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Anti-dsDNA autoantibodies are listed as one of the classification criteria for systemic lupus erythematosus (SLE) and are relatively effective indicators for monitoring disease activity and treatment response. Therefore, clinicians rely on them to diagnose and adjust medication and treatment strategies for SLE patients. However, the use of anti-dsDNA antibodies is not free from controversy. Part of this controversy stems from the fact that anti-dsDNA antibodies are found in several disorders, besides SLE. In addition to this, anti-dsDNA antibodies are a heterogeneous group of antibodies, and their determination still lacks proper standardization. Moreover, anti-dsDNA testing specificity and diagnostic performance change depending on the population under study. These and other issues result in inconsistency and encumber the clinical use of anti-dsDNA antibodies. A panel of medical laboratory and clinical experts on SLE discussed such issues based on their clinical experience in a first meeting, establishing a series of recommendations. The proceedings of this first meeting, plus an exhaustive review of the literature, were used to compose a paper draft. The panel subsequently discussed and refined this draft in a second meeting, the result of which is this paper. This document is relevant to clinical laboratories as it guides to improving diagnosis and monitoring of SLE. Simultaneously, it will help laboratories compile more informative reports, not limited to a mere number. It is also relevant to clinical doctors who wish to better understand laboratory methods so that they can do a more efficient, better-aimed laboratory test ordering. [Display omitted] • The use of laboratory tests for systemic lupus erythematosus (SLE) diagnosis and monitoring needs to be optimized. • 9 independent experts from first-order Spanish institutions have drawn up recommendations for SLE diagnosis and monitoring. • Interventions to improve SLE diagnosis and monitoring must be adapted to the level of care. [ABSTRACT FROM AUTHOR]

Rasmussen Encephalitis (RE) is classically described as a childhood encephalopathy due to a unilateral inflammation of the cerebral cortex with a presumed immune-mediated pathophysiological basis. Unusual variant forms, including adolescent and adult-onset RE have been described but there is still a doubt whether these atypical cases correspond to classical RE patients. To review evidence, a systematic PubMed search was conducted to retrieve papers addressing late onset RE to assess (i) the positivity rate of classical childhood-onset diagnostic criteria for RE in late-onset RE, (ii) the specific clinical and radiological features that could help earlier diagnosis and therapeutic interventions, (iii) the arguments for an autoimmune pathophysiology including (iiia) the association with autoimmune markers or diseases and (iiib) the effects of immunomodulatory or immunosuppressive treatments. A total of 50 papers were considered. We identified 102 late-onset RE patients with a sex ratio of 8 women for 2 men. 67% fulfilled the consensus diagnostic criteria for RE. As compared to classical RE, the late-onset RE patients exhibited: i) more frequent focal complex partial seizures, ii) less frequent epilepsia partialis continua throughout evolution, iii) a slower evolution with a delayed occurrence of cortical deficit, iv) less cognitive deterioration and v) a better outcome. A specific association with autoimmune markers or diseases was not found. Immunomodulatory therapies, even performed in a late stage, improved late-onset RE patients in 61% of cases. This review proves that late-onset RE is a reality with specific clinical and radiological features. The good response to immunomodulatory treatments brings further arguments for an immune-regulated process. [ABSTRACT FROM AUTHOR]

