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Objectives The risk of amyloidosis during the course of AS is yet to be firmly established. We aimed to evaluate the risks, predictors and prognostic outcomes of amyloidosis among patients with AS. Methods A population-based cohort study was conducted comparing AS patients (n = 5911) with age-, sex- and ethnicity-matched control subjects (n = 29 007) with regard to incident cases of amyloidosis. Hazard ratios (HRs) and odds ratios (ORs) were estimated by Cox regression and logistic regression analyses, respectively. Results The incidence rate of amyloidosis was 2.15 (95% CI 1.09, 2.82) and 0.35 (95% CI 0.16, 0.66) per 10 000 person-years among patients with AS and controls, respectively. The risk of incident amyloidosis was >6-fold higher among patients with AS relative to control subjects [adjusted HR 6.16 (95% CI 2.43, 15.62); P Conclusions Patients with AS are at an increased risk of amyloidosis. AS-associated amyloidosis is associated with an elevated risk of dialysis dependence. Awareness of the burden and consequences of this complication may be of help for rheumatologists managing patients with AS.

Objective: Estimated fetal weight, large for gestational age (eLGA) (≥90th percentile) may be associated with failed trial of labor after Cesarean (TOLAC), like fetal macrosomia. The aim of this study was to evaluate obstetrical outcome and safety of TOLAC, for women with eLGA. Design: A retrospective cohort study. Setting: a single large tertiary care center. Population or Sample: all women with singleton pregnancy, gestational age ≥ 37weeks, admitted for TOLAC between 2012 and 2017. Methods: Women with eLGA were compared to women with EFW < 90th percentile. Main outcome measures: the rate of successful vaginal delivery, adverse obstetrical outcomes. Results: 1949 women met inclusion criteria, including78 (4%) eLGA and 1871 (96%) controls. Study group were older (35 vs. 33 year; p=0.004), with higher Body Mass Index (30.9 vs. 27.5 kg/m2; p=0.001) and higher gravidity (4 vs. 3; p=0.001) compared to the controls. Median fetal weight was [3887g (IQR 3718-4073) vs. 3275g (IQR 2995-3545); p=0.001 in the study vs. controls respectively]. 55 (70.5%) women in the study group had successful vaginal delivery compared to 1506 (80.5%) women in the control (p= 0.03). The rate of obstetrical complications, including: scar dehiscence, uterine rupture, 3rd /4th degree perineal tear or shoulder dystocia were comparable. The rate of post-partum hemorrhage was increased in the study group compared to controls (7.7% vs.1.7%; p=0.001). Conclusion: TOLAC for eLGA fetuses can be considered as safe, however, lower successful VBAC rates and increased PPH rate may be expected.

Der Begriff Spondyloarthritis (SpA) bezieht sich sowohl auf die axiale als auch auf die periphere Arthritis und schließt die ankylosierende Spondylitis (AS) und die Psoriasis-Arthritis (PsA) ein. Letztere ist eng mit der Psoriasis und der im Zusammenhang mit chronisch entzündlichen Darmerkrankungen (CED) auftretenden Arthritis assoziiert. Die Begründung für die Bedeutung von Interleukin-23 (IL-23) bei Erkrankungen aus dem Formenkreis der Spondyloarthritiden stützt sich auf vier Quellen: Erstens wurde in genomweiten Assoziationsstudien (GWAS) nachgewiesen, dass alle genannten Erkrankungen Einzelnukleotid-Polymorphismen (SNPs) des IL-23-Rezeptor (IL-23R)-Signalwegs aufweisen, wohingegen HLA-B27 nicht mit diesen Erkrankungen in Zusammenhang steht, was bedeutet, dass der IL-23-Signalweg der gemeinsame genetische Nenner ist. Zweitens zeigten tierexperimentelle Modelle, dass die IL-23/IL-17-Achse eine Schlüsselrolle bei der SpA-bezogenen Arthropathie spielt, die sich initial in Form einer Enthesitis, aber auch als Synovitis und axiale Entzündung sowie als assoziierte Inflammation der Aortenwurzel und der Haut manifestiert. Drittens stützen auch die neu aufkommenden Erkenntnisse zur Immunologie der menschlichen Enthese das Vorliegen von IL-23-bildenden myeloischen Zellen nicht nur an der Enthese, sondern auch an anderen SpA-assoziierten Lokalisationen, einschließlich Haut und Darm. Und schließlich zeigen Arzneimittel, die auf den IL-23-Signalweg ausgerichtet sind, eine ausgezeichnete Wirksamkeit bei Hauterkrankungen und Wirkung bei CED und bei der mit SpA assoziierten peripheren Arthropathie. Die Tatsache, dass die IL-23-Blockade bei AS, bei der es sich im Endeffekt um eine spinale Polyenthesitis handelt, augenscheinlich versagt, jedoch Belege für die Wirksamkeit der IL-23-Hemmung bei peripherer Enthesitis bei PsA und erste Hinweise auf einen Nutzen bei axialer PsA vorliegen, wirft viele Fragen auf. Die entscheidende Frage ist, ob es bei der spinalen Entzündung unter Umständen zu einer von IL-23 unabhängigen enthesialen IL-17A-Bildung kommt, wohingegen die periphere Enthesitis hauptsächlich von der IL-23-gesteuerten IL-17-Bildung abhängt. Ferner können Strategien zur IL-23-Blockade in Tiermodellen zwar die Entwicklung einer experimentellen SpA verhindern, nicht jedoch eine bestehende Erkrankung. Dies spricht dafür, dass IL-23 möglicherweise eine Rolle bei der Auslösung von Störungen der angeborenen Immunität spielt, während eine chronische Erkrankung von Reaktionen der T-Gedächtniszellen abhängt, die die IL-17A-Bildung unabhängig von IL-23 beeinflussen. Doch sind diesbezüglich noch weitere Untersuchungen erforderlich. Außerdem ist die IL-12/23-Dosierung bei entzündlichen Darmerkrankungen wesentlich höher als die in Studien zur AS verwendete Dosierung, was ebenfalls zu berücksichtigen ist. Aus den genannten Gründen spielt der IL-23-Signalweg im Konzept der SpA eine zentrale Rolle, doch müssen die Nuancen und Feinheiten bei der Entzündung des Achsenskeletts, die auf ein Nicht-Ansprechen auf den IL-23-Antagonismus hindeuten, noch formal definiert werden. Da keine vergleichenden immunologischen Untersuchungen der verschiedenen Skelettlokalisationen vorliegen, sind die Erklärungen zum jetzigen Zeitpunkt rein hypothetisch.

