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  1. Article: Interferon and autoantigens: intersection in autoimmunity.

    Antiochos, Brendan / Casciola-Rosen, Livia

    Frontiers in medicine

    2023  Volume 10, Page(s) 1165225

    Abstract: Interferon (IFN) is a key component of the innate immune response. For reasons that remain incompletely understood, the IFN system is upregulated in several rheumatic diseases, particularly those that feature autoantibody production, such as SLE, Sjögren' ...

    Abstract Interferon (IFN) is a key component of the innate immune response. For reasons that remain incompletely understood, the IFN system is upregulated in several rheumatic diseases, particularly those that feature autoantibody production, such as SLE, Sjögren's syndrome, myositis and systemic sclerosis. Interestingly, many of the autoantigens targeted in these diseases are components of the IFN system, representing IFN-stimulated genes (ISGs), pattern recognition receptors (PRRs), and modulators of the IFN response. In this review, we describe features of these IFN-linked proteins that may underlie their status as autoantigens. Note is also made of anti-IFN autoantibodies that have been described in immunodeficiency states.
    Language English
    Publishing date 2023-05-09
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2775999-4
    ISSN 2296-858X
    ISSN 2296-858X
    DOI 10.3389/fmed.2023.1165225
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  2. Article ; Online: Association between anti-SSSCA1 antibodies and cancer in systemic sclerosis.

    Wallwork, Rachel S / Shah, Ami A / Casciola-Rosen, Livia

    Rheumatology (Oxford, England)

    2022  Volume 62, Issue 7, Page(s) 2539–2543

    Abstract: Objective: To define the clinical phenotype of SSc patients with antibodies against Sjogren's syndrome (SS)/scleroderma autoantigen 1 (SSSCA1), and to examine the association between these antibodies and cancer in SSc patients.: Methods: We conducted ...

    Abstract Objective: To define the clinical phenotype of SSc patients with antibodies against Sjogren's syndrome (SS)/scleroderma autoantigen 1 (SSSCA1), and to examine the association between these antibodies and cancer in SSc patients.
    Methods: We conducted a case-control study using data from 209 patients with SSc and cancer, and 205 SSc patients without cancer. All were randomly selected from the Johns Hopkins Scleroderma Center Research Registry. Antibodies against SSSCA1 were assayed by immunoprecipitation of 35S-methionine-labelled protein generated by in vitro transcription and translation. We performed logistic regression analysis to examine the relationship between anti-SSSCA1 antibodies and cancer.
    Results: Among the 414 study patients, 31 (7%) were anti-SSSCA1 antibody positive. Antibody-positive patients were more likely to have severe RP, a lower minimum ejection fraction, a trend towards more severe heart involvement and a lower baseline diffusing capacity of the lungs for carbon monoxide percent predicted than anti-SSSCA1-negative patients. Patients with cancer were significantly more likely to be anti-SSSCA1 positive compared with those without cancer [22/209 (11%) vs 9/205 (4%), respectively; P = 0.018]. Among patients with cancer, there was a trend towards longer cancer-SSc interval in anti-SSSCA1-positive patients compared with anti-SSSCA1-negative patients. Patients with anti-SSSCA1 antibodies had an increased adjusted risk of cancer (odds ratio 2.46, 95% CI 1.06, 5.70) compared with anti-SSSCA1-negative patients.
    Conclusions: These data suggest anti-SSSCA1 antibody status may be of utility as a cancer biomarker in SSc. Anti-SSSCA1-positive patients with SSc may be more likely to have severe Raynaud's and cardiac involvement.
    MeSH term(s) Humans ; Autoantibodies ; Case-Control Studies ; Scleroderma, Systemic ; Immunoprecipitation ; Neoplasms
    Chemical Substances Autoantibodies
    Language English
    Publishing date 2022-11-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1464822-2
    ISSN 1462-0332 ; 1462-0324
    ISSN (online) 1462-0332
    ISSN 1462-0324
    DOI 10.1093/rheumatology/keac614
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  3. Article ; Online: Autoantibodies and Cancer Association: the Case of Systemic Sclerosis and Dermatomyositis.

    Fiorentino, David F / Casciola-Rosen, Livia

    Clinical reviews in allergy & immunology

    2022  Volume 63, Issue 3, Page(s) 330–341

    Abstract: Several rheumatic diseases have a perplexing association with cancer. Unraveling this mysterious connection is likely to provide deeper understanding regarding mechanisms governing the onset of both autoimmunity and cancer immunity, in addition to ... ...

