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Sindhu R. Johnson - One of the best experts on this subject based on the ideXlab platform.
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serological abnormalities that predict progression to systemic Autoimmune Rheumatic Diseases in antinuclear antibody positive individuals
Rheumatology, 2021Co-Authors: Sindhu R. Johnson, Carolina Munozgrajales, Stephenie D Prokopec, Zahi Touma, Zareen Ahmad, Dennisse BonillaAbstract:Objective We investigated the auto-antibody (auto-Ab) profiles in anti-nuclear antibody-positive (ANA+) individuals lacking Systemic Autoimmune Rheumatic Disease (SARD) and early SARD patients, to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next two years in ANA+ individuals. Methods Using custom antigen (Ag) microarrays, 144 IgM and IgG auto-Abs were surveyed in 84 asymptomatic and 123 symptomatic (48 undifferentiated connective tissue Disease (UCTD) and 75 SARD patients) ANA+ individuals. Auto-Ab were compared in ANA+ individuals lacking a SARD diagnosis with ≥ 2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset. Results We show that ANA+ individuals have auto-Ab to many self-Ag that are not being captured by current screening techniques and very high levels of these auto-Abs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more auto-Ags than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of auto-Ab. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years follow-up the levels of auto-Ab remained remarkably stable regardless of whether individuals progressed or not. Conclusion Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of auto-Ab testing.
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the presence of anti nuclear antibodies alone is associated with changes in b cell activation and t follicular helper cells similar to those in systemic Autoimmune Rheumatic Disease
Arthritis Research & Therapy, 2018Co-Authors: Sindhu R. Johnson, Nan-hua Chang, Yuriy Baglaenko, Waleed Hafiz, Dario Ferri, Kieran P Manion, Babak NoamaniAbstract:Diagnosis of systemic Autoimmune Rheumatic Diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue Disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.
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The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic Autoimmune Rheumatic Disease
BMC, 2018Co-Authors: Yuriy Baglaenko, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Nan-hua Chang, Waleed Hafiz, Kieran Manion, Dario Ferri, Sina Rusta-sellehy, Larissa LisnevskaiaAbstract:Abstract Background Diagnosis of systemic Autoimmune Rheumatic Diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue Disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD
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presence of an interferon signature in individuals who are anti nuclear antibody positive lacking a systemic Autoimmune Rheumatic Disease diagnosis
Arthritis Research & Therapy, 2017Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Tony Liu, Carolina LandoltmarticorenaAbstract:Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic Autoimmune Rheumatic Diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue Disease (UCTD) to address this question. Healthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. The mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. An IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.
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development sensibility and validity of a systemic Autoimmune Rheumatic Disease case ascertainment tool
The Journal of Rheumatology, 2017Co-Authors: Susan M Armstrong, Joan E. Wither, Alan M Borowoy, Carolina Landoltmarticorena, Aileen M Davis, Sindhu R. JohnsonAbstract:Objective Case ascertainment through self-report is a convenient but often inaccurate method to collect information. The purposes of this study were to develop, assess the sensibility, and validate a tool to identify cases of systemic Autoimmune Rheumatic Diseases (SARD) in the outpatient setting. Methods The SARD tool was administered to subjects sampled from specialty clinics. Determinants of sensibility — comprehensibility, feasibility, validity, and acceptability — were evaluated using a numeric rating scale from 1–7. Comprehensibility was evaluated using the Flesch Reading Ease and the Flesch-Kincaid Grade Level. Self-reported diagnoses were validated against medical records using Cohen’s κ statistic. Results There were 141 participants [systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis, Sjogren syndrome (SS), inflammatory myositis (polymyositis/dermatomyositis; PM/DM), and controls] who completed the questionnaire. The Flesch Reading Ease score was 77.1 and the Flesch-Kincaid Grade Level was 4.4. Respondents endorsed (mean ± SD) comprehensibility (6.12 ± 0.92), feasibility (5.94 ± 0.81), validity (5.35 ± 1.10), and acceptability (3.10 ± 2.03). The SARD tool had a sensitivity of 0.91 (95% CI 0.88–0.94) and a specificity of 0.99 (95% CI 0.96–1.00). The agreement between the SARD tool and medical record was κ = 0.82 (95% CI 0.77–0.88). Subgroup analysis by SARD found κ coefficients for SLE to be κ = 0.88 (95% CI 0.79–0.97), SSc k = 1.0 (95% CI 1.0–1.0), PM/DM κ = 0.72 (95% CI 0.49–0.95), and SS κ = 0.85 (95% CI 0.71–0.99). The screening questions had sensitivity ranging from 0.96 to 1.0 and specificity ranging from 0.88 to 1.0. Conclusion This SARD case ascertainment tool has demonstrable sensibility and validity. The use of both screening and confirmatory questions confers added accuracy.