The immunological perturbations associated with systemic lupus erythematosus (SLE) put many patients at a higher risk of infections, including pneumococcal pneumonia. However, the uptake and utility of anti-pneumococcal vaccines in SLE patient is both controversial and not completely agreed upon. Indeed, several epidemiological studies of anti-pneumococcal vaccine safety and efficacy in SLE have reported short-term immunogenicity with elevated anti-pneumococcal antibody titres but inconsistent long-term findings, with some studies finding poor responses, mainly for long-term immune protection. Moreover, the safety and efficacy of the pneumococcal vaccine in SLE patients remains controversial due to the different types of anti-pneumococcal vaccines, and the heterogeneity of SLE patients. Several reviews addressing anti-pneumococcal vaccination in SLE patients exist, however, to the best of our knowledge, the present is the first systematic review and meta-analysis. To better understand the efficacy and safety of pneumococcal vaccination in SLE, a comprehensive literature search was performed identifying 18 studies, which have been included in the present systematic review and meta-analysis. All studies were designed as longitudinal investigations, 2, in particular, were of high quality, being randomized, double-blind trials (RCTs). Four studies had control groups. Total sample size included 601 participants. Vaccine immunogenicity in terms of subjects with protective antibody titers ranged from 36% to 97.6%. According to our systematic review and metanalysis, high erythrocyte sedimentation rate (ESR), older age, earlier SLE onset, high disease activity, and immunosuppressive therapy were predictors of poor immunogenicity, although belimumab was found to have no significant impact. With regard to safety, no serious adverse events were found, with up to one third of cases reporting mild/low-grade complaints. In conclusion, due to the high risk of pneumococcal infection in SLE patients and given the safety and, at least partial, effectiveness, according to our systematic review and meta-analysis, in such patients, preventive strategies mainly by immunization, are required in all age groups and, in those needing immunosuppressive therapy, immunization should be given prior the initiation of the treatment. PROSPERO registration code CRD42018103605.

A higher prevalence of ischemic heart disease (IHD) in patients with systemic sclerosis (SSc) was reported. However, contrasting findings were published concerning the role of SSc-related autoantibodies in IHD risk which remains controversial. The current study explored the link between SSc and IHD, impact of putative links on SSc mortality and the role of SSc-related and antiphospholipid autoantibodies in disease associated IHD.A large cohort study utilising the Clalit-Health-Service (CHS) database was conducted on 2431 SSc patients and 12,710 age- and sex matched controls. The proportion of IHD was compared between patients diagnosed with SSc and age- and gender-matched controls. The role of SSc-linked and antiphospholipid autoantibodies in disease associated IHD was assessed.The prevalence rate of IHD was significantly higher in SSc than controls (20.4% vs 15.0%, p 0.001). At the multivariate analysis, SSc was an independent predictor of IHD with an OR of 1.91 (95%CI 1.57-2.31, p 0.0001). SSc patients with IHD had a higher mortality rate with an HR of 2.67 (95%CI 2.03-3.53, p 0.0001) than those without IHD. In SSc patients positivity for anti-beta2GPI (IgM-isotype) or anti-cardiolipin (aCL) (IgA-isotype) represented a risk factor for IHD with an OR 1.89 (95% 1.04-3.45, p = 0.0369) and OR of 3.72 (95% 1.25-11.11, p = 0.0184), respectively.Patients with SSc are at higher risk for developing IHD with an additional risk for the latter in those positive for aCL or anti-beta2GPI. A high degree of suspicion is needed during routine patient follow-up and pre-emptive screening should be considered.

Psoriatic arthritis (PsA) patients are often affected by numerous comorbidities. However, contrasting results have been reported with regard to the respiratory involvement in PsA patients. The aim of this study was to evaluate the presence of subclinical airway inflammation in non-smoking PsA patients compared to patients with only psoriasis using the fraction of exhaled nitric oxide (FeNO) as an indirect marker of airway inflammation.The study included 164 non-smoking psoriatic patients (Psoriasis Area of Severity Index or PASI score 10): 82 with and 82 without PsA, who underwent FeNO tests at different flow rates (30, 50, 100, 200 mL/s). PsA patients were evaluated with Disease Activity in PSoriatic Arthritis Score (DAPSA). Both study groups were compared in terms of FeNO values and its association with the PASI score. The correlations between the variables were evaluated by means of Pearson's coefficient.Patient with PsA had higher levels of FeNO than those with psoriasis but without arthritis (at 30 mL/s, 71.09 ± 18.40 ppb vs 66.88 ± 19.12 ppb (NS); at 50 mL/s, 36.61 ± 9.30 ppb vs 30.88 ± 9.73 ppb (p 0.001); at 100 mL/s, 19.09 ± 4.66 ppb vs 16.63 ± 4.90 ppb (p 0.001); and at 200 mL/s, 10.88 ± 2.53 ppb vs 9.43 ± 2.55 ppb (p 0.001), respectively). PASI score correlated to FeNO only in psoriatic patients without arthritis. However, CASPAR index correlated with FeNO (FeNO30: r = 0.81, p 0.001; FeNO50: r = 0.84, p 0.001; FeNO100: r = 0.71, p 0.001; FeNO200: r = 0.58, p 0.001). DAPSA was also correlated with FeNO to all flows (FeNO30: r = 0.43, p 0.001; FeNO50: r = 0.33, p 0.001; FeNO100: r = 0.34, p 0.001; FeNO200: r = 0.25, p 0.001).PsA patients seem to have more commonly subclinical airway inflammation than those with only psoriasis. Further studies are needed to replicate these findings. Key Points • Fraction of exhaled nitric oxide (FeNO) is a useful device to detect and monitor airway inflammation not only in asthma but also in systemic inflammatory diseases such as psoriatic arthritis and psoriasis. • Clinicians should be aware to check respiratory diseases in patients with psoriatic arthritis.

