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Summary: Tofacitinib is an oral small molecule targeting the intracellular Janus kinase–signal transducer and activator of transcription (JAK‐STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post‐translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261‐273, B359‐369, carT261‐273, citB359‐369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme‐linked immunosorbent assay (ELISA) analysis. Tofacitinib down‐regulated inflammatory cytokines by stimulated B [interleukin (IL)‐6 and tumor necrosis factor (TNF)‐α] and T [interferon (IFN)‐γ, IL‐17 or TNF‐α] cells in the short term, while a significant reduction of IL‐17 and IL‐6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL‐10 was significantly reduced in collagen‐stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self‐epitopes in RA. Tofacitinib partially prevented the IL‐10 down‐modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes. [ABSTRACT FROM AUTHOR]

Introduction/Aims Methods Results Discussion Laboratory and clinical data suggest a link between neurologically mediated inflammation and psoriasis, but the risk and features of peripheral neuropathy in psoriasis or psoriatic arthritis remain unknown. The aim of this exploratory study was to evaluate the risk and to describe the features of peripheral neuropathy in patients with psoriasis and psoriatic arthritis.One hundred patients with psoriasis and/or psoriatic arthritis and 100 control subjects were consecutively enrolled. Diagnostic confirmation included electrophysiological examination, skin biopsy, and nerve ultrasound for confirmed polyneuropathy.Nine patients were diagnosed with confirmed polyneuropathy, while none of the control subjects had the condition (relative risk [RR] = 19.00, 95% confidence interval [CI] = 1.12–322.11). Specific relative risks for polyneuropathy were 22.09 (95% CI = 1.17–416.43) in psoriasis patients and 18.75 (95% CI = 1.07–327.62) in psoriatic arthritis patients. The observed polyneuropathy in all nine patients was length‐dependent, symmetrical, and predominantly sensory, with minimal or no disability. Comorbidities and exposure to therapies known to increase the risk of polyneuropathy were more frequent in psoriasis and/or psoriatic arthritis patients compared to controls (42% vs. 4%, p = .0001). Analyzing data after excluding possible contributory causes, the risk of polyneuropathy in patients with psoriasis and/or psoriatic arthritis was not significant.Psoriasis and psoriatic arthritis appear to be associated with an increased risk of polyneuropathy. This increased risk seems to be linked to the higher prevalence of contributing factors for polyneuropathy, rather than a direct increase in neuropathy risk specifically related to psoriasis and psoriatic arthritis. [ABSTRACT FROM AUTHOR]

The development of biologics and small oral molecules has recently changed the scenario of pharmacologic treatment of systemic rheumatic diseases and it has become a real revolution. These drugs have innovative mechanisms of action, based on the inhibition of specific molecular or cellular targets directly involved in disease pathogenesis. This new scenario has lead to a regular update of the management recommendations of several institutions, such as those for Rheumatoid Arthritis treatment that address the use of conventional and biologic therapies including TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, IL-6 inhibitors (tocilizumab and sarilumab), biosimilars and small oral molecules (the JAK inhibitors tofacitinib and baricitinib). Monotherapy, combination therapy, treatment strategies (such as treat-to-target) and the targets of sustained clinical remission or low disease activity are the final goal of the guidelines for rheumatic patients management. In another condition represented by Axial Spondyloarthritis guidelines suggest to start first with non-steroidal anti-inflammatory drugs to improve lifestyle and reduce spine inflammation, but if this is not achieved in 2–4 weeks it is important to consider the use of local therapies (i.e. glucocorticoid injections) or to start biologic therapy such as TNF inhibitors and then eventually switching to another TNF inhibitor or swapping to IL-17 inhibitor. In the case of active Psoriatic Arthritis, guidelines suggest to start with non-steroidal anti-inflammatory drugs and even local glucocorticoid injections especially for oligoarthritis, then to start conventional therapies if lack of efficacy, and finally start biologics or small oral molecules in the presence of drugs toxicity, unfavorable prognostic factors and still active arthritis. In several cases, active Psoriatic Arthritis patients develop a complex clinical condition with comorbidities such as diabetes, inflammatory bowel disease and high risk of infections, and for this reason the American College of Rheumatology and the National Psoriasis Foundation have developed specific guidelines for their management. Biologic and new small molecules therapies are very expensive, but the availability of biosimilars offers the opportunity of reducing the treatment cost and significantly decreasing the cost of originators as well. In fact, we live in a period characterized by the need to rationalize costs of these drugs, to allow treating a higher number of patients and to maintain a homogeneous possibility of treatment choice. For these reasons, we need to follow scientific guidelines and patients' clinical conditions to choose the correct treatment, also based on the economic burden of therapies. • The pharmacological scenario in systemic rheumatic diseases has deeply changed. • Recommendations and guidelines must be followed to choose the correct therapy. • Biosimilars have reduced treatment costs and allowed treating more patients. • Patients clinical conditions and treatment cost must be considered. • The lack of reliable biomarkers is an unmet need in several rheumatic diseases. [ABSTRACT FROM AUTHOR]