    Abstract Several rheumatic diseases have a perplexing association with cancer. Unraveling this mysterious connection is likely to provide deeper understanding regarding mechanisms governing the onset of both autoimmunity and cancer immunity, in addition to providing clinicians much needed guidance around whom and when to screen for occult malignancy. Systemic sclerosis (scleroderma) and dermatomyositis are two diseases in which the association with internal malignancy is well-described and can be considered as models from which to gain important insights that likely have broader applicability. The past 15 years have witnessed a striking acceleration in understanding how these two diseases are related to cancer emergence-an important crack in this inscrutable armor has been the discovery and characterization of disease-specific autoantigens that are closely tied with risk of cancer emergence. The best-described examples of this are antibodies against anti-RNA polymerase III (anti-POL3) and transcription intermediary factor 1-gamma (anti-TIF1γ). Patients with systemic sclerosis and cancer that are diagnosed within a short time interval of each other frequently have anti-POL3 antibodies. Antibodies against the minor spliceosome protein RNA-Binding Region Containing 3 (RNPC3) are also associated with increased cancer incidence in systemic sclerosis. Similarly, in the dermatomyositis spectrum, the majority of anti-TIF1γ-associated cancers are detected around the time of DM onset (most often within 1 year). Antibodies against Nuclear Matrix Protein 2 are also potentially associated with increased cancer emergence in dermatomyositis. The systemic sclerosis/anti-POL3 connection with close cancer onset led to the first experiments directly supporting the concept that rheumatic disease may in fact be a manifestation of cancer. It is now clear that studying these diseases through the lens of autoantibodies can reveal relationships and insights that would otherwise remain obscured. Extending these studies, new findings show that antibodies against RNA polymerase I large subunit are associated with protection against short interval cancers in anti-POL3-positive systemic sclerosis patients. These insights highlight the fact that autoantigen discovery related to cancer emergence remains an important priority; such new tools will enable the testing of specific hypotheses regarding mechanisms governing disease emergence and development of effective anti-tumor responses. Autoantibody phenotype will likely play an important role in the development of cancer screening guidelines that are critically needed by clinicians taking care of these patients. In this review, we will summarize the current state of knowledge regarding the different ways in which autoantibodies are connected with systemic sclerosis/dermatomyositis and malignancy and highlight potential paths forward.
    MeSH term(s) Humans ; Autoantibodies ; Dermatomyositis/epidemiology ; Scleroderma, Systemic/diagnosis ; Neoplasms/diagnosis ; Neoplasms/epidemiology ; Autoantigens ; Rheumatic Diseases
    Chemical Substances Autoantibodies ; Autoantigens
    Language English
    Publishing date 2022-05-20
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1239045-8
    ISSN 1559-0267 ; 1080-0549
    ISSN (online) 1559-0267
    ISSN 1080-0549
    DOI 10.1007/s12016-022-08944-y
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  4. Article ; Online: Anti-ANP32A antibodies in systemic sclerosis.

    Wallwork, Rachel / Casciola-Rosen, Livia / Shah, Ami A

    Annals of the rheumatic diseases

    2021  Volume 81, Issue 2, Page(s) 301–302

    MeSH term(s) Adult ; Aged ; Autoantibodies/immunology ; Autoantigens/immunology ; Carcinoma, Squamous Cell/immunology ; Female ; Humans ; Male ; Middle Aged ; Nuclear Proteins/immunology ; RNA-Binding Proteins/immunology ; Scleroderma, Systemic/complications ; Scleroderma, Systemic/immunology ; Skin Neoplasms/immunology
    Chemical Substances ANP32A protein, human ; Autoantibodies ; Autoantigens ; Nuclear Proteins ; RNA-Binding Proteins
    Language English
    Publishing date 2021-10-25
    Publishing country England
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 7090-7
    ISSN 1468-2060 ; 0003-4967
    ISSN (online) 1468-2060
    ISSN 0003-4967
    DOI 10.1136/annrheumdis-2021-221354
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  5. Article ; Online: Cessation of Immunomodulatory Medication Use in Dermatomyositis: A Single-Center Cohort Study.