Objective: The aim of this retrospective cohort study was to examine whether adherence to metformin treatment may be associated with lower onset of rheumatoid arthritis (RA).Method: Using the compu...

The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL-23R or the interleukin-23 (IL-23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin-17 (IL-17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL-23R-expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL-23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL-23R-expressing myeloid cells and various innate and adaptive T cells that produce IL-17 family cytokines have also been described in the human enthesis. Blockade of IL-23 pathway with either anti-p40 or anti-p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL-23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

ObjectiveBacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.MethodsNormal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.ResultsCD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection).ConclusionEntheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.

Background: Infertility is one of the most effective problems facing advanced and developed nations. In general, about half of all cases of infertility are caused by factors related to the male. Up till now, there is no effective treatment for patients with azoospermia, in which there is an absence of mature sperm in the testes. Although evidence suggests that many patients with male infertility may be treated with MSCs. Aim: Our study aims to investigate the effect of honey, bovine colostrum, G-CSF on homing of HSCs from their niche for treatment of induced fertility in male mice. Materials &Methods: Seventy male mice were randomly divided into seven groups and injected with cyclophosphamide to be infertile , then first group treated with honey, second treated with bovine colostrum ,third treated with MSCs, fourth treated with G-CSF , fifth treated with wheat germ , the 2nd generation of stem cells were injected intraperitoneally. Different samples were taken at the end of study for tests. Results: Azoospermatic male mice expressed SCP-3, GFRa1, Sca-1, Protamine and Prohibitin in testis tissue after treatment. Expression of SCP-3, GFRa1, and sca-1 in testis of azoospermatic male mice induced with cyclophosphamide after treatment with honey,bovine colostrum and umbilical cord derived mesenchymal stem cells.

We thank Li et al for their commentary on our recently published paper "Mortality in Ankylosing Spondylitis According to Treatment: A Nationwide Retrospective Cohort Study of 5900 Patients from Israel" (1). Their major concern was regarding the findings which demonstrated no excess mortality in ankylosing-spondylitis (AS) patients treated with TNF-inhibitors (TNFi).

Background: Suicide is a leading cause of death worldwide, affecting ~800,000 people every year. Fibromyalgia is an extremely prevalent rheumatic disease with a predisposition for comorbid anxiety and depression, which are known risk factors for suicidal behavior. Suicidality and relevant risk factors for suicidal behavior have not been thoroughly studied in patients with fibromyalgia.Objectives: To investigate the risk of suicidal ideation and attempts in patients with fibromyalgia.Methods: A systematic review and meta-analysis was conducted and reported according to the “Preferred Reporting Items for Systematic reviews and Meta-analyses” (PRISMA) standards. Also, the gray literature was extensively searched.Results: Thirteen studies were included in the present systematic review and meta-analysis, including 394,087 fibromyalgia patients. Sample size ranged from 44 to 199,739 subjects, mean age ranged from 45.8 to 54.5 years while the female percentage with fibromyalgia ranged from 17.1 to 100.0%. The overall suicide ideation prevalence was 29.57% (95%CI 1.84–72.07), with an OR 9.12 of (95%CI 1.42–58.77), ranging from 2.34 (95%CI 1.49–3.66) to 26.89 (95%CI 5.72–126.42). Pooled suicide attempt prevalence was 5.69% [95%CI 1.26–31.34], with an OR of 3.12 [95%CI 1.37–7.12]. Suicide risk was higher with respect to the general population with an OR of 36.77 (95%CI 15.55–96.94), as well as suicide events with an HR of 1.38 (95%CI 1.17–1.71). Determinants of suicidality were found to be: employment status, disease severity, obesity and drug dependence, chronic pain and co-morbidities, in particular depression, anxiety, poor sleep, and global mental health. However, in some cases, after adjusting for psychiatric conditions, the threshold of statistical significance was not achieved.Conclusion: Fibromyalgia patients are particularly prone to suicide, in terms of ideation, attempt, risk and events, warranting a pre-emptive screening of their mental health status. Given the few studies available, the high amount of heterogeneity, the evidence of publications bias and the lack of statistical significance when adjusting for underlying psychiatric co-morbidities, further high-quality studies should be conducted.Clinical Trial Registration:ClinicalTrial.gov, identifier 10.17605/OSF.IO/Y4BUE.

Entheseal spinal inflammation and new bone formation with progressive ankylosis may occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). This study evaluated whether JAK inhibition with tofacitinib modulated the key disease associated cytokines, TNF and IL-17A and whether tofacitinib also modulated bone marrow stromal cell-derived mesenchymal stem cells (MSCs) function including osteogenesis, since post inflammation new bone formation occurs in these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were in-vestigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in Tofacitinib treated (1000nM) peri-entheseal bone (PEB) and peripheral blood mononuclear cells (PBMC) following ELISA. Bone marrow stromal cell-derived mesenchymal stem cells (MSCs) colony forming unit (CFU-F) and multilineage potential was evaluated using tofacitinib (dosag-es ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cytokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by to-facitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and oste-ogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human enthe-seal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofacitinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis, the rele-vance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA.

