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Systemic lupus erythematosus (SLE) is characterized by endothelial dysfunction, arterial stiffness, and myocardial impairment. We aimed at analyzing the ratio between carotid-femoral pulse wave velocity (cfPWV) and left ventricular global longitudinal strain (GLS) as a new index to approximate ventricular-arterial coupling (VAC) in women with SLE and without cardiovascular risk factors. Half cases had impaired GLS and consequently a hampered ratio. We thus suggest referring SLE patients early to a CV prevention program. [ABSTRACT FROM AUTHOR]

Objective To analyze the performance of a line blot assay for the identification of autoantibodies in sera of patients affected by myositis, compared with immunoprecipitation (IP) as gold standard. Methods 66 sera of patients with myositis (23 polymyositis, 8 anti-synthetase syndromes, 29 dermatomyositis and 6 overlap syndromes) were tested by commercial LB (Euroimmun, Lubeck, Germany); 57 sera were analyzed also by IP of K562 cell extract radiolabeled with 35 S-methionine. Inter-rater agreement was calculated with Cohen's k coefficient. Results Myositis-specific antibodies (MSA) were detected in 36/57 sera (63%) by IP and in 39/66 sera (59%) by LB. The most frequent MSA found by LB were anti-Jo1 and anti-Mi2 found in 15% (10/66) of sera, followed by anti-NXP2 and anti-SRP detected in 106% (7/66) of sera. Anti-TIF1gamma and anti-MDA5 were found in 6 (9%) and 5 sera (7.6%), respectively. A good agreement between methods was found only for anti-TIF1γ, anti-MDA5 and anti-NXP-2 antibodies, while a moderate agreement was estimated for anti-Mi2 and anti-EJ. By contrast, a high discordance rate for the detection of anti-Jo1 antibodies was evident (k: 0.3). Multiple positivity for MSA were found in 11/66 (17%) by LB and 0/57 by IP (p: 0001). Comparing the clinical features of these 11 sera, we found total discrepancies between assays in 3 sera (27.3%), a relative discrepancy due to the occurrence of one discordant autoantibody (not confirmed by IP) in 5 cases (45.5%) and a total discrepancy between LB and IP results, but with a relative concordance with clinical features were found in other 3 sera (27.3%). The semiquantitative results do not support the interpretation of the data. Conclusions The use of LB assay allowed the detection of new MSA, such as anti-MDA5, anti-MJ and anti-TIF1gamma antibodies, previously not found with routine methods. However, the high prevalence of multiple positivities and the high discondant rate of anti-Jo1 antibodies could create some misinterpretation of the results from the clinical point of view. These data should be confirmed by enlarging the number of myositis cases. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism −174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism −174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the −174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe a single-center experience in the treatment and follow-up of cystoid macular edema patients. Clinical records of all patients with cystoid macular edema followed up in the Rheumatologic and Ophthalmological Unit of our center between 1993 and 2013 were retrospectively evaluated. The outcome was assessed by visual acuity and optical coherence tomography status during follow-up. Comparisons were made by Fisher's exact test ( p < 0.05 significant). In this study 16 eyes in 9 patients were analyzed. Our study includes mainly post-uveitic (78 %) cases with a high prevalence of human leukocyte antigen B51 (67 %). Systemic immunosuppressive therapy was prescribed in 87 % of cases. The most frequently used drugs were cyclosporine, interferon-α, and infliximab. The first two molecules appeared respectively the most used as the first option and the one with the longest survival on treatment. Interferon-α was the most effective drug in contrasting visual acuity loss compared to the majority of drugs, but significantly more effective than mycophenolate ( p = 0.01) in reducing macular edema. At the end of follow-up, 50 % of patients showed a significant visual loss, while 88 % did not present macular edema. In our small cohort, interferon-α is the most promising drug in contrasting visual acuity loss in cystoid macular edema. Visual prognosis remains severe in these patients. [ABSTRACT FROM AUTHOR]