Dennisse Bonilla - One of the best experts on this subject based on the ideXlab platform.
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serological abnormalities that predict progression to systemic Autoimmune Rheumatic Diseases in antinuclear antibody positive individuals
Rheumatology, 2021Co-Authors: Sindhu R. Johnson, Carolina Munozgrajales, Stephenie D Prokopec, Zahi Touma, Zareen Ahmad, Dennisse BonillaAbstract:Objective We investigated the auto-antibody (auto-Ab) profiles in anti-nuclear antibody-positive (ANA+) individuals lacking Systemic Autoimmune Rheumatic Disease (SARD) and early SARD patients, to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next two years in ANA+ individuals. Methods Using custom antigen (Ag) microarrays, 144 IgM and IgG auto-Abs were surveyed in 84 asymptomatic and 123 symptomatic (48 undifferentiated connective tissue Disease (UCTD) and 75 SARD patients) ANA+ individuals. Auto-Ab were compared in ANA+ individuals lacking a SARD diagnosis with ≥ 2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset. Results We show that ANA+ individuals have auto-Ab to many self-Ag that are not being captured by current screening techniques and very high levels of these auto-Abs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more auto-Ags than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of auto-Ab. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years follow-up the levels of auto-Ab remained remarkably stable regardless of whether individuals progressed or not. Conclusion Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of auto-Ab testing.
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The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic Autoimmune Rheumatic Disease
BMC, 2018Co-Authors: Yuriy Baglaenko, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Nan-hua Chang, Waleed Hafiz, Kieran Manion, Dario Ferri, Sina Rusta-sellehy, Larissa LisnevskaiaAbstract:Abstract Background Diagnosis of systemic Autoimmune Rheumatic Diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue Disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD
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presence of an interferon signature in individuals who are anti nuclear antibody positive lacking a systemic Autoimmune Rheumatic Disease diagnosis
Arthritis Research & Therapy, 2017Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Tony Liu, Carolina LandoltmarticorenaAbstract:Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic Autoimmune Rheumatic Diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue Disease (UCTD) to address this question. Healthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. The mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. An IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.
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AI-08 B cell phenotypic changes in anti-nuclear antibody positive individuals prior to the onset of systemic Autoimmune Rheumatic Disease
Lupus science & medicine, 2016Co-Authors: Joan E. Wither, Nan Chang, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Carolina Landolt-marticorenaAbstract:Background Patients with systemic Autoimmune Rheumatic Diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)+ but lack clinical symptoms. Here we sought to determine whether ANA+ individuals who lack sufficient symptoms for a SARD diagnosis share the B cell phenotypic changes seen in SARD. Materials and methods Healthy controls (HC) and ANA+ individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were stained with various combinations of fluorescently labelled antibodies and analysed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets including: increased proportions of mature naive (SSc) and T1T2 cells (SLE and SS), and decreased proportions of switched memory cells (all SARD). Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27-IgD- memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138+ plasma cells were seen in early SARD patients, these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets and ANA titer as well as the number of different anti-nuclear antibody specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical Disease in ANA+ individuals and have a pattern suggesting ongoing activation through T-B collaboration.