Psoriatic arthritis (PsA) mostly develops in patients with an established diagnosis of psoriasis (PsO).1 Following the onset of PsA, structural articular damage and loss of function often occur, leading to impairment in quality of life above and beyond that seen in PsO alone.2 PsO registry studies show a progression to PsA in around 1.5%–3% per year in PsO subjects, although figures may be even higher when PsO associates with other factors (eg, arthralgia).3 Reducing this rate of PsA development and identifying PsO subjects at higher risk for PsA progression is of paramount importance, especially given that many PsO therapies have been independently verified as being efficacious for established PsA. Therefore, by extension, these therapies might also be expected to work at the earliest stages of PsO-associated inflammatory arthritis, where better therapeutic effectiveness is generally expected.4 The ability to characterise the preclinical phases of autoimmune diseases, as initially in type 1 diabetes (T1DM),5 was followed by other diseases, including rheumatoid arthritis (RA)6 or autoimmune connective tissue diseases.7 They provide the unique window of opportunity for therapeutic interventions in the preclinical stage of disease. Interventions applied at this point, as the hypothesis goes, would minimise disease burden and subsequent irreversible joint damage leading to functional impairment and long-term disability, eventually to reducing the complications and socioeconomic impact of disease. Historically, the prevention of diseases, such as T1DM, for example, with cyclosporine, was marred by incomplete responses and drug toxicity.8 Nonetheless, proof of concept for disease prevention was established. In this editorial, we discuss emerging and conflicting evidence about early stage therapy for PsA. Specifically, we will explore the concept of prescription of disease-modifying antirheumatic drugs (DMARDs), including biological DMARDs (bDMARDs), in subjects with moderate-to-severe PsO, at no extra cost to the health payers and …

Background: The association between giant cell arteritis (GCA) and malignancies had been widely investigated with studies reporting conflicting results. Therefore, in this study, we aimed to investigate this association using a large nationwide electronic database. Methods: This study was designed as a retrospective cohort study including GCA patients first diagnosed between 2002–2017 and age, sex and enrollment time-matched controls. Follow-up began at the date of first GCA-diagnosis and continued until first diagnosis of malignancy, death or end of study follow-up. Results: The study enrolled 7213 GCA patients and 32,987 age- and sex-matched controls. The mean age of GCA diagnosis was 72.3 (SD 9.9) years and 69.1% were women. During the follow-up period, 659 (9.1%) of GCA patients were diagnosed with solid malignancies and 144 (2.0%) were diagnosed with hematologic malignancies. In cox-multivariate-analysis the risk of solid- malignancies (HR = 1.12 [95%CI: 1.02–1.22]), specifically renal neoplasms (HR = 1.60 [95%CI: 1.15–2.23]) and sarcomas (HR = 2.14 [95%CI: 1.41–3.24]), and the risk of hematologic malignancies (HR = 2.02 [95%CI: 1.66–2.47]), specifically acute leukemias (HR = 1.81 [95%CI: 1.06–3.07]), chronic leukemias (HR = 1.82 [95%CI: 1.19–2.77]), Hodgkin’s lymphomas (HR = 2.42 [95%CI: 1.12–5.20]), non-Hodgkin’s-lymphomas (HR = 1.66: [95%CI 1.21–2.29]) and multiple myeloma(HR = 2.40 [95%CI: 1.63–3.53]) were significantly increased in GCA patients compared to controls. Older age at GCA-diagnosis (HR = 1.36 [95%CI: 1.25–1.47]), male-gender (HR = 1.46 [95%CI: 1.24–1.72]), smoking (HR = 1.25 [95%CI: 1.04–1.51]) and medium-high socioeconomic status (HR = 1.27 [95%CI: 1.07–1.50]) were independently associated with solid malignancy while age (HR = 1.47 [95%CI: 1.22–1.77]) and male-gender (HR = 1.61 [95%CI: 1.14–2.29]) alone were independently associated with hematologic- malignancies. Conclusion: our study demonstrated higher incidence of hematologic and solid malignancies in GCA patients. Specifically, leukemia, lymphoma, multiple myeloma, kidney malignancies, and sarcomas. Age and male gender were independent risk factors for hematological malignancies among GCA patients, while for solid malignancies, smoking and SES were risk factors as well.

BACKGROUND: Jet-lag may affect air-travelers crossing at least 2 time-zones and has several healthcare implications. It occurs when the human biological rhythms are out of synch with respect to the day-night cycle at the country destination. Its effect in psoriasis is missing. We aimed to evaluate the effect of Jet-lag in psoriatic patients’ management. METHODS: This is a prospective observational study that enrolled psoriatic patients that underwent a flight: patients who experienced jet-lag were compared to patients who did not experience jet-lag. Before the flight, a dermatologist recorded clinical and demographical data with particular attention to Psoriasis Area Severity Index (PASI) and Disease Activity in PSoriatic Arthritis (DAPSA). Patients performed Self-Administered Psoriasis Area Severity Index (SAPASI), the Dermatology Life Quality Index (DLQI) and the pruritus Visual Analog Scale (VAS) scores. After the flight, patients completed the SAPASI, DLQI and pruritus-VAS scores. RESULTS: The sample recruited comprised of 70 psoriatic patients aged 42.4 ± 9.7 years (median 42.5 years). Thirty (42.9%) were males, mean BMI was 25.5 ± 2.2 kg/m(2). Average disease duration was 15.2 ±7.1 years, and 20 (28.6%) subjects had developed PsA. Average hours of flight were 5.4 ±3.5 (median 3.5 hours), with 34 (48.6%) subjects reporting jet-lag. At the multivariate regression analysis, the change in the SAPASI score resulted correlated with jet-lag (regression coefficient 1.63, p = 0.0092), as well the change in the DLQI score (regression coefficient = 1.73, p = 0.0009), but no change on the pruritus VAS scale was found. CONCLUSIONS: The present study suggests that jet-lag may influence disease severity and DLQI scores, but not itch in psoriatic patients.

Background: We investigated the pattern of reported immune diseases in the international ASIA syndrome registry. Methods: Data from 500 subjects exposed to adjuvants from the ASIA syndrome international registry were analysed. Results: The patient mean age was 43 ± 17 years and 89% were female. Within the reported immune diseases, 69% were well-defined immune diseases (autoimmune, autoinflammation, and mixed pattern diseases). Among the well-defined immune diseases following the exposure to adjuvants, polygenic autoimmune diseases were significantly higher than autoinflammatory disorders (92.7% vs 5.8%, respectively, p < 0.001). Polygenic autoimmune diseases such as connective tissue diseases were significantly linked to the exposure to HBV vaccine (OR 3.15 [95%CI 1.08–9.23], p = 0.036). Polygenic autoinflammatory diseases were significantly associated with the exposure to influenza vaccination (OR 10.98 [95%CI 3.81–31.67], p < 0.0001). Conclusions: Immune conditions following vaccination are rare, and among these, polygenic autoimmune diseases represent the vast majority of the well-defined immune diseases reported under the umbrella ASIA syndrome. However, vaccines benefit outweighs their autoimmune side effects.