New 2016 ACR/EULAR classification criteria for primary Sjogren's syndrome (SS) have been developed and endorsed by the ACR. The newly proposed criteria include simple-to-perform items.Two important points of the new criteria should be considered. Firstly, they indicate that either salivary gland biopsy or anti-Ro must be positive in order to corroborate the inflammatory and autoimmune nature of the disease. Secondly, the criteria recognize the systemic nature of SS, namely that patients without salivary or ocular glandular symptoms, but with extraglandular manifestations and B cell activation markers were also included in the SS classification. Additionally, the new criteria modified some technical points. The ocular staining score threshold was increased to 5 due to the higher specificity. The immunological profile includes only anti-Ro antibodies, while positivity for antinuclear antibodies and rheumatoid factor or isolated anti-La was excluded due to a lack of specificity.The 2016 ACR/EULAR criteria are suitable for early identification of SS, providing patients with the opportunity of enrollment in clinical trials for new specific treatment. Although validation has been successful, the real life application of these criteria will test their performance. [ABSTRACT FROM AUTHOR]

Objectives: We retrospectively compared disease activity, treatment, clinical and laboratory features, and rate of mortality of 535 SLE patients with adult and late disease onset. Methods: patients were divided into two groups based on the onset of the disease before or after 50 years of age. Clinical data were collected from medical reports. Disease activity was measured by ECLAM score. Parameters were compared by χ2-test, Fisher's test, Student's t or the Mann-Whitney test. Results: Forty patients (7.5%) were included in the late SLE onset group (group A), while 495 (92.5%) in the adult SLE onset group (group B). Sicca symptoms were more frequent in group A ( p < 0.0008), while glomerulonephritis ( p < 0.0069), reduced C3 ( p < 0.0006) and low C3 ( p < 0.00002) and C4 levels ( p < 0.0006) were more prevalent in group B. Twenty-two deaths (4.3%) were recorded: 14 (2.8%) in group B and 8 (20%) in group A. Deaths were mainly due to infections in group B (28.5%) and cardiovascular events in group A (50%). A lower use of HCQ and LDA were recorded in deceased versus living patients ( p < 0.0001 and 0.0166, respectively), while a higher ECLAM score was measured at onset in dead versus living patients ( p < 0.048). Conclusions: Late onset SLE occurred in 7.5% of patients and it was associated with sicca symptoms. The use of HCQ and LDA is positively correlated with survival. Death in late onset SLE occurred more frequently for cardiovascular involvement. Higher disease activity at onset of the disease might represent a poor prognostic factor for death in adult onset. [ABSTRACT FROM AUTHOR]

Abstract: Anti-RNA polymerase III antibodies (ARA) are a specific marker for Systemic Sclerosis (SSc), associated to severe disease with major organ and diffuse cutaneous involvement. In our series, ARA were found in 19 of 216 sera, in 15 cases as isolated antibodies'' specificity, with a statistically negative association with other SSc-specific autoantibodies (p: 0.00003). The prevalence of ARA among 73 anticentromere and anti-topoisomerase I (topo I) negative sera, was 20.5%. Patients with isolated ARA had more rapid disease onset, defined as the interval from the appearance of Raynaud''s phenomenon to the first symptom other than Raynaud''s, than patients with isolated anti-topo I antibodies (median: 2 months vs 13 months; p: 0.0013). A rapid onset of SSc (within 6 months from Raynaud''s phenomenon onset) was found in all patients with isolated ARA and only in 34% of those with anti-topo I (p <0.00001). Moreover, the skin thickening in the first months after SSc onset was faster in the ARA group (p <0.0001). Nevertheless, the rates of internal organ involvement and of survival rates were similar between the two groups. Our experience therefore suggests that ARA are a marker of very rapid onset of disease and skin thickening progression in SSc. [Copyright &y& Elsevier]