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THU0265 B Cell Phenotypic Changes in anti-Nuclear Antibody Positive Individuals Prior To The Onset of Systemic Autoimmune Rheumatic Disease
Annals of the Rheumatic Diseases, 2016Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Nan-hua Chang, Carolina Landolt-marticorenaAbstract:Background Patients with systemic Autoimmune Rheumatic Diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA) + but lack clinical symptoms. It has been proposed that progression from asymptomatic autoimmunity to clinical Disease is accompanied by immunologic changes that could be used as predictors of Disease development. Previous studies indicate that a number of B cell phenotypic changes are seen in SARD patients including changes in the proportions of various naive and memory B cell subsets, increased B cell activation and elevated levels of plasmablasts/plasma cells. Objectives To determine whether ANA + individuals who lack sufficient symptoms for a SARD diagnosis have B cell phenotypic changes similar to those seen in SARD. Methods Healthy controls (HC) and ANA + individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had a recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were isolated over a Ficoll gradient, stained with various combinations of fluorescently labeled antibodies and analyzed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD (24 SS, 26 SSc, 6 SLE, 2 MCTD, 1 DM) patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets, as previously reported for patients with established Disease, including: increased proportions of mature naive B cells (SSc); increased proportions of T1T2 cells (SLE and SS); and trends to decreased proportions of switched memory B cells (CD27 + IgD – ) in all SARD. Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27 – IgD – memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138 + plasma cells were seen in all SARD patients (except those with SSc), these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets, as well as the proportion of T1T2 cells, and ANA titer and the number of different anti-nuclear antibodies specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical Disease in ANA + individuals and have a pattern suggesting ongoing activation through T-B collaboration. Disclosure of Interest None declared
Babak Noamani - One of the best experts on this subject based on the ideXlab platform.
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the presence of anti nuclear antibodies alone is associated with changes in b cell activation and t follicular helper cells similar to those in systemic Autoimmune Rheumatic Disease
Arthritis Research & Therapy, 2018Co-Authors: Sindhu R. Johnson, Nan-hua Chang, Yuriy Baglaenko, Waleed Hafiz, Dario Ferri, Kieran P Manion, Babak NoamaniAbstract:Diagnosis of systemic Autoimmune Rheumatic Diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue Disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.
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The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic Autoimmune Rheumatic Disease
BMC, 2018Co-Authors: Yuriy Baglaenko, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Nan-hua Chang, Waleed Hafiz, Kieran Manion, Dario Ferri, Sina Rusta-sellehy, Larissa LisnevskaiaAbstract:Abstract Background Diagnosis of systemic Autoimmune Rheumatic Diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue Disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD
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presence of an interferon signature in individuals who are anti nuclear antibody positive lacking a systemic Autoimmune Rheumatic Disease diagnosis
Arthritis Research & Therapy, 2017Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Tony Liu, Carolina LandoltmarticorenaAbstract:Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic Autoimmune Rheumatic Diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue Disease (UCTD) to address this question. Healthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. The mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. An IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.
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AI-08 B cell phenotypic changes in anti-nuclear antibody positive individuals prior to the onset of systemic Autoimmune Rheumatic Disease
Lupus science & medicine, 2016Co-Authors: Joan E. Wither, Nan Chang, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Carolina Landolt-marticorenaAbstract:Background Patients with systemic Autoimmune Rheumatic Diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)+ but lack clinical symptoms. Here we sought to determine whether ANA+ individuals who lack sufficient symptoms for a SARD diagnosis share the B cell phenotypic changes seen in SARD. Materials and methods Healthy controls (HC) and ANA+ individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were stained with various combinations of fluorescently labelled antibodies and analysed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets including: increased proportions of mature naive (SSc) and T1T2 cells (SLE and SS), and decreased proportions of switched memory cells (all SARD). Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27-IgD- memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138+ plasma cells were seen in early SARD patients, these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets and ANA titer as well as the number of different anti-nuclear antibody specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical Disease in ANA+ individuals and have a pattern suggesting ongoing activation through T-B collaboration.