Juvenile temporal arteritis (JTA) is a recently-described and little-known inflammatory disease and its etiology is undetermined. Less than forty cases have been published. This paper is aimed at reporting the largest JTA series and to compare it to literature data to better evaluate its characteristics at diagnosis, its evolution and treatment options. We conducted a retrospective and descriptive multicentric study in France by identifying adult patients under the age of 50 which had a pathological temporal artery biopsy owing to the presence of a temporal arteritis. Patients with temporal arteritis as a manifestation of systemic vasculitis were excluded. We included 12 patients and the literature review identified 32 cases described in 27 articles, thus a total of 44 patients – 34 men and 10 women – with a median age of 30 and a maximum of 44. All patients presented either a lump in the temporal region or prominent temporal arteries, and 47.7% of patients suffered from headaches. Only 11.4% of patients presented general symptoms and 6.8% a biological inflammatory syndrome; 34.1% had peripheral blood eosinophilia; 83.7% presented a single episode and complete excision without further treatment was documented for 72.7%. Pathology analysis revealed infiltrate of inflammatory cells in the arterial wall in 97.6% of patients but also sparse giant cells for 25% and granuloma for 22.9%, perivascular extension of the inflammation for 82.6%, and presence of lymphoid follicles or germinal centres for 60%. Clinical relapses were present in 16.3% of cases. JTA is a rare, localized and benign disease. The majority of cases have only one episode which is cured by local surgery. • Juvenile temporal arteritis, is a rare, localized, and benign disease affecting the temporal artery in patients aged less than <50 years. • JTA presenting as a lump in the forehead, sometimes painful, without systemic symptoms or biological inflammation. • JTA is most frequently cured by biopsy or excision. • Kimura disease and angiolymphoid hyperplasia with eosinophilia must be considered as alternate diagnosis. [ABSTRACT FROM AUTHOR]

Even though the association of anti-phospholipid antibodies (aPL) with infertility is debated, infertile women are commonly screened for aPL. To review evidence, a systematic PubMed search was conducted to retrieve papers addressing (i) the association between aPL and infertility, (ii) the positivity rate of criteria and non-criteria aPL in women with infertility, (iii) the association between aPL and assisted reproduction technologies (ART) outcome, (iv) the efficacy of medical treatments on ART outcome, and (v) the effects of ART on thrombotic risk. A total of 46 papers were considered; several limitations emerged: (i) wide heterogeneity in study populations, (ii) non-prospective design in 90% of studies, and (iii) aPL cutoffs not conforming to international guidelines in more than 75% of studies; aPL positivity not confirmed in 89% of studies. Most studies evinced an association between infertility and anti-β2GPI antibodies and almost all non-criteria aPL. The association rate with infertility was below 50% for lupus anti-coagulant, anti-cardiolipin antibodies (aCL), and anti-phosphatidic acid antibodies. According to our estimates, overall positivity rates of criteria and non-criteria aPL tests are 6% and 3% among infertile women, 1% and 2% among controls, respectively. A significant difference in the positivity rate of patients versus controls emerged for aCL only. Five of 18 studies reported a detrimental effect of aPL on ART outcome. Only one of the six studies assessing the effects of treatment on ART outcome among aPL-positive infertile women reported a benefit. All relevant studies reported no increase in the rate of thrombosis among aPL-positive women undergoing ART. [ABSTRACT FROM AUTHOR]

The outcome of lupus nephritis (LN) has changed since the introduction of glucocorticoids (GCs), which dramatically reduced the mortality related to one of the most severe complications of systemic lupus erythematosus (SLE). Since the 1950′s, other immunosuppressants, including biologic drugs (i.e. rituximab) have aided in maintaining remission, preserving kidney function, but not preventing treatment-related toxicity. GCs still remain the cornerstone in the treatment of SLE, including LN, and they are widely used in clinical practice. However, GC administration represents a double-edged sword. Indeed, from one side they allow a fast and effective control of disease activity by dampening inflammation; from the other side, they have many and severe side effects leading to organ damage. In this paper, we will discuss pros and cons of the chronic use of GCs, especially focusing on LN. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) is a granulomatous vasculitis affecting large arteries, especially the aorta and the extracranial branches of the external carotid artery. Its exact pathogenesis is not fully understood but major progress has been made in recent years, leading to new therapeutic targets like inhibition of the interleukin-6 pathway or the modulation of immune checkpoints. The cause of GCA has not been clearly identified but it is thought that GCA occurs on a genetic background and is triggered by unknown environmental factors that could activate and lead to the maturation of dendritic cells localized in the adventitia of normal arteries. These activated dendritic cells then produce chemokines which trigger the recruitment of CD4 + T cells, which in turn become activated, proliferate and polarize into Th1 and Th17 cells, which produce IFN-γ and IL-17, respectively. Exposed to IFN-γ, endothelial cells and vascular smooth muscle cells produce chemokines leading to the recruitment of further Th1 cells, CD8 + T cells and monocytes. The latter differentiate into macrophages, which, when persistently exposed to IFN-γ, form giant cells, the histological hallmark of GCA. With the contribution of vascular smooth muscle cells, immune cells then trigger the destruction and remodeling of the arterial wall, thus leading to the formation of a neo-intima resulting in progressive occlusion of the arterial lumen, which is responsible for the ischemic symptoms of GCA. In this paper, we review recent progress in our understanding of GCA pathogenesis in the fields of genetics, epigenetics, infections, immunology and vascular remodeling. [ABSTRACT FROM AUTHOR]