Abstract: Anti-phospholipid syndrome (APS) is defined by recurrent arterial/venous thrombosis and/or fetal losses in the persistent presence of anti-phospholipid antibodies (aPL). In in vivo experimental models aPL thrombogenic activity is associated with a pro-inflammatory endothelial phenotype (increased adhesion molecule [ADM] expression and leukocyte adhesion) in addition to a pro-coagulant one (tissue factor [TF] expression). This is in line with the in vitro aPL ability to trigger intracellular signalling and to up-regulate ADM, TF and pro-inflammatory cytokine/chemokine expression at the mRNA and protein level in endothelial cells. Comparable effects were also reported in monocytes in vitro. In addition, complement activation is required by aPL to display their thrombogenic activity in in vivo models. Interestingly, complement activation blocking as well as Tumor Necrosis Factor alpha neutralization protect animals from aPL-induced fetal losses. Altogether these findings speak in favour for a role of inflammation in APS in spite of the absence of a clear inflammatory signature in the patients. We could not find any complement (C3c and C4d) deposition in the placentas from 2 late abortions (20weeks of gestation) in APS women. Further studies are necessary to investigate whether complement activation and inflammatory processes found in animal models are taking place in APS patients. [Copyright &y& Elsevier]

Background: the reference method for detection of myositis-specific and myositis-associated antibodies (MSAs and MAAs) is considered immunoprecipitation (IP), but it is routinely replaced by semi-automated methods, like lineblot (LB). Few data are available on the consistency with clinical diagnoses; thus, we aim at analysing these aspects. Methods: sixty-nine patients with idiopathic inflammatory myopathies (IIM) were studied via LB (Myositis Antigens Profile 3 EUROLINE, Euroimmun) and IP (RNA and protein antigens). The degree of concordance between methods was calculated using Cohen's coefficient. Results: a substantial concordance was found for anti-Ku and anti-PM/Scl and a moderate concordance was found for anti-Jo1 and anti–Mi-2, while a fair concordance was found for anti-EJ, anti-SRP, and anti-Ro52 antibodies. The concordance could not be calculated for anti-OJ, anti-PL-7, anti-PL-12, anti-NXP2, anti-TIF1ɣ, and anti-MDA5, because they were only detected with one method. Multiple MSAs were found only with LB in 2/69 sera. Anti-MDA5, TIF1ɣ, NXP2 (detected via IP), and anti-Jo1 in anti-synthetase syndrome (both LB and IP) had the best concordance with clinical diagnosis. Conclusions: LB and IP show substantial concordance for PM/Scl and Ku, and moderate concordance for Jo1 and Mi-2, with a good concordance with clinical diagnoses. IP shows a high performance for DM-associated MSAs. LB seems to be more sensitive in detecting anti-Ro52 antibodies, but it identified multiple MSAs, unlike IP. [ABSTRACT FROM AUTHOR]

despite the absence of specific guidelines, the treatment with intravenous immunoglobulins (IvIg) is considered effective in patients with refractory idiopathic inflammatory myopathies (IIM). The aim of our study is to evaluate the effectiveness and the safety of IvIg and define the possible profile of IIM patients candidate to IvIg treatment. we performed a retrospective study of IIM pts. treated with IvIg (2 g/kg/month). We collected demographic, epidemiological, laboratory and clinical data. Additionally, to evaluate the toxicity, the adverse events occurred during the treatment were collected. 123 patients with IIM were included in the study. The main indications for the prescription of IvIg were muscle (83.7% of patients) and esophageal involvement (45.5% of patients). IvIg were started mainly for refractory disease. At the end of treatment (mean duration 14 months), muscular necrosis enzymes decreased significantly and dysphagia VAS decreased significantly (p < 0.001), while MMT value increased (104.6 ± 24.2 vs. 127.0 ± 22.2 p < 0.001). Ninety-six pts. (78%) responded to IvIg. They had a shorter disease duration (p < 0.001), higher creatine kinase levels (p < 0.001), and higher prevalence of myalgias at the baseline (p = 0.023) compared to non-responders. The presence of Raynaud's phenomenon (p = 0.023–odds ratio 0.28 [0.11–0.72]) and skin involvement (p = 0.004, odds ratio 0.18 [0.06–0.55]), were associated to a worse response. Adverse events were mostly mild and transitory. Despite their high cost, IvIg confirmed their effectiveness in refractory IIM pts., particularly in muscular and esophageal manifestations. Specific clinical characteristics at the baseline may identify the patients with higher probability of response to the treatment. • Intravenous immunoglobulins may represent a valid therapeutic approach for IIM patients • The right selection of the patient candidate to the treatment may increase the probability of clinical response • IvIgs are effective and relatively safe in the majority of the patients but the relapse at the suspension is possible [ABSTRACT FROM AUTHOR]

