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We aim at investigating the association between subclinical autoimmunity and immune-related adverse events (irAEs) in a cohort of patients treated by immune checkpoint inhibitors for solid metastatic cancer. In the context of an oncology/rheumatology outpatient clinic, we evaluated patients treated with anti-PD-1 or anti-PD-L1. Before treatment, each patient underwent a physical evaluation and a blood sample to identify the presence of a set of autoantibodies. Indeed, all the patients were followed during treatment to identify irAEs and to assess the association with autoantibodies. Fifty-one patients (M/F 16/35; median age 70 years, IQR 16.5) were evaluated; 34.8% of patients showed ANA positivity, 6.5% ENA positivity (anti-SSA), 4.3% Ratest positivity, and 2.1% (one patient) ACPA positivity. During a median period of 21 months (IQR 38.75), 39.2% of patients developed irAEs. Musculo-skeletal manifestations, in particular arthritis, were the most frequent. We found a significant association between the positivity for ANA and the development of irAES (p = 0.03, RR 2.01, 95% CI 1.03–3.92). Furthermore, the progression-free survival was significantly longer in patients developing irAEs compared to those who are not experiencing these events (p = 0.007). This study underlines the potential role of ANA positivity as a predictive biomarker for the development of irAEs. [ABSTRACT FROM AUTHOR]

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad's phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of "seronegative" SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2–7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients' stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns' interpretation. The gold-standard technique for autoantibodies' identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients. [ABSTRACT FROM AUTHOR]

The diagnosis of systemic autoimmune diseases (SAID) is challenging, due to overlapping features with other non-immune disorders. Anti-nuclear antibodies (ANA)/anti-cellular antibodies are the sensitive screening tests but anti-double-stranded-deoxyribonucleic acid-antibody (anti-ds-DNA) and ANA-specific antibodies are specific for SAID. We aimed to look at ANA-specific antibodies in our patients and correlated them with ANA patterns, anti-ds-DNA, and clinical diagnosis for proper interpretation and better patient management cost-effectively. A retrospective data analysis of 641 patients was done (1st of February 2019 to 31st of July 2021) who were tested for ANA-specific antibodies at the Immunology Department of Indus Hospital and Health Network. ANA and anti-ds-DNA results and clinical diagnosis were also analyzed for ANA-specific antibody-positive patients. Descriptive data were presented in mean ± standard deviation and frequency percentages whereas inferential data were analyzed with a chi-square test for association between ANA-specific antibodies status, ANA, anti-ds-DNA, and clinical features. ANA-specific antibodies test revealed positivity for at least one autoantibody in 245 (38.2%) patients. Of these, ANA was tested in 206 patients reactive for ANA-specific antibodies and found positive in 195 (95%) as compared to negative (< 0.001). Speckled and homogenous were predominant ANA patterns in ANA-specific antibody-positives (56% and 42% respectively). Multiple ANA patterns were found in 18 patients most commonly with systemic lupus erythematosus (SLE) and mixed connective tissue disorder (MCTD). Anti-SSA were the most common ANA-specific antibodies (50%) and were mostly found in sera with speckled (61/97) and homogenous (38/97) patterns and associated mostly with SLE (48%) and Sjogren's syndrome (86%). Among ANA-negative patients, anti-SSA were the most common antibodies (n = 5). Anti-ds-DNA was found in 66% of SLE patients along with another ANA-specific antibody. This study showed that testing for ANA-specific antibodies cannot be gated on ANA patterns. Also, there is a redundancy of these antibodies with various clinical diagnoses. Moreover, they are useful in making a diagnosis in ANA-negative patients as well with clinical suspicion. [ABSTRACT FROM AUTHOR]