Background Rheumatoid Arthritis (RA) is a chronic inflammatory disease, affecting women more than men, with a more aggressive course in women. Design A prospective study that recruited 58 patients (46 women aged 56 ± 12 years) with active long-standing RA disease (>12 months). Our goals were to measure their endothelial function, part of the cardiovascular risk assessment. Methods The Brachial Artery method measured endothelial function (the flow mediated percent change [FMD percentage] of the brachial artery diameter). A senior Rheumatologist clinically evaluated all subjects. Mann Whitney rank sum test estimated gender differences among the RA patients. Results Median FMD% change for men was −6.07%, while median FMD% change for women was 0.44% (Z = 2.38, P = 0.01). Baseline Brachial artery diameter was larger in men (Z = 2.52, P = 0.01); however, tender joints count and BMI were greater in women (Z=−2.24, P = 0.01; Z=−3.99, P = 0.001), respectively. Conclusions Women with RA have significantly better endothelial function than men with RA. It means that even though RA is 3-fold more prevalent in women, women are more protected from atherosclerotic coronary artery disease and cardiac events.

The heterodimeric IL-12 family member cytokines including, IL-12, IL-23, IL-27, and IL-35 and have multiple roles in regulating innate and adaptive immunity with crucial functions in inflammatory disorders such as psoriasis. Chain pairing promiscuity is a feature of the IL-12 family. Recently, based on murine data, a new family member, IL-39, was proposed, consisting of IL23p19 (shared with IL-23) and EBI3 (shared with IL-27 and IL-35). IL-39 has subsequently been implicated in experimental murine lupus. Given the success of IL-23p19 therapeutic targeting in diseases including psoriasis, it is of great interest to confirm the presence of IL-39 in man. Human IL-39 is yet to be either detected or expressed, which has halted research in this area. Using a disulphide-linked human chimera protein composing of IL-23p19 and EBI3 human chains, we stimulated human leukocytes, and analysed cytokine secretion and STAT3 phosphorylation. We report that this cytokine shows no activity in human cells. IL-39 chimera protein failed to induce either IL-6, IL-8, TNF, or IL-17A from leukocytes or STAT3 phosphorylation and thus, remains a ‘theoretical cytokine' in humans.

Objective To investigate whether sonographically determined subclinical enthesopathy in patients with moderate‐to‐severe psoriasis regresses with the use of ustekinumab therapy for skin disease. Methods Seventy‐three patients with moderate‐to‐severe psoriasis, who were not treated with systemic therapy and did not have symptoms of psoriatic arthritis (PsA), and 23 healthy volunteers were screened by ultrasound for subclinical enthesitis. Subsequently, 23 patients with psoriasis whose ultrasound results showed inflammatory changes were treated with ustekinumab for 52 weeks. The evolution of sonographic abnormalities of the upper and lower limb entheses was assessed using an extensive gray‐scale and power Doppler (PD) ultrasound protocol at weeks 0, 12, 24, and 52. For each parameter, a gray‐scale or PD ultrasound score of >0 was determined to be abnormal, and a summative score based on the Glasgow Ultrasound Enthesitis Scoring System was calculated. Results Of all the patients with psoriasis screened using ultrasound, 49.3% had at least 1 inflammatory entheseal abnormality. Mean ± SD inflammation scores were higher in the patients with psoriasis compared with the healthy volunteers (9.9 ± 6.6 versus 1.0 ± 1.4). With treatment, the mean inflammation scores decreased significantly by 42.2% from week 0 to week 24 (–4.2 [95% confidence interval –6.3, –2.1]; P < 0.001) and by 47.5% by week 42 (–4.7 [95% confidence interval –7.1, –2.3]; P = 0.001). Entheseal structural abnormalities did not change significantly during treatment. Conclusion Within 12 weeks of treatment, interleukin‐12 (IL‐12)/IL‐23 inhibition for psoriasis appears to suppress subclinical enthesopathy, and the suppression is maintained through week 52. Further longitudinal studies are needed to determine whether therapy initiated for skin disease may prevent the development of PsA.

Rheumatoid arthritis (RA) is the most common inflammatory joint disorder presenting also with extra-articular manifestations. As many other autoimmune diseases, it has been suggested that infectious diseases might contribute to its emergence. Hepatitis viruses were suggested by several reports as a trigger of RA onset. We aimed to assess the association between RA and chronic hepatitis B viral infection (HBV). Patients with RA were compared with age- and sex-matched controls regarding the proportion of chronic HBV infection in a case-control study. The chi-square and t tests were used for univariate analysis, whereas a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. There was a significantly higher proportion of chronic HBV infection in RA patients compared with controls (1.19% vs 0.63%, respectively; p

Background and Aims. We aimed to assess whether chronic statins used (> 6 months) were protective of the development of esophagitis in patients with gastroesophageal reflux disease. In the presence of esophagitis, complications such as strictures, Barrett's esophagus, and adenocarcinoma were the most common. Statins, lipid lowering drugs with a pleiotropic effect, are recently implicated in various pathologies. Nevertheless, the possible impact of statins in esophagitis development has never been assessed. Methods. We performed a retrospective, cross-sectional, single center study that included 4148 gastroesophageal reflux disease patients from 2014 and 2018 at EMMS Nazareth Hospital. We divided the patients into 5 groups. The groups were split into positive control group, which was the nonesophagitis group, and the other 4 groups were A-D (as per Los Angeles classification). Results. Overall, out of the 4148 patients included, 48% were males and 2840 patients were in the control group. In groups A, B, C, and D there were 818, 402, 72, and 16 patients, respectively. Logistic regression analysis revealed that chronic statins usage is protective by preventing development esophagitis (OR 0.463 [95%CI 0.370–0.579], p < 0.0001). NSAIDS use, Hiatus hernia, and H. pylori were promoting factors (OR, 1.362, 1.779, and 1.811; 95% CI, 1.183-1.569, 1.551-2.040, and 1.428-2.298; P Conclusion. Using chronic statins was protective to the development of esophagitis among GERD patients. Our findings of potential clinical application mandate further randomized controlled trials to better assess the impact of statins on esophagitis.