Background: The impact of immunosuppressive therapies on the efficacy of vaccines to SARS-CoV-2 is not completely clarified. We analyzed humoral and T cell-mediated response after COVID-19 mRNA vaccine in immunosuppressed patients and patients with common variable immunodeficiency disease (CVID). Patients: We enrolled 38 patients and 11 healthy sex- and age-matched controls (HC). Four patients were affected by CVID and 34 by chronic rheumatic diseases (RDs). All patients with RDs were treated by corticosteroid therapy and/or immunosuppressive treatment and/or biological drugs: 14 patients were treated with abatacept, 10 with rituximab, and 10 with tocilizumab. Methods: Total antibody titer to SARS-CoV-2 spike protein was assessed by electrochemiluminescence immunoassay, CD4 and CD4-CD8 T cell-mediated immune response was analyzed by interferon-γ (IFN-γ) release assay, the production of IFN-γ-inducible (CXCL9 and CXCL10) and innate-immunity chemokines (MCP-1, CXCL8, and CCL5) by cytometric bead array after stimulation with different spike peptides. The expression of CD40L, CD137, IL-2, IFN-γ, and IL-17 on CD4 and CD8 T cells, evaluating their activation status, after SARS-CoV-2 spike peptides stimulation, was analyzed by intracellular flow cytometry staining. Cluster analysis identified cluster 1, namely the "high immunosuppression" cluster, and cluster 2, namely the "low immunosuppression" cluster. Results: After the second dose of vaccine, only abatacept-treated patients, compared to HC, showed a reduced anti-spike antibody response (mean: 432 IU/ml ± 562 vs mean: 1479 IU/ml ± 1051: p = 0.0034), and an impaired T cell response, compared with HC. In particular, we found a significantly reduced release of IFN-γ from CD4 and CD4-CD8 stimulated T cells, compared with HC (p = 0.0016 and p = 0.0078, respectively), reduced production of CXCL10 and CXCL9 from stimulated CD4 (p = 0.0048 and p = 0.001) and CD4-CD8 T cells (p = 0.0079 and p = 0.0006). Multivariable General Linear Model analysis confirmed a relationship between abatacept exposure and impaired production of CXCL9, CXCL10, and IFN-γ from stimulated T cells. Cluster analysis confirms that cluster 1 (including abatacept and half of rituximab treated cases) showed a reduced IFN-γ response, as well as reduced monocyte-derived chemokines All groups of patients demonstrated the ability to generate specific CD4 T activated cells after spike proteins stimulation. After the third dose of vaccine, abatacept-treated patients acquired the ability to produce a strong antibody response, showing an anti-S titer significantly higher compared to that obtained after the second dose (p = 0.0047), and comparable with the anti-S titer of the other groups. Conclusions: Patients treated with abatacept showed an impaired humoral immune response to two doses of COVID-19 vaccine. The third vaccine dose has been demonstrated to be useful to induce a more robust antibody response to balance an impaired T cell-mediated one. All patients, exposed to different immunosuppressive drugs, were able to produce specific CD4-activated T cells, after spike proteins stimulation. Trial registration: Local Ethical Committee NP4187. [ABSTRACT FROM AUTHOR]