Objective To describe a new immunoprecipitation pattern identified in Italian patients affected by systemic sclerosis (SSc), corresponding to the pyruvate dehydrogenase antigen complex recognized by anti-mitochondrial antibodies (AMA) in primary biliary cholangitis (PBC). Methods Autoantibodies in sera from 85 patients with SSc were tested by protein- and RNA-immunoprecipitation. Immunoprecipitation-Western blot was used to determine the identified proteins, and medical records re-evaluated for liver function tests and PBC. Results In 13/85 (15%) SSc sera, a unique set of 75-50-40-34 kD proteins that had not been previously reported, was noted. The four proteins were identified as the proteins X/E3BP, E1α, E1β, and E2/E3 of the pyruvate dehydrogenase antigen complex by immunoprecipitation-Western blot. From clinical record evaluation, 9/13 (69%) SSc patients with this new pattern were positive for AMA by routine indirect immunofluorescence, and 7/13 (54%) had a diagnosis of PBC, while 4/13 (31%) manifested no biochemical signs of cholestasis. Twelve of 13 patients with SSc and AMA by immunoprecipitation have a limited cutaneous form of SSc and anti-centromere antibodies. Conclusions We describe a pattern of 4 proteins in 15% of SSc patients, identified for the first time by protein-immunoprecipitation. This pattern corresponds to serum AMA against the pyruvate dehydrogenase antigen complex and it must be considered in the interpretation of protein-immunoprecipitation results. [ABSTRACT FROM AUTHOR]

Autoimmunity and chronic inflammation recognize numerous shared factors and, as a result, the resulting diseases frequently coexist in the same patients or respond to the same treatments. Among the convenient truths of autoimmune and chronic inflammatory diseases, there is now agreement that these are complex conditions in which the individual genetic predisposition provides a rate of heritability. The concordance rates in monozygotic and dizygotic twins allows to estimate the weight of the environment in determining disease susceptibility, despite recent data supporting that only a minority of immune markers depend on hereditary factors. Concordance rates in monozygotic and dizygotic twins should be evaluated over an observation period to minimize the risk of false negatives and this is well represented by type I diabetes mellitus. Further, concordance rates in monozygotic twins should be compared to those in dizygotic twins, which share 50% of their genes, as in regular siblings, but also young-age environmental factors. Twin studies have been extensively performed in several autoimmune conditions and cumulatively suggest that some diseases, i.e. celiac disease and psoriasis, are highly genetically determined, while rheumatoid arthritis or systemic sclerosis have a limited role for genetics. These observations are necessary to interpret data gathered by genome-wide association studies of polymorphisms and DNA methylation in MZ twins. New high-throughput technological platforms are awaited to provide new insights into the mechanisms of disease discordance in twins beyond strong associations such as those with HLA alleles. [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]