Background: To evaluate the interpretation and reporting of antinuclear antibodies (ANA) by indirect immunofluorescence assay (IFA) using HEp-2 substrates based on common practice and guidance by the International Consensus on ANA patterns (ICAP). Method: Participants included two groups [16 clinical laboratories (CL) and 8 in vitro diagnostic manufacturers (IVD)] recruited via an email sent to the Association of Medical Laboratory Immunologists (AMLI) membership. Twelve (n = 12) pre-qualified specimens were distributed to participants for testing, interpretation and reporting HEp-2 IFA. Results obtained were analyzed for accuracy with the intended and consensus response for three main categorical patterns (nuclear, cytoplasmic and mitotic), common patterns and ICAP report nomenclatures. The distributions of antibody titers of specimens were also compared. Results: Laboratories differed in the categorical patterns reported; 8 reporting all patterns, 3 reporting only nuclear patterns and 5 reporting nuclear patterns with various combinations of other patterns. For all participants, accuracy with the intended response for the categorical nuclear pattern was excellent at 99% [95% confidence interval (CI): 97–100%] compared to 78% [95% CI 67–88%] for the cytoplasmic, and 93% [95% CI 86%–100%] for mitotic patterns. The accuracy was 13% greater for the common nomenclature [87%, 95% CI 82–90%] compared to the ICAP nomenclature [74%, 95% CI 68–79%] for all participants. Participants reporting all three main categories demonstrated better performances compared to those reporting 2 or less categorical patterns. The average accuracies varied between participant groups, however, with the lowest and most variable performances for cytoplasmic pattern specimens. The reported titers for all specimens varied, with the least variability for nuclear patterns and most titer variability associated with cytoplasmic patterns. Conclusions: Our study demonstrated significant accuracy for all participants in identifying the categorical nuclear staining as well as traditional pattern assignments for nuclear patterns. However, there was less consistency in reporting cytoplasmic and mitotic patterns, with implications for assigning competencies and training for clinical laboratory personnel. [ABSTRACT FROM AUTHOR]

Purpose: Hyperprolactinemia (HPRL) has been reported in many autoimmune diseases. However, the serum autoantibody profile and peripheral B-cell subset distribution in women with HPRL are largely unknown. The current study aimed to investigate the autoantibody prevalence and cytokine levels as well as to further explore the B-cell subset distribution in women with HPRL. Methods: Sera from 202 women with HPRL and 97 healthy women were included in this study. All sera were examined for prolactin (PRL), anti-nuclear antibody (ANA), rheumatoid factor, anticardiolipin (ACL), immunoglobulin G, immunoglobulin M, complement 3, complement 4, interleukin 4 (IL-4) and interleukin 6 (IL-6). Peripheral blood was collected from 22 women with HPRL and 19 healthy women, and B-cell subsets were measured by flow cytometry. Results: At least one autoantibody was found in 47 out of 202 women with HPRL compared with 9 of 97 healthy women (p < 0.001). The levels of IL-4 (p < 0.0001) and IL-6 (p < 0.0001) were significantly higher in women with HPRL than in healthy women. The percentages of naive IgD+IgM− B cells (BND cells, p < 0.0001), antibody-secreting cells (p = 0.007) and unswitched memory B cells (p = 0.004) among the total B cells from HPRL women were significantly higher than those from healthy women. Conclusions: Women with HPRL had a higher prevalence of autoantibodies, higher serum levels of IL-4 and IL-6, and more BND cells, antibody-secreting B cells and unswitched memory B cells than healthy women. These data imply that a high level of PRL is associated with autoimmune diseases. [ABSTRACT FROM AUTHOR]

On average, 10 % of infertile couples have unexplained infertility. Auto-immune disease (systemic lupus erythematosus, anti-phospholipid syndrome) accounts for a part of these cases. In the last 20 years, aspecific auto-immunity, defined as positivity of auto-antibodies in blood sample without clinical or biological criteria for defined diseases, has been evoked in a subpopulation of infertile women. A systematic review was performed (PUBMED) using the MESH search terms 'infertility' and 'auto-immunity' or 'reproductive technique' or 'assisted reproduction' or 'in vitro fertilization' and 'auto-immunity.' We retained clinical and physiopathological studies that were applicable to the clinician in assuming joint management of both infertility associated with serum auto-antibodies in women. Thyroid auto-immunity which affects thyroid function could be a cause of infertility; even in euthyroidia, the presence of anti-thyroperoxydase antibodies and/or thyroglobulin are related to infertility. The presence of anti-phospholipid (APL) and/or anti-nuclear (ANA) antibodies seems to be more frequent in the population of infertile women; serum auto-antibodies are associated with early ovarian failure, itself responsible for fertility disorders. However, there exist few publications on this topic. The methods of dosage, as well as the clinical criteria of unexplained infertility deserve to be standardized to allow a precise response to the question of the role of serum auto-antibodies in these women. The direct pathogenesis of this auto-immunity is unknown, but therapeutic immunomodulators, prescribed on a case-by-case basis, could favor pregnancy even in cases of unexplained primary or secondary infertility. [ABSTRACT FROM AUTHOR]