We have identified 12 patients, mainly females ( I n i = 9, 75%), with a median age of 51 years (interquartile range - IQR 48-63.5) and a median ASSD disease duration of 60.5 months (IQR 21-77) at COVID-19 onset. Dear Editor Although the effect of COVID-19 on patients with rheumatic disorders has been extensively assessed [[1]-[3]], the influence of SARS-CoV2 infection on the clinical course of these diseases is not fully elucidated. A strict clinical-instrumental follow-up is necessary for ASSD patients after healing from COVID-19 because of the risk of possible worsening of the disease. [Extracted from the article]

Anti-nuclear antibody (ANA) assay is a screening test used for almost all autoimmune rheumatic diseases, and in a number of these cases, it is a diagnostic/classification parameter. In addition, ANA is also a useful test for additional autoimmune disorders. The indirect immunofluorescence technique on monolayers of cultured epithelial cells is the current recommended method because it has higher sensitivity than solid phase assays. However, the technique is time-consuming and requires skilled operators. Automated ANA reading systems have recently been developed, which offer the advantage of faster and much easier performance as well as better harmonization in the interpretation of the results. Preliminary validation studies of these systems have given promising results in terms of analytical specificity and reproducibility. However, these techniques require further validation in clinical studies and need improvement in their recognition of mixed or less common staining patterns. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical 'sicca syndrome', but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment. [ABSTRACT FROM AUTHOR]

Objectives. Primary anti-phospholipid syndrome (PAPS) is an autoimmune condition defined by anti-phospholipid antibodies (aPL) and thrombotic or obstetric events. Some PAPS can evolve into systemic lupus erythematosus (SLE) during follow-up. Few studies systematically examined lupus autoantibodies and their clinical significance in PAPS. The aim of our study is to analyze the clinical and laboratory correlations with lupus-related autoantibodies, detected by immunoprecipitation (IP), a technique not yet systematically applied to investigate autoantibodies in this condition. Methods. Sera from 52 PAPS patients were screened by indirect immunofluorescence (IIF) antinuclear antibodies (ANA), IP of 35S-labeled K562 cell extract, and ELISA [anti-Argonaute2 (Ago2, Su), 60kRo, 52kRo, La, dsDNA)]. Anti-Ago2/Su positive sera were also tested for anti-GW bodies (GWBs) by IIF double staining, using rabbit anti-Rck/p54 serum. Results. First, 56% of PAPS patients (29/52) were ANA positive, mainly with speckled pattern. Anti-Ago2/Su antibodies were found in 13% (7/52), anti-Ro/SSA in 10% (5/52), anti-La in one case. The clinical profile of patients did not seem to be related to the presence of these antibody specificities. However, levels of IgG anti-ββ2 glycoprotein I antibodies were lower in anti-Ago2/Su positive patients ( p  ==  0.02). None of anti-Ago2/Su or --Ro patients developed SLE during a 2-year follow-up. Ago2 is a key component of GWBs, however, only 1/7 anti-Ago2/Su serum showed a typical cytoplasmic GWBs staining. Conclusions. Anti-Ago2/Su and -Ro antibodies are the two autoantibodies detected by IP in our PAPS cohort. Clarifying why Ago2/Su and Ro are specific targets of autoimmunity may help to understand the mechanisms of autoantibody production. [ABSTRACT FROM AUTHOR]

The complement (C') cascade is an important part of the innate immunity. It acts through three major pathways: classical (CP), alternative (AP) and mannose-binding-lectin (MP). C' reduction is a key feature in systemic lupus erythematosus (SLE), for its pathogenesis and for disease relapse. The aims of our study are to correlate C' variations with disease activity and verify the presence of C' deficiencies. We tested for three C' pathways 52 sera from 20 patients affected by SLE. A significant correlation between the ECLAM score and the degree of activation of the CP (Mann-Whitney; P= 0.001) was recorded, while the correlation with anti-dsDNA antibodies did not reach statistical significance (Mann-Whitney; P > 0.05). In conclusion, the ELISA assay can be considered well suited for testing SLE samples. We detected a significant link between the phases of lupus activity and the reduction of the CP. [ABSTRACT FROM AUTHOR]