Dactylitis is diffuse swelling of the digits that is usually related to an underlying inflammatory or infiltrative disorder. Psoriatic arthritis (PsA) is the most common severe disease thought to cause dactylitis. Our understanding of the pathogenesis of PsA-related dactylitis comes from experimental animal models of PsA-like disease, as well as advances in imaging and other clinical studies. Clinical trials in PsA have increasingly included dactylitis as an important secondary outcome measure. These studies indicate that cytokines drive multi-locus microanatomical pan-digital pathology. Given the importance of pro-inflammatory cytokines, the pathogenesis of dactylitis is best understood as an initial aberrant innate immune response to biomechanical stress or injury, with subsequent adaptive immune mechanisms amplifying the dactylitis inflammatory response. Regarding the treatment of dactylitis, no studies have been conducted using dactylitis as the primary outcome measure, and the current knowledge comes from analysis of dactylitis as a secondary outcome measure.

Background Diabetes mellitus (DM) is a prevalent metabolic disease characterized by chronic hyperglycemia. A primary burden of DM is related to its long-term complications, which have been shown to impact the course of hospitalization and to influence patients’ outcome. Aim To assess the role of in-hospital glucose control on length of stay, 30-days and 1-year mortality. Methods This is a retrospective study that included patients admitted to the cardiac intensive care unit (CICU) of the Edith Wolfson Medical Centre between 01 January, 2010 and 31 December 2013. Blood glucose was measured by glucometer and fed into an interactive database. Glucose status was referred to as controlled when more than 50% of a given patients glucose values were between 71 and 200 mg/dL. Chisquared tests were used to assess the distribution of categorical variables, while the ttest was applied for continuous variables. A multivariate logistic regression model was used to analyze the association between glucose control and mortality. Cox regression was conducted to assess survival and 1-year mortality. Results 2466 patients were admitted to the CICU over the study period, of which 370 had concomitant diabetes mellitus. Controlled glucose status was associated with shorter length of hospital stay (1.6 ± 1.7 versus 2.6 ± 3.0, p

Background: Rheumatoid arthritis (RA) is associated with an increased risk for venous thromboembolism. However, so far, relatively few and small size-based studies have been conducted. We aimed to investigate the link between RA and venous thromboembolism utilizing a large sample of subjects originating from a large data base. Materials and methods: The study was performed utilizing the medical database of Clalit Health Services, the largest healthcare provider in Israel. We enrolled all patients with RA and age- and gender-matched controls. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for a multivariate analysis. RA patients were compared to controls regarding the proportion of venous thromboembolic events (defined as deep vein thrombosis, pulmonary embolism or both). Multivariate logistic regression was employed to assess factors associated with thromboembolic events. Results: The study included 11,782 patients with RA and 57,973 age- and gender-matched controls. RA patients had a higher rate of venous thromboembolism events compared with controls (6.92% vs. 3.18%, respectively, p

If not properly treated, human papillomavirus (HPV) infection may evolve from a common sexually transmitted disease to genital warts and cervical cancer. Various prophylactic HPV vaccines (HPVv), approved to reduce the incidence of the infection, have been found to be effective and safe; however, accounts of post-vaccination autoimmune phenomena, including systemic lupus erythematosus (SLE), have been reported in genetically susceptible individuals.Infectious agents play a role in breaking the immunologic tolerance to self-antigens, resulting in autoimmune events. There is molecular evidence supporting the involvement of HPV in SLE, with a high prevalence of L1 HPV peptide homology to proteins being associated with SLE. Therefore, approaches in vaccine preparations aiming to prevent adverse immune cross-reactivity are sought. Performing a broad search of the literature, we review the association between SLE, HPV, and HPVv, with a focus on the mechanisms of molecular mimicry and cross-reactivity, and the approaches currently being elaborated towards preventing such phenomena.The advantages of using low-similarity peptide antigens may be two-fold, abolishing the risk of cross-reactivity and eliminating the vaccine adjuvantation procedure. Vaccines based on pathogen unique sequences would provide effective vaccine preparation while curbing the risk for the human host.

Background: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. Methods: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. Findings: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the MRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Atypical rheumatic manifestations included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. Interpretation: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. Funding: none.

Polymyositis (PM) and dermatomyositis (DM) are autoimmune-mediated multisystemic myopathies, characterized mainly by proximal muscle weakness. A connection between epilepsy and PM/DM has not been reported previously. Our study aim is to evaluate this association. A case–control study was conducted, enrolling a total of 12,278 patients with 2085 cases (17.0%) and 10,193 subjects in the control group (83.0%). Student’s t-test was used to evaluate continuous variables, while the chi-square test was applied for the distribution of categorical variables. Log-rank test, Kaplan–Meier curves and multivariate Cox proportional hazards method were performed for the analysis regarding survival. Of the studied 2085 cases, 1475 subjects (70.7%) were diagnosed with DM, and 610 patients (29.3%) with PM. Participants enrolled as cases had a significantly higher rate of epilepsy (n = 48 [2.3%]) as compared to controls (n = 141 [1.4%], p &lt, 0.0005). Using multivariable logistic regression analysis, PM was found only to be significantly associated with epilepsy (OR 2.2 [95%CI 1.36 to 3.55], p = 0.0014), whereas a non-significant positive trend was noted in DM (OR 1.51 [95%CI 0.99 to 2.30], p = 0.0547). Our data suggest that PM is associated with a higher rate of epilepsy compared to controls. Physicians should be aware of this comorbidity in patients with immune-mediated myopathies.

