulmonary function tests, 2D-echocardiography, nailfold capillaroscopy and laboratory tests. Our cohort consisted of 69 SSc patients (61 females, mean age 64.5±12.5 years, median disease duration 9.0 (IQR 8) years) and 77 healthy controls (28 females, mean age 49.7±10.2 years). In the group of SSc patients, 19 (27.5%) suffered from a diffuse form of SSc. All patients were receiving IV prostanoids, and some of them were concomitantly treated with immunosuppressive drugs (prednisone, hydroxychloroquine, mofetil mycophenolate, methotrexate, cyclosporin A and azathioprine). The median serum concentration of klotho was significantly lower in patients compared to controls (0.23 ng/mL vs 0.60 ng/mL; p<0.001). However, Spearman's test showed no significant association between klotho serum levels and disease activity, concerning either clinical, laboratory or instrumental findings. Our data show a significant deficit of klotho in SSc patients although any significant association was detected between klotho serum concentration and the clinical, laboratory or instrumental features of the disease. However, due to the limits of the study, further investigations are required.

To investigate the influence of fibromyalgia (FM) on achieving remission defined on the basis of the Simplified Disease Activity Index (SDAI) remission criteria in patients with long-standing rheumatoid arthritis (RA). This observational longitudinal cohort consisted of long-standing RA patients being treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biological DMARDs (bDMARDs). After 6 months of follow-up, the patients fulfilling or not fulfilling the remission criteria were identified and compared with each other in terms of the presence of FM, neuropathic pain, and other comorbidities. At the end of the 6-month observation period, 24 of the 117 patients (20.4%) met the SDAI remission criteria. Logistic regression analysis showed that the modified Rheumatic Disease Comorbidity Index (mRDCI) (p = 0.0001), the FM presence (p = 0.0001), and the 36-item short-form health survey Mental Component Summary (SF-36 MCS) Score (p = 0.0088) were the strongest predictors of not being in SDAI remission. None of the patients with concomitant FM (17.1%) achieved SDAI remission. In comparison with the non-FM patients, the patients with RA and FM patients had worse scores on the SF-36 MCS (p = 0.011), on the sleep Visual Analogue Scale (VAS) (p = 0.018), on the self-counts of tender joints (p = 0.039), and on the PainDetect Questionnaire (PDQ) (p = 0.001). To avoid over treatment, an assessment of FM should be considered in RA patients who do not fulfil the remission criteria.

Our objective was to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in T-helper-9 (Th9) percentages induced by an in vitro stimulation test., Methods: Peripheral blood mononuclear cells collected from 55 consecutive rheumatoid arthritis (RA) outpatients (15 drug free, 20 successfully treated with branded infliximab, 20 branded infliximab inadequate responders) and 10 healthy controls were cultured, with or without 50 μg/mL of infliximab originator (Remicade ® ) or 50 μg/mL of infliximab biosimilar (Remsima ® ) for 18 h. Th9 lymphocytes were identified by means of flow cytometry as PU.1 and IRF4-expressing, IL-9-secreting CD4⁺ T cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9 producer cells., Results: Under unstimulated conditions, the drug-free RA patients had the highest percentages of Th9 lymphocytes. Following stimulation with branded infliximab, the percentages of PU.1 and IRF4-expressing Th9 cells, CCR7⁺, CD45RA - (central memory) and CCR7 - , CD45RA - (effector memory) cells significantly increased in the group of inadequate responders, but no significant variation was observed after exposure to the biosimilar of infliximab., Conclusions: Th9 cells seem to be involved in the immune response to the epitopes of branded, but not biosimilar, infliximab, and this may depend on the recall and stimulation of both central and effector memory cells., Competing Interests: The authors declare no conflict of interest.