The prevalence of ANA and anti-ENA in the general population is not well established, especially their clinical significance in healthy subjects. We herein determined the prevalence and predictive value of serum ANA and anti-ENA for connective tissue diseases (CTD), cancer, and mortality. We took advantage of a randomly selected sample of the 1998 general population (Isola I) consisting of 2828 subjects (53% women, age 43 ± 13 years) from a well-defined Northern Italian area. Serum ANA and anti-ENA were tested on the 2690 samples available in 2012 (Isola II, 50% women, age 58 ± 13 years). Administrative databases were searched for CTD, cancer diagnosis, and death cases occurring between enrollment and December 31, 2013. The hazard ratio (HR) was calculated for incident cases. Serum ANA is positive in 18.1% for any titer and 6.1% for titers ≥ 1:160, 23% in subjects over 50 years and 13.1% and 6.1% for any titer and titers ≥ 1:160, respectively, in women. The HR for CTD development was significantly high for all ANA titers, with the highest for ANA ≥ 1:160 (HR 14.19, 95% CI 3.07–65.68). ANA positivity was not associated with cancer (HR 1.03; 95% CI 0.75–1.43), or with mortality (HR adjusted for age and sex 1.40; 95% CI 0.94–2.09). Serum anti-ENA is positive in a minority of subjects with highest figures for anti-nucleosome (1.9%), -histone (1.6%) and -PM/Scl (1.5%). In conclusion, serum ANA prevalence in the general population is highest in senior subjects and in women, while the female predominance is significantly lower compared to overt CTD. Serum ANA is associated with an increased probability of CTD development over time, but does not influence survival or cancer risk. [ABSTRACT FROM AUTHOR]

Spondyloarthritidies represent a group of conditions affecting the axial and peripheral muscoloskeletal apparatus and are often associated with psoriasis, infections, and inflammatory bowel diseases. Other diseases included in this category are psoriatic arthritis, ankylosing spondylitis, and enteropathic arthritis. Reactive arthritis is an elusive spondyloarthritis, commonly occurring 1 to 3 weeks after a digestive or a genitourinary tract infection, in which microorganisms do not infect the joint directly. Reactive arthritis is classically characterized by large-joint arthritis, urethritis in men and cervicitis in women, and eye inflammation (usually conjunctivitis or uveitis) but encompasses numerous other symptoms and signs, including manifestations of dermatologic interest such as keratoderma blenorrhagicum and circinate balanitis. The diagnosis of reactive arthritis is clinical, and the infectious agent cannot always be identified due to disease latency after the infection. Most cases are self-limiting, but reactive arthritis may become chronic in 30% of cases. Treatment options include anti-inflammatory drugs, steroids, and sulfasalazine; biologic agents, such as tumor necrosis factor α (TNF-α) blockers, have been recently used, but there are only a few randomized clinical trials on the treatment of reactive arthritis. The effectiveness of antimicrobials needs further evaluation. [ABSTRACT FROM AUTHOR]

Purpose: Anemia is one of the most common hematological manifestations in SLE patients, occurring in about 50 % of active cases. STAT1 is a critical signaling molecule required for the production of type-1 interferon (I-IFN), CCL2, and CXCL10, all of which are upregulated in SLE. Overexpression of STAT1 has been described to be involved in anemia in animal models. The aim of this study is to analyze how these components are involved in SLE-associated anemia. Methods: Blood samples were collected from 39 healthy donors and 101 SLE patients fulfilling ACR criteria. Samples were collected from a total of 180 visits (58 patients had 2 or more visits) of which 52 visits included a diagnosis of anemia. Healthy donors had only single visit. Total RNA, isolated from leukocytes, was analyzed by Taqman qPCR. Relative expression levels of I-IFN signature genes, chemokines, and miR-146a were determined by the ΔΔCT method. Results were correlated with clinical data and analyzed by the Wilcoxon/Kruskal-Wallis test and Fisher's exact test. Results: Significant increases in IFN score ( p < 0.0001), STAT1 ( p < 0.0001), miR-146a ( p < 0.0005), CCL2 ( p = 0.0047), and CXCL10 ( p = 0.017), as well as a significant decrease in pri-miR-146a ( p = 0.0002), were detected in the anemic SLE patient visits ( n = 52) compared to non-anemic SLE visits ( n = 128). Regardless of disease activity, lupus nephritis, or race, anemic SLE patients displayed significantly elevated levels of STAT1 and miR-146a compared to non-anemic SLE patients. Conclusions: STAT1 and miR-146a may be upregulated during inflammation and via proinflammatory cytokines and chemokines in SLE. Prolonged upregulation of STAT1 and miR-146a appears to play an important role in anemia in SLE patients. [ABSTRACT FROM AUTHOR]