Autoantibodies specific for idiopathic inflammatory myopathy (myositis-specific autoantibodies (MSAs)) are clinically useful biomarkers to help the diagnosis of polymyositis/dermatomyositis (PM/DM). Many of these are also associated with a unique clinical subset of PM/DM, making them useful in predicting and monitoring certain clinical manifestations. Classic MSAs known for over 30 years include antibodies to Jo-1 (histidyl transfer RNA (tRNA) synthetase) and other aminoacyl tRNA synthetases (ARS), anti-Mi-2, and anti-signal recognition particle (SRP). Anti-Jo-1 is the first autoantibodies to ARS detected in 15-25 % of patients. In addition to anti-Jo-1, antibodies to seven other aminoacyl tRNA synthetases (ARS) have been reported with prevalence, usually 1-5 % or lower. Patients with any anti-ARS antibodies are associated with anti-synthetase syndrome characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon, and others. Several recent studies suggested heterogeneity in clinical features among different anti-ARS antibody-positive patients and anti-ARS may also be found in idiopathic ILD without myositis. Anti-Mi-2 is a classic marker for DM and associated with good response to steroid treatment and good prognosis. Anti-SRP is specific for PM and associated with treatment-resistant myopathy histologically characterized as necrotizing myopathy. In addition to classic MSAs, several new autoantibodies with strong clinical significance have been described in DM. Antibodies to transcription intermediary factor 1γ/α (TIF1γ/α, p155/140) are frequently found in DM associated with malignancy while anti-melanoma differentiation-associated gene 5 (MDA5; CADM140) are associated with clinically amyopathic DM (CADM) complicated by rapidly progressive ILD. Also, anti-MJ/nuclear matrix protein 2 (NXP-2) and anti-small ubiquitin-like modifier-1 (SUMO-1) activating enzyme (SAE) are recognized as new DM-specific autoantibodies. Addition of these new antibodies to clinical practice in the future will help in making earlier and more accurate diagnoses and better management for patients. [ABSTRACT FROM AUTHOR]

Anti-nuclear antibody (ANA) positivity suggests CTD but can also lead to a diagnosis of UCTD when a patient does not fulfill the CTD diagnostic criteria. An anti-dense fine speckled (DFS) immunofluorescence (IIF) pattern can be observed when using an ANA test on HEp-2 cells and is due to the presence of antibodies to the nuclear DFS70 antigen that has rarely found in CTD. Serological testing for anti-DFS70 antibodies could therefore play a very interesting negative predictive role in stratifying patients on the basis of the evolution of UCTD to CTD. We described two patients ANA and anti-DFS70 positive in which the use of new method allowing the immunoadsorption of anti-DFS70 antibodies has permitted to exclude the incorrect diagnosis of CTD. [ABSTRACT FROM AUTHOR]

The use of diagnostic testing in the clinical practice of medicine has been a shifting landscape from the time that the first blood test was utilized. This is no different in the field of immunology and in particular rheumatology. As the field of immunology is relatively young, the clinical tests are not well established and therefore guidelines for use are still under debate. In this review, we seek to look at some of the key autoantibodies, as well as other tests that are available to diagnose suspected rheumatologic disease, and examine how to best use these tests in the clinic. In particular, we will focus on the anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, complement, cryoglobulins, rheumatoid factor, and anti-citrullinated protein antibodies. [ABSTRACT FROM AUTHOR]