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THU0265 B Cell Phenotypic Changes in anti-Nuclear Antibody Positive Individuals Prior To The Onset of Systemic Autoimmune Rheumatic Disease
Annals of the Rheumatic Diseases, 2016Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Nan-hua Chang, Carolina Landolt-marticorenaAbstract:Background Patients with systemic Autoimmune Rheumatic Diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA) + but lack clinical symptoms. It has been proposed that progression from asymptomatic autoimmunity to clinical Disease is accompanied by immunologic changes that could be used as predictors of Disease development. Previous studies indicate that a number of B cell phenotypic changes are seen in SARD patients including changes in the proportions of various naive and memory B cell subsets, increased B cell activation and elevated levels of plasmablasts/plasma cells. Objectives To determine whether ANA + individuals who lack sufficient symptoms for a SARD diagnosis have B cell phenotypic changes similar to those seen in SARD. Methods Healthy controls (HC) and ANA + individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had a recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were isolated over a Ficoll gradient, stained with various combinations of fluorescently labeled antibodies and analyzed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD (24 SS, 26 SSc, 6 SLE, 2 MCTD, 1 DM) patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets, as previously reported for patients with established Disease, including: increased proportions of mature naive B cells (SSc); increased proportions of T1T2 cells (SLE and SS); and trends to decreased proportions of switched memory B cells (CD27 + IgD – ) in all SARD. Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27 – IgD – memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138 + plasma cells were seen in all SARD patients (except those with SSc), these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets, as well as the proportion of T1T2 cells, and ANA titer and the number of different anti-nuclear antibodies specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical Disease in ANA + individuals and have a pattern suggesting ongoing activation through T-B collaboration. Disclosure of Interest None declared
Marie Hudson - One of the best experts on this subject based on the ideXlab platform.
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fine particulate air pollution and systemic Autoimmune Rheumatic Disease in two canadian provinces
Environmental Research, 2016Co-Authors: Cheryl Barnabe, Marie Hudson, Sasha Bernatsky, Audrey Smargiassi, Lawrence W Svenson, Allan Brand, Randall V MartinAbstract:Abstract Objective To estimate the degree to which fine particulate (PM2.5) air pollution is associated with systemic Autoimmune Rheumatic Diseases (SARDs). Methods We used population-based administrative data from Alberta (1993–2007) and Quebec (1989–2011). SARD algorithms included ≥2 physician billing codes, or ≥1 rheumatology billing code, or ≥1 hospitalization diagnostic code (for systemic lupus, Sjogren's Syndrome, scleroderma, polymyositis, dermatomyositis, or undifferentiated connective tissue Disease). Bayesian hierarchical latent class regression models estimated the probability that any given resident was a SARD case, based on the algorithms. Mean 2001–2006 residential ambient PM2.5 levels were assigned using satellite-derived data for dissemination area regions in Alberta and CLSC regions in Quebec. The sum of individual level probabilities provided the estimated total cases per region in each province, according to age, sex, urban-versus-rural residence, income, and PM2.5 levels. In Alberta, we ran separate models for First-Nations (FN) and non-First Nations subgroups. Bayesian logistic regression modeling generated odds ratio (OR) estimates for being a SARD case, accounting concurrently for demographics, as well as an interaction term between age and sex. Results Our data suggested that the probability of being a SARD case was higher among females versus males and for residents aged >45 versus younger, with the highest ORs for older females. Independently, the odds of being a SARDs case increased with PM2.5 levels in both provinces. Conclusion Our data suggest that PM2.5 exposure may be associated with an increased risk of SARDs.