    Cho, Sung Kyung / Casciola-Rosen, Livia / Kapoor, Puneet / Chung, Lorinda / Fiorentino, David

    Arthritis care & research

    2023  Volume 75, Issue 6, Page(s) 1376–1381

    Abstract: Objective: To determine the frequency with which adults with dermatomyositis (DM) are able to discontinue systemic immunomodulatory therapy and factors associated with medication cessation.: Methods: We studied a cohort of adult DM patients seen in a ...

    Abstract Objective: To determine the frequency with which adults with dermatomyositis (DM) are able to discontinue systemic immunomodulatory therapy and factors associated with medication cessation.
    Methods: We studied a cohort of adult DM patients seen in a rheumatology/dermatology clinic between 2013 and 2020. All patients had exposure to at least 1 systemic immunomodulatory medication for a minimum of 3 months and were followed until medications were discontinued for at least 12 months. Survival analysis was performed using Kaplan-Meier curves with log-rank analyses, and multivariate analysis was done using Cox proportional hazards models.
    Results: A total of 246 DM patients were followed up for a median time of ∼7 years (47-134 months). Forty-seven patients (19%) discontinued all immunomodulatory medications with a median follow-up of ∼3 years (interquartile range 22-108 months) following DM onset. Log-rank analysis demonstrated that those with anti-MDA5 autoantibodies discontinued medications faster compared with those without autoantibodies (P = 0.03). Multivariate modeling showed that clinically amyopathic patients were 2.7-fold (95% confidence interval [95% CI] 1.34-5.59) more likely to discontinue medications than those with muscle disease. Those with anti-MDA5, anti-NXP2, and anti-SAE1 antibodies had increased likelihood of medication cessation with hazard ratios of 9.83 (95% CI 2.00-48.2), 8.92 (95% CI 1.69-47.0), and 10.8 (95% CI 2.06-56.6), respectively, when compared with the autoantibody-negative group.
    Conclusion: Approximately 20% of adult DM patients discontinued immunomodulatory medications over a median 7-year follow-up. Those with clinically amyopathic disease, anti-MDA5, anti-NXP2, and anti-SAE1 antibodies have a higher likelihood of medication cessation.
    MeSH term(s) Adult ; Humans ; Dermatomyositis/diagnosis ; Dermatomyositis/drug therapy ; Cohort Studies ; Interferon-Induced Helicase, IFIH1 ; Lung Diseases, Interstitial ; Autoantibodies
    Chemical Substances Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13) ; Autoantibodies
    Language English
    Publishing date 2023-01-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 645059-3
    ISSN 2151-4658 ; 0893-7524 ; 2151-464X
    ISSN (online) 2151-4658
    ISSN 0893-7524 ; 2151-464X
    DOI 10.1002/acr.24980
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  6. Article ; Online: Cancer and Scleroderma.

    Weeding, Emma / Casciola-Rosen, Livia / Shah, Ami A

    Rheumatic diseases clinics of North America

    2020  Volume 46, Issue 3, Page(s) 551–564

    Abstract: Individuals with scleroderma have an increased risk of cancer compared with the general population. This heightened risk may be from chronic inflammation and tissue damage, malignant transformation provoked by immunosuppressive therapies, or a common ... ...

    Abstract Individuals with scleroderma have an increased risk of cancer compared with the general population. This heightened risk may be from chronic inflammation and tissue damage, malignant transformation provoked by immunosuppressive therapies, or a common inciting factor. In unique subsets of patients with scleroderma, there is a close temporal relationship between the onset of cancer and scleroderma, suggesting cancer-induced autoimmunity. This article discusses the potential mechanistic links between cancer and scleroderma, the serologic and clinical risk factors associated with increased cancer risk in patients with scleroderma, and implications for cancer screening.
    MeSH term(s) Early Detection of Cancer ; Humans ; Neoplasms/complications ; Neoplasms/diagnosis ; Neoplasms/immunology ; Neoplasms/physiopathology ; Scleroderma, Systemic/complications ; Scleroderma, Systemic/epidemiology ; Scleroderma, Systemic/immunology
    Language English
    Publishing date 2020-06-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 92118-x
    ISSN 1558-3163 ; 0889-857X
    ISSN (online) 1558-3163
    ISSN 0889-857X
    DOI 10.1016/j.rdc.2020.03.002
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  7. Article: Advances at the Interface of Cancer and Systemic Sclerosis.