common feature between patients with a certain group of systemic autoimmune pathologies (SAPs) with rheumatic component, such as lupus erythematosus (LE) in all its forms, is the presence of cutaneous photosensitivity (CP) as well as the existence of autoantibodies (Aabs). These Aabs have also high incidence in other SAPs that do not present CP, like primary Sjögren's syndrome and rheumatoid arthritis. Cutaneous photosensitivity is a condition that consists of an exacerbated skin reaction to solar radiations; its incidence can reach 90% in systemic LE. The mechanisms involved in the development of CP have been extensively studied focusing on different approaches; however, the exact mechanism has not been fully elucidated yet. There are many theories that relate specifically the presence of circulating anti-Ro/SS-A Aabs with the CP phenomenon, though there are several studies which are in disagreement. In this study, we evaluated the Aabs profile (anti-Ro/SS-A 52 kDa, anti-Ro/SS-A 60 kDa, anti-La/SS-B, anti-Sm and ANAs) as well as their titer or reactivity, in a local cohort of 169 patients with SAPs. We related those Aabs profiles and titers with the presence or absence of CP, and we found that there was no significant association between the presence of anti-Ro/SS-A Aabs and the occurrence of CP. On the other hand, a statistically significant positive association was found between CP and high reactivity anti-Sm Aabs, though this fact could be biased by the incidence of both events in SLE patients. To sum up, in the particular population studied, there is no direct relationship between anti-Ro/SS-A Aabs and CP, which is in agreement with some authors and in disagreement with many others, contributing to the endless discussion of this issue. [ABSTRACT FROM AUTHOR]

Non-organ-specific autoantibodies (NOSAs) are frequently found in patients with hepatitis C virus (HCV) chronic infection. Genetics is likely involved in the development of autoimmune reactivities, and differences in the prevalence of HCV-related autoantibodies among populations of various geographic areas should be expected. We evaluated the prevalence and the clinical impact of NOSAs in a series of HCV-infected patients from southern Italy. We studied 283 consecutive anti-HCV positive patients (162 men, 121 women, mean age 54.5 +/- 13.5 years), 94 of whom were cirrhotics and 189 noncirrhotics. Serum from each patient and from 41 hepatitis B surface antigen (HBsAg)-positive/anti-HCV negative control subjects were tested (dilution 1:40) for autoantibodies by indirect immunofluorescence. Qualitative/quantitative HCV-RNA determinations were also performed. The prevalence of NOSAs was significantly higher in anti-HCV-positive subjects than in HBsAg-positive patients (P < 0.006). Autoantibodies were significantly associated with both cirrhosis (P < 0.0001) and older age (P < 0.05). No significant association between NOSAs and either female gender or virological parameters (HCV-RNA positivity, viral load, and genotype) was found. In conclusion, the autoantibody positivity in HCV-infected patients from southern Italy is significantly related to cirrhosis and older age, although its general prevalence is similar to that reported in populations from the north of the country. [ABSTRACT FROM AUTHOR]

Autoimmune diseases arise from a host's immune response against self-antigens. The triggering events ultimately resulting in such a break of tolerance are largely unknown. It is also not known why certain molecular structures become autoantigenic. The hypothesis has long been proposed that autoimmune diseases arise from molecular mimicry followed by an epitope spreading mechanism. Recently we have shown that the anti-centromere-associated protein A (CENP-A) immune response is directed against an autoantigenic motif, G/A-P-R/S-R-R, that occurs three times in the N-terminal amino acids of CENP-A. In the present study we used mutational analyses with immobilized oligopeptide arrays to identify the amino acids in this motif that are responsible for antibody binding. In particular, we found that surprisingly mimotopes of this motif are present in a vast number of autoantigens and in the Epstein-Barr nuclear antigen 1. With affinity-purified antibodies we show that the antibodies against this motif are polyclonal and cross-react with several autoantigens. However, in these autoantigens this motif often represents a cryptic epitope explaining the obvious conflict between our results and the known high specificity of autoantibodies. The presence of such an ubiquitous structure on autoantigens suggests a novel peptide-driven mechanism for the evolution of autoantibodies. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the clinical significance of anti-nuclear antibodies (ANA) detected in the early stages of rheumatoid arthritis (RA), by a retrospective comparison of the clinical, laboratory, and therapeutic characteristics of patients with or without ANA. The files of 99 longstanding seropositive RA patients were reviewed. Data relating to demographics, medical history, family history, physical findings, extra-articular complications, laboratory tests, drugs [dosage, duration, efficacy, combinations, adverse effects (AEs)], intra-articular injections, and surgery were recorded. Patients with or without ANA at presentation of their disease were compared using chi-square and t-tests. Fifty-two ANA positive (group 1) and 47 ANA negative (group 2) patients were enrolled in the study. All were comparable in terms of their mean age, age at diagnosis, follow-up duration (∼10.5 years), and male:female (M:F) ratio. On admission, pain complaints were more pronounced in group 1 (P = 0.004 in the feet), but the physical findings did not differ. Deformities and nodules developed in similar numbers. Extra-articular complications were evenly distributed; vasculitis, however, was significantly more prevalent in ANA positive (10/52) than in ANA negative (2/47) patients. Thyroid disease was more common in group 2 (10/47 vs 3/52). Laboratory tests (presentation and maximal values) were similar, with the exception of higher anti-DNA (but within normal ranges) and γ-globulin% in group 1. Group 1 used more drugs prior to diagnosis. Corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) were evenly used. Combination therapy, joint injections, and surgery were more prevalent in group 2. AEs to various DMARDs were more common in group 1. Although similar in many aspects, RA patients with ANA tend to present with more pain complaints, a higher risk of vasculitis and AEs relating to use of DMARDs, while those without ANA needed more aggressive therapeutic modalities. [ABSTRACT FROM AUTHOR]