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fine particulate air pollution nitrogen dioxide and systemic Autoimmune Rheumatic Disease in calgary alberta
Environmental Research, 2015Co-Authors: Cheryl Barnabe, Sasha Bernatsky, Audrey Smargiassi, Lawrence W Svenson, Allan Brand, Markey Johnson, Gilaad G Kaplan, Stefania Bertazzon, Marie HudsonAbstract:Objective To estimate the association between fine particulate (PM2.5) and nitrogen dioxide (NO2) pollution and systemic Autoimmune Rheumatic Diseases (SARDs).
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systemic Autoimmune Rheumatic Disease prevalence in canada updated analyses across 7 provinces
The Journal of Rheumatology, 2014Co-Authors: Laurel Broten, Antonio J Avinazubieta, Diane Lacaille, L Joseph, John G Hanly, Lisa M Lix, Siobhan Odonnell, Cheryl Barnabe, Paul R Fortin, Marie HudsonAbstract:Objective. To estimate systemic Autoimmune Rheumatic Disease (SARD) prevalence across 7 Canadian provinces using population-based administrative data evaluating both regional variations and the effects of age and sex. Methods. Using provincial physician billing and hospitalization data, cases of SARD (systemic lupus erythematosus, scleroderma, primary Sjogren syndrome, polymyositis/dermatomyositis) were ascertained. Three case definitions (rheumatology billing, 2-code physician billing, and hospital diagnosis) were combined to derive a SARD prevalence estimate for each province, categorized by age, sex, and rural/urban status. A hierarchical Bayesian latent class regression model was fit to account for the imperfect sensitivity and specificity of each case definition. The model also provided sensitivity estimates of different case definition approaches. Results. Prevalence estimates for overall SARD ranged between 2 and 5 cases per 1000 residents across provinces. Similar demographic trends were evident across provinces, with greater prevalence in women and in persons over 45 years old. SARD prevalence in women over 45 was close to 1%. Overall sensitivity was poor, but estimates for each of the 3 case definitions improved within older populations and were slightly higher for men compared to women. Conclusion. Our results are consistent with previous estimates and other North American findings, and provide results from coast to coast, as well as useful information about the degree of regional and demographic variations that can be seen within a single country. Our work demonstrates the usefulness of using multiple data sources, adjusting for the error in each, and providing estimates of the sensitivity of different case definition approaches.
Joan E. Wither - One of the best experts on this subject based on the ideXlab platform.
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presence of an interferon signature in individuals who are anti nuclear antibody positive lacking a systemic Autoimmune Rheumatic Disease diagnosis
Arthritis Research & Therapy, 2017Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Tony Liu, Carolina LandoltmarticorenaAbstract:Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic Autoimmune Rheumatic Diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue Disease (UCTD) to address this question. Healthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. The mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. An IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.
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development sensibility and validity of a systemic Autoimmune Rheumatic Disease case ascertainment tool
The Journal of Rheumatology, 2017Co-Authors: Susan M Armstrong, Joan E. Wither, Alan M Borowoy, Carolina Landoltmarticorena, Aileen M Davis, Sindhu R. JohnsonAbstract:Objective Case ascertainment through self-report is a convenient but often inaccurate method to collect information. The purposes of this study were to develop, assess the sensibility, and validate a tool to identify cases of systemic Autoimmune Rheumatic Diseases (SARD) in the outpatient setting. Methods The SARD tool was administered to subjects sampled from specialty clinics. Determinants of sensibility — comprehensibility, feasibility, validity, and acceptability — were evaluated using a numeric rating scale from 1–7. Comprehensibility was evaluated using the Flesch Reading Ease and the Flesch-Kincaid Grade Level. Self-reported diagnoses were validated against medical records using Cohen’s κ statistic. Results There were 141 participants [systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis, Sjogren syndrome (SS), inflammatory myositis (polymyositis/dermatomyositis; PM/DM), and controls] who completed the questionnaire. The Flesch Reading Ease score was 77.1 and the Flesch-Kincaid Grade Level was 4.4. Respondents endorsed (mean ± SD) comprehensibility (6.12 ± 0.92), feasibility (5.94 ± 0.81), validity (5.35 ± 1.10), and acceptability (3.10 ± 2.03). The SARD tool had a sensitivity of 0.91 (95% CI 0.88–0.94) and a specificity of 0.99 (95% CI 0.96–1.00). The agreement between the SARD tool and medical record was κ = 0.82 (95% CI 0.77–0.88). Subgroup analysis by SARD found κ coefficients for SLE to be κ = 0.88 (95% CI 0.79–0.97), SSc k = 1.0 (95% CI 1.0–1.0), PM/DM κ = 0.72 (95% CI 0.49–0.95), and SS κ = 0.85 (95% CI 0.71–0.99). The screening questions had sensitivity ranging from 0.96 to 1.0 and specificity ranging from 0.88 to 1.0. Conclusion This SARD case ascertainment tool has demonstrable sensibility and validity. The use of both screening and confirmatory questions confers added accuracy.