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS.Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somatic mutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated “autoinflammatory disease” (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups.Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p < 0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02–4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22–6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080).Conclusions: Autoinflammatory complications are common in MDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis.

The term spondyloarthritis pertains to both axial and peripheral arthritis including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which is strongly linked to psoriasis and also the arthritis associated with inflammatory bowel disease. The argument supporting the role for IL-23 across the spectrum of SpA comes from 4 sources. First, genome wide associated studies (GWAS) have shown that all the aforementioned disorders exhibit IL-23R pathway SNPs, whereas HLA-B27 is not linked to all of these diseases-hence the IL-23 pathway represents the common genetic denominator. Secondly, experimental animal models have demonstrated a pivotal role for the IL-23/IL-17 axis in SpA related arthropathy that initially manifests as enthesitis, but also synovitis and axial inflammation and also associated aortic root and cutaneous inflammation. Thirdly, the emergent immunology of the human enthesis also supports the presence of IL-23 producing myeloid cells, not just at the enthesis but in other SpA associated sites including skin and gut. Finally, drugs that target the IL-23 pathway show excellent efficacy for skin disease, efficacy for IBD and also in peripheral arthropathy associated with SpA. The apparent failure of IL-23 blockade in the AS which is effectively a spinal polyenthesitis but evidence for efficacy of IL-23 inhibition for peripheral enthesitis in PsA and preliminary suggestions for benefit in axial PsA, raises many questions. Key amongst these is whether spinal inflammation may exhibit entheseal IL-17A production independent of IL-23 but peripheral enthesitis is largely dependent on IL-23 driven IL-17 production. Furthermore, IL-23 blocking strategies in animal models may prevent experimental SpA evolution but not prevent established disease, perhaps pointing towards a role for IL-23 in innate immune disease initiation whereas persistent disease is dependent on memory T-cell responses that drive IL-17A production independently of IL-23, but this needs further study. Furthermore, IL-12/23 posology in inflammatory bowel disease is substantially higher than that used in AS trials which merits consideration. Therefore, the IL-23 pathway is centrally involved in the SpA concept but the nuances and intricacies in axial inflammation that suggest non-response to IL-23 antagonism await formal definition. The absence of comparative immunology between the different skeletal sites renders explanations purely hypothetical at this juncture.

In this large population-based study we aimed: 1) to assess mortality in patients with ankylosing spondylitis (AS) compared to the general population, considering demographics, comorbidities, and treatment, and 2) to assess factors associated with mortality within patients with AS.This study was designed as a retrospective cohort study using the electronic database of the largest health maintenance organization in Israel. All patients with AS diagnosed between 2002 and 2018 were included. Controls were matched by age, sex, clinic, and enrollment time. Follow-up continued until death or the end of the study.The study comprised 5,930 AS patients and 29,018 matched controls who were followed up for a median period of 7.5 years. There were 667 deaths within the AS cohort and 2,919 deaths within controls; the mean age at death was 76.9 years and 77.1 years, respectively (P = 0.74). A total of 3,249 AS patients (54.8%) were treated only with nonsteroidal antiinflammatory drugs, 1,760 (29.7%) were treated with tumor necrosis factor inhibitors (TNFi), and 1,687 (28.4%) with disease-modifying antirheumatic drugs (DMARDs). Mortality rates were increased among AS patients compared to controls, with an age- and sex-adjusted hazard ratio (HR) of 1.19 (95% confidence interval [95% CI] 1.10-1.30). The association was significant for men (HR 1.15 [95% CI 1.04-1.27]) and women (HR 1.32 [95% CI 1.13-1.54]), and after adjusting for background comorbidities (HR 1.14 [95% CI 1.05-1.24]). AS patients treated with TNFi or with a combination of TNFi and DMARDs did not have significant difference in mortality rates compared to controls (HR 0.67 [95% CI 0.38-1.18] and HR 0.93 [95% CI 0.69-1.25], respectively). Age, male sex, mean C-reactive protein (CRP) levels and general comorbidities were predictors of mortality within the AS cohort.AS patients had an increased mortality risk compared to the general population after adjusting for age, sex, and baseline comorbidities. AS patients treated with TNFi did not demonstrate excess mortality compared to matched controls. Within the AS cohort, age, male sex, background comorbidities, and higher CRP levels were identified as risk factors for mortality.

COVID-19 has been occasionally linked to histologically confirmed cutaneous vasculitis and a Kawasaki-like vasculitis, with these entities generally having minimal or no lung involvement and a good prognosis. Unlike these vasculitis types, patients with severe COVID-19 pneumonia can develop cutaneous vasculitis-like lesions and systemic arterial and venous thromboemboli, including cryptogenic strokes and other vasculopathy features. Proposed underlying mechanisms for these severe manifestations have encompassed immune dysregulation, including an anti-phospholipid syndrome-like state, complement activation, viral dissemination with direct systemic endothelial infection, viral RNAaemia with immunothrombosis, clotting pathway activation mediated by hypoxaemia, and immobility. In this Viewpoint, we highlight how imaging and post-mortem findings from patients with COVID-19 indicate a novel thrombosis in the pulmonary venous territory distal to the alveolar capillary bed, a territory that normally acts as a clot filtration system, which might represent an unappreciated nidus for systemic microembolism. Additionally, we suggest that this mechanism represents a novel vasculitis mimic related to COVID-19 that might lead to cryptogenic strokes across multivessel territories, acute kidney injury with haematuria, a skin vasculitis mimic, intestinal ischaemia, and other organ ischaemic manifestations. This finding is supported by pathological reports of extensive pulmonary venular thrombosis and peripheral organ thrombosis with pauci-immune cellular infiltrates. Therefore, severe COVID-19 pneumonia with extensive pulmonary intravascular coagulopathy might help to explain the numerous systemic complications of COVID-19, in which the demonstration of direct organ infection has not adequately explained the pathology.