We found anti-nuclear antibodies (ANA) (1 : 20 or higher) in sera from 11 of 16 patients with a diagnosis of the optic-spinal form of multiple sclerosis (OpS-MS) and 13 of 59 patients with other forms of MS (other MS), both rates being significant ( P = 0.0004). Six of the OpS-MS patients had a high level of ANA (1 : 80 or higher), while levels were high in only three of the other MS patients, showing a significant difference ( P = 0.0022). Titres of ANA were significantly higher in OpS-MS patients than in other MS patients ( P < 0.0001). There was no relationship between the presence of ANA and age in OpS-MS patients, while patients with were older than those without high ANA levels among other MS patients. ANA-positive rate and titres were significantly higher in OpS-MS patients than in sex- and age-matched other MS patients. These results support the concept that OpS-MS constitutes a distinct subgroup among patients with a clinical diagnosis of MS and may indicate that systemic dysregulation of the inflammatory or immune response is more common in OpS-MS patients; the possible pathogenetic relevance of ANA-associated vasculopathy to some patients with a clinical diagnosis of OpS-MS should be considered. [ABSTRACT FROM AUTHOR]

A 78-year-old Japanese woman with Sjögren's syndrome complicating immune-mediated aplastic anaemia is described. A diagnosis of aplastic anaemia was made from severe pancytopenia with hypoplastic marrow. Laboratory studies suggested an association of bone marrow suppressive T-lymphocytes with the pathogenesis of aplastic anaemia. Following the administration of mepithiostan and prednisolone, pancytopenia improved gradually. Two years after the onset of aplastic anaemia, Raynaud's phenomenon developed and examinations revealed the existence of keratoconjunctivitis sicca and anti-SSA/Ro and anti-SSB/La antibodies. [ABSTRACT FROM AUTHOR]

Among 340 patients with rheumatic diseases, two cases of chronic destructive monoarthritis of the wrist with anti-SSA/Ro antibodies and rheumatoid factor, were observed for over three years. It is not clear whether these cases represent a specific subset of rheumatoid arthritis (RA) or whether they may progress to diffuse symmetrical destructive polyarthritis typical of RA. Long-term follow-up studies including analysis of autoantibodies will be needed to clarify the characteristics and course of chronic monoarthritis. [ABSTRACT FROM AUTHOR]

In vivo deposits of IgG have previously been demonstrated in the epidermal intercellular area of clinically unaffected skin from 68% of patients with primary Sjögren's syndrome (primary SS). This study compared circulating IgG from patients with primary SS with that from secondary SS in their ability to bind normal human epidermal cells in vitro. We observed a granular pattern of IgG binding to the normal epidermal cell surfaces with 9 of 18 sera from patients with primary SS (50%), 3 of 19 sera from patients with SS secondary to rheumatoid arthritis (16%) ( p=0.025), and none of 24 normal control sera ( p<0.001). In a subsequent analysis of polyethylene glycol separated sera from two normal controls and two primary SS patients, the epidermal IgG binding capacity was found only in the precipitates of the patients. These findings support our previous hypothesis that the in vivo intraepithelial IgG deposits in primary SS patients are due, at least in part, to cell surface-bound immune complexes. [ABSTRACT FROM AUTHOR]