Purpose: Autoantibodies to cytoplasmic structures called rods and rings (RR) are primarily specific to patients with hepatitis C virus (HCV) infection treated with pegylated interferon-alpha/ribavirin (IFN/R). Our aim is to examine anti-RR antibodies specificity and correlation with the response to IFN/R therapy in two independent cohorts (US and Italy) of HCV patients. Methods: Sera from the US cohort ( n = 47) and the Italian cohort ( n = 46) pre-selected for anti-RR antibodies were analyzed by immunofluorescence and radioimmunoprecipitation. The prevalence and titers of anti-RR were analyzed for correlation with the response to IFN/R therapy. Results: In the US cohort, anti-RR antibodies were more frequently non-responders to IFN/R (71 % vs 29 % responders). Titers in responder patients ( n = 11) were ≤1:3200, whereas titers in non-responder patients ( n = 27) reached 1:819,200 ( p = 0.0016). In the Italian cohort, anti-RR titers ranged from 1:200 to >1:819,200 and only relapsers had the highest anti-RR titers. Radioimmunoprecipitation demonstrated that anti-RR autoantibodies were mainly anti-inosine monophosphate dehydrogenase 2 (IMPDH2) - 96 % in the Italian cohort vs. 53 % in the US cohort. Conclusions: In the two cohorts analyzed, the anti-IMPDH2 response as a component of the anti-RR response is much more prominent in the Italian cohort. The reason for the difference between the US and Italian cohorts is unclear but it possibly illustrates the heterogeneity in response and the overall negative correlation between the production of these autoantibodies and response to IFN/R therapy. Patients with high titer anti-RR antibodies are either relapsers (Italian) or non-responders/relapsers (US). [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various articles within the issue on topic related to the immunopathological aspects associated with hepatitis B (HBV) and hepatitis C (HCV) infections.

The role of microRNAs (miRNAs) in the regulation of many physiological and pathological processes has been intensely studied in recent years. Some miRNAs, such as miR-146a and miR-182, play a dominant role in the regulation of the innate and adaptive immune responses, respectively. Many miRNAs are reportedly deregulated in autoimmune diseases, but miR-146a in particular seems to be consistently altered. The overexpression or underexpression of miRNAs can influence specific targets and pathways, leading to autoimmune disease phenotypes, and this is supported also by some in vivo studies. Targeting miRNAs could represent a valid future therapeutic option for autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract: Rheumatoid arthritis (RA) is a chronic and severe autoimmune disease that affects joint tissues, bone, and cartilage. However, the pathogenesis of RA is still unclear. Autoantibodies such as rheumatoid factor and anti-cyclic citrullinated peptide are useful tools for early diagnosis, monitoring disease activity, and predicting prognosis. Recently, many groups have focused their attention on the role of microRNAs in the pathogenesis of RA, as well as a potential biomarker to monitor RA. In fact, the expression of some microRNAs, such as miR-146a, is upregulated in different cell types and tissues in RA patients. MicroRNAs in RA could also be considered as possible future targets for new therapeutic approaches. [Copyright &y& Elsevier]

The authors discuss the association between microRNA and methylation regulation by DNA methyltransferases (Dnmt) and the role of microRNA in lupus CD4+ T cell hypomethylation and the pathogenesis of Systemic Lupus Erythematosus (SLE). A critical review of and main differences between two studies focusing on the role of microRNA overexpression affecting the DNA methylation mechanism in SLE T cells including one by S. Zhao and colleagues, and the other by W. Pan and colleagues, is provided.

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]

The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19. • CoViD-19 is a pandemic caused by SARS-CoV2, that can lead to acute respiratory distress syndrome. • Antimalarial drugs, anti-IL-1 and anti-IL-6 may be used in severe cases targeting the cytokine storm induced by CoViD-19. • Recommendations for rheumatic disease patients include the prevention of infection by avoiding social contacts. • Patients should also continue their ongoing therapy except in the case of overt infection. [ABSTRACT FROM AUTHOR]

In the article, the authors present a case of a 27-year-old female with spondyloarthritis concomitantly with SARS-CoV-2 infection to discuss psoriatic arthritis triggered by said infection. In the case, the patient developed acute arthritis of the left ankle, dysgeusia and anosmia. Also cited are the subgroups of arthritis possibly linked to viral infections like reactive arthritis, viral arthritis and chronic arthritis.