Objectives Some evidence suggests that exposure to free crystalline silica may contribute to the risk of developing SLE. A systematic search was carried out for all published epidemiological studies concerning this association. A meta-analysis was conducted on relevant studies. Methods We searched PubMed and EMBASE databases for original articles published from 1960 to November 2019 in any language. In addition, we also searched the reference lists of included studies manually for additional relevant articles. Finally, seven studies were included in the systematic review and six studies in the meta-analysis (four case–control and two cohort studies). The odds ratio and 95% CI were calculated using a random effect meta-analysis. Results The meta-analysis of the studies, applying a random effect model, yielded an overall odds ratio of 3.49 (95% CI, 1.24, 9.83), with I 2 = 92.36% (pronounced heterogeneity). We also stratified the meta-analysis by study design; case–control studies: odds ratio 1.85 (95% CI, 0.96, 3.59) with I 2 = 75.92%; and cohort studies (cases with silicosis): odds ratio 9.71 (95% CI, 1.13, 83.58) with I 2 = 72.65%. Conclusions The obtained results support the hypothesis of a possible association between occupational exposure to free crystalline silica and SLE, in particular at higher exposure levels, known to induce silicosis. The studies that have investigated this association are still scarce and the heterogeneity between the studies remains high. New studies are deemed necessary to confirm the association. [ABSTRACT FROM AUTHOR]

Background: Anti-mitochondrial antibodies (AMA) are found in >90% of primary biliary cholangitis patients. Anti-rods/rings antibodies (anti-RR) are most commonly associated with interferon-a and ribavirin treatment in hepatitis C patients. Clinical laboratories routinely screen for AMA and anti-RR using indirect immunofluorescence on HEp-2 cells (HEp-2-IFA). Therefore, we sought to establish reference materials for use in AMA and anti-RR testing. Methods: AMA-positive and anti-RR-positive human plasma samples (AMA-REF and RR-REF), identified as potential reference materials based on preliminary data, were further validated by multiple laboratories using HEp-2-IFA, immunoprecipitation (IP), western blotting, IP-western, line immunoassay (LIA), addressable laser bead immunoassay (ALBIA) and enzyme-linked immunosorbent assay (ELISA). Results: AMA-REF showed a strong positive cytoplasmic reticular/AMA staining pattern by HEp-2-IFA to =1:1280 dilution and positive signal on rodent kidney/stomach/liver tissue. AMA-REF reacted with E2/E3, E3BP, E1a and E1ß subunits of the pyruvate dehydrogenase complex by IP and western blotting and was positive for AMA antigens by LIA, ALBIA and ELISA. RR-REF showed a strong positive rods and rings staining pattern by HEp-2-IFA to =1:1280 dilution. RR-REF reacted with inosine monophosphate dehydrogenase by IP, IP-western and ALBIA. RR-REF also produced a nuclear homogenous staining pattern by HEp-2-IFA, immunoprecipitated proteins associated with anti-U1RNP antibody and reacted weakly with histones, nucleosomes, Sm and nRNP/Sm by LIA. Conclusions: AMA-REF and RR-REF are useful reference materials for academic or commercial clinical laboratories to calibrate and establish internal reference standards for immunodiagnostic assays. AMA-REF and RR-REF are now available for free distribution to qualified laboratories through Plasma Services Group. [ABSTRACT FROM AUTHOR]