    Mecoli, Christopher A / Rosen, Antony / Casciola-Rosen, Livia / Shah, Ami A

    Journal of scleroderma and related disorders

    2020  Volume 6, Issue 1, Page(s) 50–57

    Abstract: The interface between systemic sclerosis (SSc) and cancer has offered valuable insights into our understanding of SSc disease pathogenesis. Defining SSc subgroups both temporally and serologically has been instrumental in stratifying cancer risk, with ... ...

    Abstract The interface between systemic sclerosis (SSc) and cancer has offered valuable insights into our understanding of SSc disease pathogenesis. Defining SSc subgroups both temporally and serologically has been instrumental in stratifying cancer risk, with autoantibodies to RNA polymerase 3 (RNApol3), RNA polymerase I large subunit (RPA194), RNA Binding Region Containing 3 (RNPC3), and centromere identifying subgroups at increased or decreased risk of cancer. Clinically, improved subgrouping of SSc patients provides the opportunity to detect cancer at earlier stages of disease while increasing our efficiency of cancer assessment. Additional studies are needed to define the optimal approach to cancer screening in SSc, and validation studies in different cohorts will be needed to confirm all findings.
    Language English
    Publishing date 2020-03-17
    Publishing country England
    Document type Journal Article
    ISSN 2397-1983
    ISSN 2397-1983
    DOI 10.1177/2397198320905983
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  8. Article: Autoantibodies in post-treatment Lyme disease and association with clinical symptoms.

    Keshtkarjahromi, Marzieh / Rebman, Alison W / Antar, Annukka A R / Manabe, Yukari C / Gutierrez-Alamillo, Laura / Casciola-Rosen, Livia A / Aucott, John N / Miller, John B

    Clinical and experimental rheumatology

    2024  

    Abstract: Objectives: Autoantibodies have been described in the post-infectious state, specifically after Lyme disease and COVID-19. We aimed to describe the prevalence and potential clinical utility of several commercially available autoantibodies after these ... ...

    Abstract Objectives: Autoantibodies have been described in the post-infectious state, specifically after Lyme disease and COVID-19. We aimed to describe the prevalence and potential clinical utility of several commercially available autoantibodies after these infections.
    Methods: Euroimmun panels (myositis, scleroderma and ANA5) were assayed using sera from patients with Lyme disease with return to health (RTH) (n=70), post-treatment Lyme disease (n=58), COVID-19 RTH (n=47) and post-acute symptoms of COVID-19 (n=22). The post-Lyme questionnaire of symptoms (PLQS) was used to determine symptom burden after Lyme disease.
    Results: There was no statistically significant difference in autoantibody prevalence across the four groups (p=0.746). A total of 21 different antibodies were found in the Lyme cohorts and 8 different antibodies in the COVID-19 cohorts. The prevalence of scleroderma-associated antibodies was higher after Lyme disease than COVID-19 (12.5% vs. 2.9%, p=0.026). There was no statistically significant difference in symptom burden based on antibody status.
    Conclusions: Several autoantibodies were found after Borrelia burgdorferi and SARS-CoV2 infection, although the prevalence was similar in those with persistent symptoms and those who returned to health. While our data show no difference in autoantibody prevalence across the four post-infectious states, we do not imply that autoantibodies are irrelevant in this setting. Rather, this study highlights the need for novel antibody discovery in larger cohorts of well-defined patient populations.
    Language English
    Publishing date 2024-04-05
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 605886-3
    ISSN 1593-098X ; 0392-856X
    ISSN (online) 1593-098X
    ISSN 0392-856X
    DOI 10.55563/clinexprheumatol/qcupkk
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  9. Article ; Online: Clinical Features and Immunogenetic Risk Factors Associated With Additional Autoantibodies in Anti-Transcriptional Intermediary Factor 1γ Juvenile-Onset Dermatomyositis.

    Sherman, Matthew A / Yang, Qingyuan / Gutierrez-Alamillo, Laura / Pak, Katherine / Flegel, Willy A / Mammen, Andrew L / Rider, Lisa G / Casciola-Rosen, Livia A

    Arthritis & rheumatology (Hoboken, N.J.)

    2024  Volume 76, Issue 4, Page(s) 631–637

    Abstract: Objective: Novel autoantibody specificities including anti-CCAR1 were recently discovered in adult patients with anti-transcriptional intermediary factor (TIF1)-positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims ...