The sequencing of the human genome is now well recognized as the starting point of personalized medicine. Nonetheless, everyone is unique and can develop different phenotypes of the same disease, despite identical genotypes, as well illustrated by discordant monozygotic twins. To recognize these differences, one of the easiest and most familiar examples of biomarkers capable of identifying and predicting the outcome of patients is represented by serum autoantibodies. In this review, we will describe the concept of personalized medicine and discuss the predictive, prognostic and preventive role of antinuclear antibodies (ANA), anti-citrullinated peptide antibodies (ACPA), rare autoantibodies and anti-drug antibodies (ADA), to evaluate how these can help to identify different disease immune phenotypes and to choose the best option for treating and monitoring rheumatic patients in everyday practice. The importance of ANA resides in the prediction of clinical manifestations in systemic sclerosis and systemic lupus erythematosus and their association with malignancies. ACPA have a predictive role in rheumatoid arthritis, they are associated with the development of a more aggressive disease, extra-articular manifestations and premature mortality in RA patients; moreover, they are capable of predicting therapeutic response. Rare autoantibodies are associated with different disease manifestations and also with a greater incidence of cancer. The determination of ADA levels may be useful in patients where the clinical efficacy of TNF-α inhibitor has dropped, for the assessment of a right management. The resulting scenario supports serum autoantibodies as the cornerstone of personalized medicine in autoimmune diseases. [ABSTRACT FROM AUTHOR]

The sequencing of the human genome is now well recognized as the starting point of personalized medicine. Nonetheless, everyone is unique and can develop different phenotypes of the same disease, despite identical genotypes, as well illustrated by discordant monozygotic twins. To recognize these differences, one of the easiest and most familiar examples of biomarkers capable of identifying and predicting the outcome of patients is represented by serum autoantibodies. In this review, we will describe the concept of personalized medicine and discuss the predictive, prognostic and preventive role of antinuclear antibodies (ANA), anti-citrullinated peptide antibodies (ACPA), rare autoantibodies and anti-drug antibodies (ADA), to evaluate how these can help to identify different disease immune phenotypes and to choose the best option for treating and monitoring rheumatic patients in everyday practice. The importance of ANA resides in the prediction of clinical manifestations in systemic sclerosis and systemic lupus erythematosus and their association with malignancies. ACPA have a predictive role in rheumatoid arthritis, they are associated with the development of a more aggressive disease, extra-articular manifestations and premature mortality in RA patients; moreover, they are capable of predicting therapeutic response. Rare autoantibodies are associated with different disease manifestations and also with a greater incidence of cancer. The determination of ADA levels may be useful in patients where the clinical efficacy of TNF-α inhibitor has dropped, for the assessment of a right management. The resulting scenario supports serum autoantibodies as the cornerstone of personalized medicine in autoimmune diseases. [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]

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]

Antiphospholipid antibodies (aPL) are known to be pathogenic in experimental models and are predictive of thrombosis and miscarriages in patients, so it is important to correctly evaluate their presence for identifying patients at risk. Despite many years of work, the standardization of aPL ELISA remains an open problem, so evaluation of newly introduced commercial preparations is mandatory. A total of 80 sera were collected (10 primary antiphospholipid syndromes (APSs), 10 APSs associated with systemic lupus erythematosus, 20 infectious diseases, 20 rheumatoid arthritis and 20 normal blood donors) and tested for IgG/IgM anti-cardiolipin and anti-beta2GPI antibodies on commercial ELISA kits (ETI) by DiaSorin and on home-made ELISA. Both methods displayed good sensitivity and specificity for APS and were found to be concordant, especially in determining antibodies of IgG class. [ABSTRACT FROM AUTHOR]