This study aims to characterize myositis-specific antibodies in a well-defined cohort of patients with idiopathic inflammatory myopathy and to determine their association with cancer. Sera from 40 patients with polymyositis, dermatomyositis, and controls were tested by protein and RNA immunoprecipitation to detect autoantibodies, and immunoprecipitation-Western blot was used for anti-MJ/NXP-2, anti-MDA5, and anti-TIF1γ/α identification. Medical records were re-evaluated with specific focus on cancer. Anti-MJ/NXP-2 and anti-TIF1γ/α were the most common antibodies in dermatomyositis. In six dermatomyositis cases, we found five solid forms of cancer and one Hodgkin's lymphoma in long-term remission. Among patients with cancer-associated dermatomyositis, three were positive for anti-TIF1γ/α, two for anti-Mi-2, and one for anti-MJ/NXP-2. The strongest positivity of anti-TIF1γ was seen in two active forms of cancer, and this antibody was either negative or positive at low titers in the absence of cancer or in the 7-year remission Hodgkin's lymphoma. Four out of twenty (20 %) patients with polymyositis had solid cancer, but no specific association with autoantibodies was identified; further, none of the four cases of antisynthetase syndrome had a history of cancer. No serum myositis-associated autoantibody was observed in control sera, resulting in positive predictive value 75 %, negative predictive value 78.5 %, sensitivity 50 %, specificity 92 %, and area under the ROC curve 0.7083 for the risk of paraneoplastic DM in anti-TIF1γ/α (+) patients. Myositis-specific autoantibodies can be identified thanks to the use of immunoprecipitation, and their association with cancer is particularly clear for anti-TIF1γ/α in dermatomyositis. This association should be evaluated in a prospective study by immunoprecipitation in clinical practice. [ABSTRACT FROM AUTHOR]

Objective. Serum prealbumin is a recognized marker of malnutrition, but its role in the prognosis of patients with SSc has not yet been investigated. The aim of the present multicentre prospective study was to investigate the association between prealbumin and mortality, independent of clinical features, in a cohort of SSc outpatients. Methods. Patients were followed up according to standard clinical guidelines with visits at least every 6 months. Data collected included records of skin and internal organ involvement, survival and causes of death. Results. During a median follow-up of 48 months [interquartile range (IQR) 25-58], 34/299 patients (11%) died. In univariable survival analysis, age; male sex; lung, gastrointestinal or multiple visceral organ involvement (two or more); co-morbidities (two or more) and low serum prealbumin were significant predictors of mortality. In bivariable Cox models, alternatively adjusted for significant predictors, prealbumin was independently and significantly associated with the outcome. Mortality rates were particularly influenced by low prealbumin in patients without significant co-morbidities or multiple organ involvement. Conclusion. In SSc patients, low serum prealbumin is an independent predictor of mortality, particularly in those without significant internal organ involvement. Further research on this nutritional marker is warranted. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities. • Higher prevalence of severe clinical/serological SSc phenotypes in Southern, compared to other Italian macro-areas. • The updated review of the world literature supports the geographical heterogeneity of SSc phenotypes. • Possible role of genetic/environmental etiopathogenetic factors. • Possible role of not uniform network of specialized territorial referral centers. [ABSTRACT FROM AUTHOR]

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable. •Autoimmune systemic diseases (ASD) revealed impaired immunogenicity to COVID-19 vaccine. •Even booster COVID-19 vaccine elicided significant lower NAb titers in ASD than controls. •ASD patients showed high rate of absent/suboptimal response to booster COVID-19 vaccine. •A deficient response to booster vaccine correlated with ongoing immunomodifier treatments. •Long-term monitoring of serum NAb and treatment adjustments are highly advisable in ASD. [ABSTRACT FROM AUTHOR]

Anti-nuclear antibody (ANA) assay is a screening test used for almost all autoimmune rheumatic diseases, and in a number of these cases, it is a diagnostic/classification parameter. In addition, ANA is also a useful test for additional autoimmune disorders. The indirect immunofluorescence technique on monolayers of cultured epithelial cells is the current recommended method because it has higher sensitivity than solid phase assays. However, the technique is time-consuming and requires skilled operators. Automated ANA reading systems have recently been developed, which offer the advantage of faster and much easier performance as well as better harmonization in the interpretation of the results. Preliminary validation studies of these systems have given promising results in terms of analytical specificity and reproducibility. However, these techniques require further validation in clinical studies and need improvement in their recognition of mixed or less common staining patterns. [ABSTRACT FROM AUTHOR]

Sjögren's syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical 'sicca syndrome', but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment. [ABSTRACT FROM AUTHOR]

