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.
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.
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.
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 35S-methionine. Inter-rater agreement was calculated with Cohen's k coefficient.
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.
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.
Interstitial lung disease (ILD) represents one of the most severe extra-muscular features of idiopathic inflammatory myositis (IIM). We aimed to identify any clinical and serological predictors of ...ILD in a monocentric cohort of 165 IIM patients.
ILD+ patients were defined as having restrictive impairment in lung function tests and signs of ILD at chest high-resolution computed tomography (HRCT). Available HRCT images were centralized and classified in different ILD patterns: non-specific interstitial pneumonia (NSIP), organizing pneumonia (OP), usual interstitial pneumonia-like (UIP), indeterminate for UIP, and interstitial lung abnormalities (ILA). Lung function test data were recorded at onset, at 1 and 5 years after ILD diagnosis.
ILD was found in 52 IIM patients (31.5%): 46.2% was affected by anti-synthetase syndrome (ARS), 21% by polymyositis (PM), 19% by dermatomyositis (DM), and 13.5% by overlap myositis. Most of ILD+ showed NSIP (31.9%), OP (19%), indeterminate for UIP (19%), and UIP (12.8%) patterns. At multivariate analysis, ILD was predicted by anti-Ro52 (
p
: 0.0026) and dyspnea (
p
: 0.015) at IIM onset. Most of ILD onset within is 12 months after IIM. In five cases, ILD occurs after 12 months since IIM diagnosis: these patients more frequently show dry cough and anti-Ku antibodies. Anti-Ro52 + ILD patients showed a significant increase of DLCO at 1 and 5 years of follow-up, compared with anti-Ro52 negative cases.
ILD occurs in about one third of IIM and was predicted by dyspnea at onset and anti-Ro52 antibodies. Anti-Ro52 defines a subgroup of ILD showing a significant improvement of DLCO during follow-up.
This retrospective study has been approved by local ethic committee (ASST-Spedali Civili of Brescia, Italy); protocol number: NP3511
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).
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.
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.
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.
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.
Local Ethical Committee NP4187.
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.
A high rate of left ventricular diastolic dysfunction (LVDD) has been described in rheumatoid arthritis (RA), compared with general population. A prospective study demonstrated that LVDD occurred in ...24% in one year of follow-up in RA patients without cardiac disease. Older age, higher systolic arterial pressure and lower E/A ratio are considered predictive factors. In addition, in RA, LVDD is known to be the only risk factor for the development of cardiovascular (CV) events, also in absence of classical CV risk factors. Some occasional reports suggest that early and aggressive treatment of RA could influence the evolution of LVDD and, accordingly, modify the rate of CV events. Therefore, a correct assessment of diastolic function should be considered of pivotal importance in the routine follow-up of RA patients.
Abstract Objective Arthritis, myositis and interstitial lung disease (ILD) constitute the classic clinical triad of anti-synthetase syndrome (ASSD). These patients experience other accompanying ...features, such as Raynaud's phenomenon, fever or mechanic's hands. Most ASSD patients develop the complete triad during the follow-up. In the present study we aimed to determine whether the subsequent appearance of accompanying features may suggest the development of triad findings lacking at the onset in anti-Jo1 positive ASSD patients. Methods Anti-Jo1 positive patients presenting with incomplete ASSD (no > 2 classic triad features) were assessed. Clinical characteristics and clusters of disease manifestations were retrospectively collected and analyzed in a large international multicenter cohort of ASSD patients. Results 165 patients (123 women) with incomplete ASSD were identified. Ninety-five patients (57.5%) developed new classic triad manifestations after 15 months median (IQR 9–51) and 40 (24%) developed new accompanying features after 19 months median (IQR 6–56) from disease onset. During the follow-up, the ex-novo occurrence of triad features was observed in 32 out of 40 patients (80%) with new accompanying findings and in 63 out of 125 patients (50.5%) without new accompanying findings ( p = 0.002). In patients with at least one new accompanying feature the odds ratio for the occurrence of new triad manifestations was 3.94 with respect to patients not developing ex-novo accompanying findings (95% CI 1.68–9.21, p = 0.002). Conclusion Anti-Jo1 ASSD patients with incomplete forms at disease onset are at high risk for the subsequent occurrence of lacking classic triad findings. Although all ASSD patients should be carefully assessed for the occurrence of new triad features, a closer follow-up should be considered in the subgroup of patients developing ex novo accompanying findings. These patients, indeed, have near four-fold increased risk for new classic triad manifestation occurrence with respect to patients not presenting ex novo accompanying findings.
Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3
CD31
CXCR4
T cells (T
...), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a T
subset with immunosenescent features, such as the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between T
subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and T
subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-
were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects' serum stimulation were also evaluated. Results showed that the percentage of T
and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28
cells among T
subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to T
cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of T
and inversely related to the CD28
T
subsets. We indirectly evaluated the role of the T
subset on the endothelium upon stimulation with serum from subjects with a low percentage of T
CD3
cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of T
compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the CD28
subset exerts detrimental role over the T
phenotype, where T
could exert an anti-inflammatory effect on endothelial cells and might orchestrate
IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.
The objective of this study was to evaluate the prevalence, clinicopathologic features, and outcome of renal involvement in a large cohort of patients with primary antiphospholipid syndrome (PAPS).
...We retrospectively examined medical records of 160 patients with a diagnosis of PAPS of two general hospitals of northern Italy between 1985 and 2008.
There were 140 women and 20 men. Mean age was 35+/-12 yr. PAPS was characterized by thrombotic events in 41.2%, fetal loss in 39.4%, and both in 19.4%. Signs of renal abnormalities were present in 14 (8.7%) patients. All patients had proteinuria, in the nephrotic range in five; four patients had moderate chronic renal insufficiency, and one had end-stage kidney disease (ESKD). Two patients presented with acute renal failure and one with nephritic syndrome. Ten patients underwent a renal biopsy, which showed a membranous glomerulonephritis in four, proliferative glomerulonephritis in two, thrombotic microangiopathy in two, and vascular lesions consistent with chronic antiphospholipid antibodies nephropathy in two. Patients with renal involvement were older (41.8 versus 34.3 years; P=0.0269), more frequently lupus anticoagulant positive (92.3 versus 48.9%; P=0.0068), and had hypocomplementemia (P<0.05).
Renal abnormalities are present in approximately 9% of patients with PAPS. In addition to APS nephropathy, the prevailing picture is membranous nephropathy. Outcome and long-term follow-up usually are good. Not all of the clinical manifestations of PAPS can be ascribed to thrombotic mechanisms. The heterogeneity of renal involvement confirms the presence of a continuum between systemic lupus erythematosus and PAPS.
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