Editorial on the Research Topic Early Origins of Psoriatic Arthritis

Background: Dupilumab (Dupixent®) is a monoclonal antibody that inhibits IL-4 and IL-13 signaling used for the treatment of allergic diseases. Whilst biological therapy is generally associated with an increased risk of infectious disease, prior studies have suggested Dupilumab may be protective. Objective: We investigated the link between Dupilumab therapy and SARS-CoV-2 infection. Methods: We carryied out a comprehensive data-mining and disproportionality analysis of the WHO global pharmacovigilance database. One asymptomatic COVID-19 case, 106 cases of symptomatic COVID-19, and 2 cases of severe COVID-19 pneumonia were found. Results: Dupilumab treated patients were at higher risk of COVID-19 (with an IC0.25 of 3.05), even though infections were less severe (IC0.25 of -1.71). The risk of developing COVID-19 was significant both among males and females (with an IC0.25 of 0.24 and 0.58, respectively). The risk of developing COVID-19 was significant in the age-group of 45-64 years (with an IC0.25 of 0.17). Limitations: Limitations include: the heterogeneous nature of the database sources. Furthermore, a direct causal relationship cannot be inferred from the current investigation. Conclusion: Dupilumab use was found to reduce COVID-19 related severity. Further studies are needed to better understand the immunological mechanisms and clinical implications of these findings.

Fibromyalgia (FM) is presented in approximately 2–8% of the population [1]. It is characterized by a chronic widespread musculoskeletal pain associated with tenderness of at least 11 of 18 defined points of palpitation [1]. Besides pain, fatigue, sleep disturbances, depression, concentration, and memory problems can also be noted in FM patients [1, 2].

Status epilepticus (SE) can be defined as abnormally prolonged, persistent, or recurrent clinical and/or electrographic epileptic activity and, as such, is a challenging medical emergency requiring an aggressive treatment aimed at promptly terminating the seizures. It imposes a relevant clinical burden, both in terms of comorbidity and mortality. In the era of the Web 2.0, most people search the Web to obtain SE-related information. The current investigation aimed at qualitatively characterizing the pins related to SE: Pinterest, "the world's catalog of ideas", is a visual social networking site that enables users to freely upload visual material, to bookmark, and to share it (repin). Using SE as a keyword, 192 pins were extracted and analyzed on the basis of their content. Fifty-five were found to meet the inclusion criteria. Fifty-six point four percent of the pins reported at least one cause of SE, the most quoted of which being remote brain injuries (47.3% of the pins); 54.5% and 45.5% of the included pins reported SE symptoms and diagnosis, respectively; 72.7% and 40.0% of pins focused on SE treatment and on prognosis, respectively; and 50.9%, 30.9%, and 40.0% of the pins were intended for physicians, medical/nursing students, and lay people, respectively. Only 12.7% of pins were patient-centered and devoted to fund-raising and advocacy. In the field of neurological diseases, Pinterest, despite being a "pinstructive" tool, is too much overlooked and underused for advocacy purposes. Healthcare workers and stakeholders should be aware of the opportunities offered by Pinterest and exploit this visual social networking site for raising awareness of the life-threatening condition of SE, promoting fund-raising campaigns.

Background: Systemic lupus erythematosus (SLE) is a chronic, auto-immune, multi-organ disease that can affect both the skin and the lungs. Malar rash is a common skin manifestation of SLE and is linked to SLE disease activity, whereas lung involvement is a generally negative prognostic factor for these patients. However, a sensitive and non-invasive screening tool for potential lung involvement in SLE patients is still not available. Methods: This study aimed to investigate the relationship between malar rash and airway inflammation in adult SLE patients who were not known to have any lung involvement (clinical or radiologic). The study comprised of the measurement of the concentration of NO in exhaled breath or fraction of exhaled nitric oxide (FeNO) and levels were compared between those with and without malar rash. This tool is considered as a sensitive and non-invasive method that is routinely used in patients with asthma or other respiratory diseases to identify airway inflammation. Results: A total of 125 patients (100 females, 25 males) were enrolled during the study period from January 2011 to December 2014. Patients with malar rash (N = 35) had a significant decrease in serum levels of C4 (p < 0.05) compared to patients without malar rash (N = 90). The mean levels of FeNO in overall patients were 36.44 ± 8.87 ppb. A statistically significant difference in FeNO50 values between patients with malar rash (43.46 ± 6.72 ppb) and without (29.43 ± 3.64 ppb) was found (p < 0.001). FeNO50 values were inversely correlated only with serum C4 (p < 0.01). However, no correlation between FeNO50 values and SLE clinical disease activity scores was found. Conclusions: The presence of a malar rash may predict sub-clinical airway inflammation in SLE patients. Further prospective studies are needed to confirm the usefulness of FeNO measurements in monitoring SLE-associated airway inflammation.

Is physical activity after embryo transfer, as assessed by a smart band activity tracker, associated with decreased pregnancy rates?Prospective observational cohort study comprising infertile women aged38 years, who had undergone fewer than three previous embryo transfers, achieved a good ovarian response and were undergoing frozen-thawed embryo transfer in a tertiary-referral centre. A validated smart band activity tracker was used to assess physical activity level immediately after the embryo transfer and until the pregnancy test. No specific recommendations were given to participants on level or intensity of physical activity. Physicians and patients were blinded to the data stored in the pedometer. Primary outcome was ongoing pregnancy rate.Fifty women met the inclusion criteria. Ongoing pregnancy rate was 30%. In a pooled analysis, participants walked significantly fewer steps per day on the day of embryo transfer compared with the first 2 days after embryo transfer (4075, interquatile range [IQR] 2932-5592 versus 5204, IQR4203-8584, P = 0.01). No significant difference was observed between pregnant women and non-pregnant women in the median steps per day after embryo transfer until serum beta-HCG was measured (7569, IQR 6008-10884 versus 6572.5, IQR 5299-8786, P = 0.43). No significant difference was observed in the median number of steps on the day of embryo transfer or the first 2 days after embryo transfer between pregnant and non-pregnant women.A quantitative objective assessment of the association between physical activity and pregnancy rates after frozen-thawed embryo transfer was conducted. Ambulation after embryo transfer has no adverse effect on pregnancy rates and, therefore, women should resume regular activity immediately after embryo transfer.