Intravenous immunoglobulins (IVIG) are a new therapeutic approach in systemic sclerosis SSc. An immunomodulatory and antifibrotic activity has been postulated. IVIG are generally well tolerated and have only rare side effects. Our retrospective study focused its attention on SSc, an autoimmune connective tissue disease, characterized by several complications which has a significant impact on patient's quality of life. The pathophysiology comprises fibrotic, vascular and immunological aspects. The aim of this study was to verify the effectiveness of IVIG on SSc skin involvement. Moreover, a systematic review of the literature (SLR) of the results obtained to date on the use of Intravenous immunoglobulin (IVIG) in SSc has been also performed. The data of 24 patients (21 women, 3 male) with refractory diffuse SSc skin involvement were evaluated (mean age was 52.13 years). IVIG infusion at a dosage of 2 g/Kg body weight for 4 consecutive days/month, was started between 2002 and 2019. Skin involvement was evaluated with the modified Rodnan Skin Score (mRSS) before therapy and then again after 6 and 12 months. To perform the SLR, the PubMed, Medline, Embase, and Web of Science database were searched from 1990 to 2020 (keywords: IVIG, systemic sclerosis). Three assessors (E.A., C.B. & M.M.C) identified the criteria to scan all papers. From the total SLR (106 results), 17 papers were identified after the separation of the clinical cases from the studies (total number of treated patients 183). The studies were classified according to the organ involvement considered in each study, as well as the prescribed dose (high or low doses), and the therapeutic regimens. In the selected papers, the organs mainly involved were the skin, the gastrointestinal, the joint and the cardiovascular systems. Only in one case, plasmapheresis was associated to IVIG. All papers reported significant reduction of the skin involvement, although generally the strength of the works was limited the lack of control cases or by the low number of patients involved. From the real life experience, a statistically significant reduction of mRSS was obtained at 6 months follow-up (average value of −6.61 ± 5.2, p < 0.001), and it was further maintained with a significant stabilization after 12-months (−11.45 ± 9.63, p < 0.002). This SLR and the data of the retrospective study suggest that IVIG may improve skin involvement reducing mRSS in particular in those patients that were refractory to other standard of care therapies and represents a therapeutic option in patients with concomitant myositis. The literature review revealed encouraging perspectives on the use of this therapy, given the effectiveness found in the selected works. [ABSTRACT FROM AUTHOR]

Introduction The aim of our study was to systematically review the growing body of published literature reporting on one specific multiple sclerosis (MS) treatment, fingolimod, in the real world to assess its effectiveness in patients with MS, evaluate methodologies used to investigate MS in clinical practice, and describe the evidence gaps for MS as exemplified by fingolimod. Methods We conducted a PRISMA-compliant systematic review of the literature (cut-off date: 4 March 2016). Published papers reporting real-world data for fingolimod with regard to clinical outcomes, persistence, adherence, healthcare costs, healthcare resource use, treatment patterns, and patient-reported outcomes that met all the eligibility criteria were included for data extraction and quality assessment. Results and discussion Based on 34 included studies, this analysis found that fingolimod treatment improved outcomes compared to the period before treatment initiation and was more effective than interferons or glatiramer acetate. However, among studies comparing fingolimod with natalizumab, overall trends were inconsistent: some reported natalizumab to be more effective than fingolimod and others reported similar effectiveness for natalizumab and fingolimod. These studies illustrate the challenges of investigating MS in the real world, including the subjectivity in evaluating some clinical outcomes and the heterogeneity of methodologies used and patient populations investigated, which limit comparisons across studies. Gaps in available real-world evidence for MS are also highlighted, including those relating to patient-reported outcomes, combined clinical outcomes (to measure overall treatment effectiveness), and healthcare costs/resource use. Conclusions The included studies provide good evidence of the real-world effectiveness of fingolimod and highlight the diversity of methodologies used to assess treatment benefit in clinical practice. Future studies could address the evidence gaps found in the literature and the challenges associated with researching MS when designing real-world studies, assessing data, and comparing evidence across studies. [ABSTRACT FROM AUTHOR]