Background: Biomarkers are important for guiding the clinical and therapeutic management of all phases of rheumatoid arthritis because they can help to predict disease development in subjects at risk, improve diagnosis by closing the serological gap, provide prognostic information that is useful for making therapeutic choices and assessing treatment responses and outcomes, and allow disease activity and progression to be monitored. Various biomarkers can be used to identify subjects susceptible to the disease and those with pre-clinical rheumatoid arthritis before the onset of symptoms such as rheumatoid factor and anti-citrullinated protein antibodies. They can be correlated with a risk of developing rheumatoid arthritis and can predict more bone erosions and severe disease progression. Biomarkers such as the erythrocyte sedimentation rate and C-reactive protein levels provide information about disease activity, while predictive biomarkers allow clinicians to assess the probability of a treatment response before starting a particular therapy particularly in the era of biological drugs. This move from traditional approaches to patient stratification and targeted treatment should greatly improve patient care and reduce medical costs.

Objectives: To investigate the 6-month impact of the catastrophic earthquakes that struck central Italy in August and October 2016 on the health-related quality of life (HRQoL) of patients with fibromyalgia (FM)., Methods: We compared a cohort of 55 consecutive FM patients who had been exposed to an earthquake with a control group of 49 FM patients who had not been exposed to it. At each time-point (baseline, and after one, two, four and six months), the patients completed self-reported electronic versions of the revised Fibromyalgia Impact Questionnaire (FIQR) and the Fibromyalgia Activity Score (FAS) on a web platform., Results: At baseline, there were no significant between-group differences in the total FIQR score or the scores of its three domains of function, overall impact and symptoms, and no significant differences in the total FAS score or the FAS fatigue, quality of sleep, and Self-Assessment Pain Scale (SAPS) scores. However, after six months of observation, the median total FIQR score was higher in the earthquake-exposed patients (241.00, 95% confidence interval [CI] 230.55-255.35) than in the unexposed patients (177.50, 95% CI 157.30-185.48; p<0.0001), and the same was true of the median total FAS score (26.86, 95% CI 25.78-28.18 vs. 22.76, 95% CI 20.92-24.34; p<0.0001). Moreover, there were also significant differences in all of the FIQR and FAS domain scores., Conclusions: A natural catastrophe such as an earthquake can have a significant impact on the major domains of pain, fatigue, sleep, and the overall quality of life of FM patients.

Objectives: Fibromyalgia (FM) is a clinical syndrome characterised by widespread musculoskeletal pain, chronic fatigue, cognitive deficits, and sleep and mood disorders. The effectiveness of most pharmacological treatments is limited, and there is a need for new, effective and well-tolerated therapies. It has recently been shown that transcranial direct-current stimulation (tDCS) of the motor cortex reduces pain, and that tDCS of the dorso-lateral prefrontal cortex (DLPFC) improves anxiety, depression and cognitive impairment in FM patients. The new technique of transcranial random noise stimulation (tRNS) using randomly changing alternating currents has very recently been shown to improve working memory and pain in limited series of patients with FM or neuropathic pain. The aim of this study was to investigate the clinical effects of primary motor cortex (M1) tRNS in FM patients., Methods: Twenty female FM patients aged 26-67 years were randomised to undergo active (real) or placebo (sham) tRNS sessions on five days a week (Monday-Friday) for two weeks. Each patient was evaluated before and after treatment using a visual analogue scale (VAS), the Fibromyalgia Impact Questionnaire (FIQ), the Hospital Anxiety and Depression Scale (HADS), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT), the Forward and Backward Digit Span test, and the FAS verbal fluency test., Results: In comparison with sham treatment, active tRNS of M1 induced a general improvement in the clinical picture of FM, with a significant reduction in pain, depression, anxiety and FIQ scores and a significant improvement in TMT (A), RAVLT and FAS scores., Conclusions: These findings suggest that tRNS of M1 can be very effective in relieving FM symptoms. Unlike motor cortex tDCS, it seems to counteract both pain and cognitive disturbances, possibly because the invoked mechanism of stochastic resonance synchronises neural firing and thus leads to more widespread and lasting effects.

Fibromyalgia (FM) is a complex syndrome characterised by chronic pain, fatigue and functional symptoms. Widespread pain is often its most typical feature, whereas other manifestations may be associated to various extents. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings relating to the aetiopathogenesis, assessment and treatment of FM published between January 2016 and January 2017.