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AI-08 B cell phenotypic changes in anti-nuclear antibody positive individuals prior to the onset of systemic Autoimmune Rheumatic Disease
Lupus science & medicine, 2016Co-Authors: Joan E. Wither, Nan Chang, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Carolina Landolt-marticorenaAbstract:Background Patients with systemic Autoimmune Rheumatic Diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)+ but lack clinical symptoms. Here we sought to determine whether ANA+ individuals who lack sufficient symptoms for a SARD diagnosis share the B cell phenotypic changes seen in SARD. Materials and methods Healthy controls (HC) and ANA+ individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were stained with various combinations of fluorescently labelled antibodies and analysed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets including: increased proportions of mature naive (SSc) and T1T2 cells (SLE and SS), and decreased proportions of switched memory cells (all SARD). Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27-IgD- memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138+ plasma cells were seen in early SARD patients, these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets and ANA titer as well as the number of different anti-nuclear antibody specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical Disease in ANA+ individuals and have a pattern suggesting ongoing activation through T-B collaboration.
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THU0265 B Cell Phenotypic Changes in anti-Nuclear Antibody Positive Individuals Prior To The Onset of Systemic Autoimmune Rheumatic Disease
Annals of the Rheumatic Diseases, 2016Co-Authors: Joan E. Wither, Babak Noamani, Dennisse Bonilla, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Arthur Bookman, Nan-hua Chang, Carolina Landolt-marticorenaAbstract:Background Patients with systemic Autoimmune Rheumatic Diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA) + but lack clinical symptoms. It has been proposed that progression from asymptomatic autoimmunity to clinical Disease is accompanied by immunologic changes that could be used as predictors of Disease development. Previous studies indicate that a number of B cell phenotypic changes are seen in SARD patients including changes in the proportions of various naive and memory B cell subsets, increased B cell activation and elevated levels of plasmablasts/plasma cells. Objectives To determine whether ANA + individuals who lack sufficient symptoms for a SARD diagnosis have B cell phenotypic changes similar to those seen in SARD. Methods Healthy controls (HC) and ANA + individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had a recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were isolated over a Ficoll gradient, stained with various combinations of fluorescently labeled antibodies and analyzed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD (24 SS, 26 SSc, 6 SLE, 2 MCTD, 1 DM) patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets, as previously reported for patients with established Disease, including: increased proportions of mature naive B cells (SSc); increased proportions of T1T2 cells (SLE and SS); and trends to decreased proportions of switched memory B cells (CD27 + IgD – ) in all SARD. Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27 – IgD – memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138 + plasma cells were seen in all SARD patients (except those with SSc), these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets, as well as the proportion of T1T2 cells, and ANA titer and the number of different anti-nuclear antibodies specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical Disease in ANA + individuals and have a pattern suggesting ongoing activation through T-B collaboration. Disclosure of Interest None declared