There is no agreement on the prevalence of anti-phospholipid antibodies (aPLs) and the correlation with atherosclerosis and cardiovascular (CV) events in the general population. We performed a cross-sectional study on 1712 randomly enrolled subjects from a Northern Italian city to investigate the presence of aPLs and the association with subclinical atherosclerosis (using the carotid artery intima media thickness measured as inter-adventitia common carotid artery diameters - ICCAD) and retrospectively collected CV factors and events (i.e. acute myocardial infarction, stroke, and peripheral obliterans arterial vasculopathy) using physician-assisted questionnaires. We tested serum IgG, IgM, and IgA anti -cardiolipin, anti-beta2glycoprotein I (aGPI), and anti -phosphatidylserine-prothrombin antibodies. Positive aPLs were found in 15.1% of the subjects, with no differences between sex but with higher rates in older subjects. Carotid subclinical atherosclerosis was more frequent in aPL positive subjects; more specifically, aGPI IgA were associated with higher ICCAD average (adjusted beta 0.51, 95% confidence interval (CI)0.17–0.84; p = 0.003). A positive history of CV events was also more frequent in aPL positive subjects (odds ratio (OR) 1.67, 95%CI 1.08–2.54; p = 0.012), particularly peripheral obliterans arterial vasculopathy (OR 2.02 ; 95%CI 1.14–3.57; p = 0.015). Among subjects with a Framingham risk score >20, and/or diabetes, and/or body mass index >3 5 kg/m 2 , aPL positivity was associated to the highest risk of CV events (OR 2.52, 95%CI 1.24–5.11; p = 0.011). APL prevalence in the general population is higher than previously reported. CV events and subclinical atherosclerosis are more frequent in the presence of aPL, particularly when a high CV risk coexists. • Positive aPL are common in the population but their CV significance is unclear. • CV events are more frequent in subjects with aPL and an elevated CV risk. • aPLs are associated with ultrasound signs of atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age.Methods: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149).Results: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning.Conclusion: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication. [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]

The pediatric syndrome characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and adult Behçet's disease share some clinical manifestations and are both polygenic autoinflammatory disorders with interleukin-1β showing to play a pivotal role. However, the diagnosis is mostly clinical and we hypothesize that specific criteria may be addressed differently by different physicians. To determine the diagnostic variability, we compared the answers of 80 patients with a definite diagnosis of Behçet's disease (age 42.1 ± 13.7 years) obtained by separate telephone interviews conducted by a rheumatologist, a pediatrician, and an internist working largely in the field of autoinflammatory disorders. Questions were related to the age of symptom onset, the occurrence of recurrent fevers during childhood, and the association with oral aphthosis, cervical adenitis and/or pharyngitis, previous treatments, possible growth impairment, the time lapse between PFAPA-like symptoms and the onset of Behçet's disease, and the occurrence of Behçet-related manifestation during childhood. The rheumatologist identified 30 % of patients with Behçet's disease fulfilling PFAPA syndrome diagnostic criteria, compared to the pediatrician and the internist identifying 10 and 7.5 %, respectively. Most of the patients suffered from recurrent oral aphthosis in childhood also without fever (50, 39, and 48 % with each interviewer), yet no patient fulfilled the Behçet's disease diagnostic criteria. Our data suggest that physician awareness and expertise are central to the diagnosis of autoinflammatory disorders through an accurate collection of the medical history. [ABSTRACT FROM AUTHOR]

Autoantibodies to topoisomerase I (topo I), RNA polymerase III (RNAPIII), centromere, U3RNP/fibrillarin, Th, PM-Scl, and U1RNP found in scleroderma (SSc) are associated with unique clinical subsets. The effects of race and gender on autoantibody prevalence and clinical manifestations were examined. Autoantibodies in sera from 105 SSc (include 75 Caucasian, 24 African-American, 6 others; 89 females and 16 males) were analyzed by immunofluorescence and immunoprecipitation. Clinical information was from database. SSc-related autoantibodies seldom coexist except for anti-topo I and anti-U1RNP. Anti-topo I (35% vs 15%), anti-U3RNP (30% vs 3%, p = 0.0005), and anti-U1RNP (30% vs 13%) were more common in African-Americans vs Caucasians. Anti-centromere (17%) and anti-PM-Scl (only in 8% of female) were found only in Caucasians. In race/gender combination, all three African-American males had anti-topo I ( p = 0.04). Anti-U3RNP (35% vs 3%, p = 0.0005) and anti-U1RNP were common in African-American females. In African-American, all nucleolar dominant staining sera had anti-U3RNP; nuclear pattern was topo I (50%), U1RNP (19%), and RNAPIII (13%). In Caucasian, nucleolar was anti-Th (43%) and PM-Scl (29%); nuclear pattern was RNAPIII (29%), topo I (24%), and U1RNP (18%). Anti-topo I, anti-RNAPIII, and anti-U3RNP were associated with diffuse SSc while anti-centromere, anti-Th, and anti-U1 with limited disease. Proximal scleroderma was less common in African-American with anti-topo I (38% vs 91% in Caucasian, p = 0.04). The production of SSc-related autoantibodies is gender and race dependent, and this can be highly relevant in understanding their clinical significance. [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]