    Abstract Objective: Novel autoantibody specificities including anti-CCAR1 were recently discovered in adult patients with anti-transcriptional intermediary factor (TIF1)-positive dermatomyositis (DM) and were associated with attenuated cancer emergence. The aims of the present study were to examine whether these autoantibodies occur in patients with juvenile-onset DM (JDM) and to determine their associated features.
    Methods: Sera from 150 patients with anti-TIF1γ autoantibody-positive JDM in a cross-sectional cohort and 90 juvenile healthy controls were assayed for anti-CCAR1, anti-C1Z1, anti-IMMT, anti-TBL1XR1, and anti-Sp4 autoantibodies. Demographics, myositis autoantibodies, clinical features, medications, outcomes, and HLA-DRB1 and HLA-DQA1 alleles were compared between those with and without these autoantibodies.
    Results: Any one of the anti-TIF1γ-associated autoantibodies was present in 44 patients (29%) overall, including 25 (17%) with anti-Sp4, 22 (15%) with anti-TBL1XR1, 14 (9%) with anti-CCAR1, 2 (1%) with anti-C1Z1, and 2 (1%) with anti-IMMT autoantibodies. These anti-TIF1γ-associated autoantibodies frequently co-occurred. Patients with any of the anti-TIF1γ-associated autoantibodies had less frequent falling (34% [15] vs. 53% [56], P = 0.032) and lower peak muscle enzymes. None of the patients had cancer. Among White patients, HLA-DRB1*03 was protective against an anti-TIF1γ-associated autoantibody (odds ratio 0.20, 95% confidence interval 0.07-0.52).
    Conclusion: Autoantibodies associated with anti-TIF1γ were found in isolation and in combination among a subset of patients with JDM. Patients with these autoantibodies had less severe muscle disease and were not enriched for HLA-DRB1*03. Additional autoantibodies among patients with positive anti-TIF1γ with JDM likely contribute to the heterogeneity of the anti-TIF1γ serologic subgroup.
    MeSH term(s) Adult ; Humans ; Dermatomyositis ; Mediation Analysis ; HLA-DRB1 Chains ; Autoantibodies ; Cross-Sectional Studies ; Immunogenetics ; Risk Factors ; Neoplasms
    Chemical Substances HLA-DRB1 Chains ; Autoantibodies
    Language English
    Publishing date 2024-01-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2756371-6
    ISSN 2326-5205 ; 2326-5191
    ISSN (online) 2326-5205
    ISSN 2326-5191
    DOI 10.1002/art.42768
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  10. Article ; Online: A Bayesian approach to restricted latent class models for scientifically structured clustering of multivariate binary outcomes.

    Wu, Zhenke / Casciola-Rosen, Livia / Rosen, Antony / Zeger, Scott L

    Biometrics

    2020  Volume 77, Issue 4, Page(s) 1431–1444

    Abstract: This paper presents a model-based method for clustering multivariate binary observations that incorporates constraints consistent with the scientific context. The approach is motivated by the precision medicine problem of identifying autoimmune disease ... ...

    Abstract This paper presents a model-based method for clustering multivariate binary observations that incorporates constraints consistent with the scientific context. The approach is motivated by the precision medicine problem of identifying autoimmune disease patient subsets or classes who may require different treatments. We start with a family of restricted latent class models or RLCMs. However, in the motivating example and many others like it, the unknown number of classes and the definition of classes using binary states are among the targets of inference. We use a Bayesian approach to RLCMs in order to use informative prior assumptions on the number and definitions of latent classes to be consistent with scientific knowledge so that the posterior distribution tends to concentrate on smaller numbers of clusters and sparser binary patterns. The paper derives a posterior sampling algorithm based on Markov chain Monte Carlo with split-merge updates to efficiently explore the space of clustering allocations. Through simulations under the assumed model and realistic deviations from it, we demonstrate greater interpretability of results and superior finite-sample clustering performance for our method compared to common alternatives. The methods are illustrated with an analysis of protein data to detect clusters representing autoantibody classes among scleroderma patients.
    MeSH term(s) Bayes Theorem ; Cluster Analysis ; Humans ; Latent Class Analysis ; Markov Chains ; Models, Statistical ; Monte Carlo Method
    Language English
    Publishing date 2020-10-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 213543-7
    ISSN 1541-0420 ; 0099-4987 ; 0006-341X
    ISSN (online) 1541-0420
    ISSN 0099-4987 ; 0006-341X
    DOI 10.1111/biom.13388
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