Objective Autoantibodies in the systemic rheumatic diseases are clinically useful biomarkers of the diagnosis or of certain clinical characteristics. An unusual pattern of immunoprecipitation, in which the D, E, F, and G proteins of small nuclear RNPs (snRNP) but without other components of the snRNP, was noticed at the autoantibody screening. The purpose of this study was to examine the target antigens and clinical manifestations associated with this specificity. Methods Autoantibodies in sera from 1,966 American patients (including 434 with systemic lupus erythematosus, 121 with scleroderma, 86 with polymyositis/dermatomyositis [PM/DM]) and 248 Italian patients with autoimmune diseases were screened by immunoprecipitation of [ABSTRACT FROM AUTHOR]

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53–1203) vs 825 (451–1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals. • Autoimmune systemic diseases (ASD) show impaired immunogenicity to Covid-19 vaccines. • ASD show significantly higher percentage of non-responder patients than controls. • Early neutralizing Ab post-vaccine detection is recommended in immunocompromised patients. • Patients with suboptimal response should be prioritized for a booster-dose of vaccine. • A different type of Covid-19 vaccine could be attempted in non-responder individuals. [ABSTRACT FROM AUTHOR]

Abstract: If a woman suffers from autoimmune disease (AD), several factors can affect pregnancy or neonatal outcome: repeated spontaneous pregnancy losses (frequently related to antiphospholipid antibodies (aPL)), neonatal lupus with complete congenital heart block (CHB) (linked to transplacental passage of IgG anti Ro/SS-A antibodies) and the disease activity itself that can affect the mother, the pregnancy and fetal outcome. If appropriately managed, the antiphospholipid syndrome (APS) is “one of the few tractable causes of pregnancy losses.” A recent case control study, on babies from APS-mothers and healthy mothers, did not show any difference in the occurrence of neonatal complications. There are few data about the long-term outcome of babies born to patients with AD. We recently reported increased occurrence of learning disabilities in children born to aPL positive mothers with systemic lupus erythematosus (SLE). The modern management of pregnancy in patients with AD includes the treatment of disease flares, using drugs effective but safe for fetus. Corticosteroids and some immunosuppressive drugs can be used in pregnancy to control maternal disease. A prolonged fetal exposure to dexamethasone was reported to impair cerebral development, but we recently studied 6 children, born to patients treated with dexamathasone because of CHB, showing a normal intelligence quotient. The last 10-year experience shows that fetal exposure to antimalarial drugs should not be regarded as an important risk factor for gestational nor neonatal complications. However, information about long-term outcome of children exposed to immunosuppressive drugs “in utero” are still lacking and more efforts are needed in this research area. [Copyright &y& Elsevier]

The aim of this study was to evaluate health-related quality of life (HR-QOL) in patients with systemic sclerosis (SSc), to compare it with that of patients with rheumatoid arthritis (RA), and to correlate it with other parameters. HR-QOL was evaluated by the Short Form 36 (SF-36), SSc disease activity and severity by preliminary indexes recently proposed, disability by the Health Assessment Questionnaire (HAQ), and depressive symptoms by the Beck Depression Inventory. HR-QOL perception was not statistically different in patients with SSc and RA, except that patients with diffuse cutaneous involvement had worse scores in the general health and mental health dimensions than patients with RA (p=0.03). Compared with RA, patients with SSc tended to perceive less bodily pain (p=0.06) and have less disability (p=0.04) but to report higher depressive symptom scores (p=0.05). SSc patients’ HR-QOL was associated with some disease severity scales (general, kidney and, less significantly, heart), but it was poorly correlated with the other evaluated disease activity and severity indexes. A strong correlation with disability and with depressive symptoms was observed. In conclusion, patients with SSc perceived a reduced HR-QOL similar to that of patients with RA. SF-36 may provide useful information in their evaluation. [ABSTRACT FROM AUTHOR]

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24–72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0–2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement. [ABSTRACT FROM AUTHOR]

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition. [ABSTRACT FROM AUTHOR]