Immunoglobulin (IG) therapy is actually used for a broad range of diseases including primary and secondary immunodeficiency disorders, and autoimmune diseases. This therapy is available for intravenous (IV) and subcutaneous (SC) administration. The efficacy of the IG therapy has been demonstrated in numerous studies and across different diseases. Generally, IG infusions are well tolerated; however some well-known adverse reactions, ranging from mild to severe, are associated with the therapy. The most common adverse reactions including headache, nausea, myalgia, fever, chills, chest discomfort, skin and anaphylactic reactions, could arise immediately during or after the infusion. Delayed events could be more severe and include migraine headaches, aseptic meningitis, haemolysis renal impairment and thrombotic events. This paper reviews all the potential adverse events related to IG therapy and establishes a comprehensive guideline for the management of these events. Moreover it resumes the opinions and clinical experience of expert endorsers on the utilization of the treatment. Published data were classified into levels of evidence and the strength of the recommendation was given for each intervention according to the GRADE system. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic. Methods: The study included 87 patients (male/female 19/68, mean age 62.3±11.4SD years, mean disease duration 9±6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab. Results: A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient''s visual analogical scale from 62±25 to 37±27; p≤.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8±1.1SD to 1.4±0.8SD mg/dl, p≤.0001; 24-hour proteinuria from 2.2±2.1SD to 0.9±1.7SD g/24h, p≤.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin''s B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients. Conclusions: Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs. [Copyright &y& Elsevier]

Abstract: Multi-organic failure in the context of autoimmune diseases is a multi-factorial condition where different pathways concur to produce a global system breakdown. Some of these pathways include the coagulation, fibrinolysis, kinin and complement cascades which in normal conditions work together to provide a comprehensive response to injury. In pathologic conditions these regulatory mechanisms are replaced by positive feed-back loops. The common response pattern is the activation of the immune system via endothelium activation. Furthermore, these different plasma-driven mechanisms may induce standardised endothelial cell responses of which the most relevant are the activation of p38, JNK, NF-kβ and IRF-3 pathways. In this paper we review the common points between these major pathways and how they become activated, contributing to a global clinical picture. We present two examples of apparently different clinical settings, caused by the same global dysfunction: the Macrophage Activation Syndrome and the iatrogenic “cytokine storm” triggered by the administration of anti-CD28 monoclonal antibody TGN1412 in a phase 1 trial. [Copyright &y& Elsevier]

Abstract: A second-line treatment protocol including plasma exchange (PE) in addition to the standard therapies was scheduled and utilized in our hospital with the intent of improving the outcome of high risk pregnancies of women with primary antiphospholipid syndrome (APS). This paper chronologically reports and discusses the results obtained in these patients over a 15-year period. Between April 1991 and September 2006, 142 pregnancies of patients with APS were followed by us. Nine of these (6.3%), who did not respond to the conventional procedures or showed complications during the treatments were shifted to a PE protocol management. All these women had a history of previous thromboembolism associated to triple antiphospholipid antibody positivity. Nine pregnancies of 7 patients (2 women were treated twice) were thus followed using PE therapy, which has undergone modification over the years. In the cases studied the outcome of pregnancy varied according to the different PE therapy conditions. This study suggests that prophylactic PE treatment administered along with full anticoagulation and IVIG therapy could be a valuable therapeutic option in high risk pregnant APS women. Further studies in this type of patients are certainly warranted. [Copyright &y& Elsevier]