29 results on '"Stone, John"'
Search Results
2. Identification of Galectin-3 as an Auto-Antigen in IgG4-Related Disease
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Perugino, Cory A., AlSalem, Sultan B., Mattoo, Hamid, Della-Torre, Emanuel, Mahajan, Vinay, Ganesh, Gayathri, Allard-Chamard, Hugues, Wallace, Zachary, Montesi, Sydney B., Kreuzer, Johannes, Haas, Wilhelm, Stone, John H., and Pillai, Shiv
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CD4-Positive T-Lymphocytes ,Male ,integumentary system ,Galectin 3 ,fungi ,Plasma Cells ,Immunoglobulins ,Immunoglobulin E ,Middle Aged ,Lymphocyte Activation ,Autoantigens ,Article ,Mass Spectrometry ,Recombinant Proteins ,Immunoglobulin G ,parasitic diseases ,Humans ,Female ,Immunoglobulin G4-Related Disease ,Immunosorbent Techniques ,Autoantibodies ,Cell Proliferation - Abstract
BACKGROUND: The antigenic trigger that drives the expansion of circulating plasmablasts and CD4(+) cytotoxic T cells (CD4(+) CTLs) in patients with IgG4-Related Disease (IgG4-RD) is presently unknown. OBJECTIVE: We sought to sequence Ig genes from single cell clones of dominantly-expanded plasmablasts and generate recombinant human monoclonal antibodies to identify relevant antigens in IgG4-RD using mass spectrometry. METHODS: Paired heavy and light chain cDNAs from dominant plasmablast clones were expressed as monoclonal antibodies (mAbs) and used to purify antigens using immunoaffinity chromatography. Affinity-purified antigens were identified by mass spectrometry and validated by ELISA. Plasma levels of the antigen of interest were also determined using ELISA RESULTS: mAbs expressed from the two dominant plasmablast clones of a patient with multi-organ IgG4-RD stained human pancreatic tissue sections. Galectin-3 was identified as the antigen specifically recognized by both mAbs. Anti-galectin-3 autoantibody responses were predominantly of the IgG4 isotype (28% of the IgG4-RD cohort, p = 0.0001) and IgE isotype (11% of IgG4-RD cohort, p = 0.009). No significant responses were seen from the IgG1, IgG2 or IgG3 isotypes. IgG4 anti-galectin-3 autoantibodies correlated with elevated plasma galectin-3 levels (p=0.001), lymphadenopathy (p=0.04), total IgG elevation (p=0.05), and IgG4 elevation (p=0.03). CONCLUSION: Affinity chromatography using patient-derived monoclonal antibodies identifies relevant auto-antigens in IgG4-RD. IgG4 galectin-3 autoantibodies are present in a subset of IgG4-RD patients and correlate with galectin-3 plasma levels. The marked elevations of circulating IgG4 and IgE observed clinically are, at least in part, due to the development of IgG4 and IgE specific autoantibody responses.
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- 2018
3. IgG4-related disease: an update on pathophysiology and implications for clinical care.
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Perugino, Cory A. and Stone, John H.
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CYTOTOXIC T cells , *T helper cells , *ANTIGEN presenting cells , *B cells , *PLASMA cells , *FIBROSIS , *DISEASE progression , *FIBROBLASTS , *IMMUNOGLOBULINS , *MACROPHAGES , *RESEARCH funding , *T cells - Abstract
IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease.
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Liu, Hang, Perugino, Cory A., Ghebremichael, Musie, Wallace, Zachary S., Montesi, Sydney B., Stone, John H., and Pillai, Shiv
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ANTIGENS ,AUTOANTIBODIES ,C-reactive protein ,ENZYME-linked immunosorbent assay ,IMMUNOGLOBULINS ,SEVERITY of illness index ,DESCRIPTIVE statistics - Abstract
Objective: Four autoantigens have been described recently in IgG4‐related disease (IgG4‐RD): prohibitin, annexin A11, laminin 511‐E8, and galectin‐3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4‐RD. Methods: Autoantibody responses against prohibitin, annexin A11, and laminin 511‐E8 were measured among a clinically diverse cohort of IgG4‐RD patients (n = 100) using enzyme‐linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution. Results: The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511‐E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti–galectin‐3 antibody responses, with 25 patients (29%) having IgG4 anti–galectin‐3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C‐reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement. Conclusion: Antibodies against prohibitin, annexin A11, and laminin 511‐E8 were found in only a small portion of patients with IgG4‐RD. A subset of IgG4‐RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4‐RD was associated with more severe disease. [ABSTRACT FROM AUTHOR]
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- 2020
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5. A CD8α− Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4‐Related Disease and Decreases Following Glucocorticoid Treatment.
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Della‐Torre, Emanuel, Bozzalla‐Cassione, Emanuele, Sciorati, Clara, Ruggiero, Eliana, Lanzillotta, Marco, Bonfiglio, Silvia, Mattoo, Hamid, Perugino, Cory A., Bozzolo, Enrica, Rovati, Lucrezia, Arcidiacono, Paolo Giorgio, Balzano, Gianpaolo, Lazarevic, Dejan, Bonini, Chiara, Falconi, Massimo, Stone, John H., Dagna, Lorenzo, Pillai, Shiv, and Manfredi, Angelo A.
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AUTOIMMUNE diseases ,FLOW cytometry ,GENE expression ,GLUCOCORTICOIDS ,IMMUNOGLOBULINS ,PROTEOLYTIC enzymes ,T cells ,DISEASE remission ,MEMBRANE glycoproteins ,SEQUENCE analysis - Abstract
Objective: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7–positive (SLAMF7+) cytotoxic effector memory T (T
EM ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4‐related disease (IgG4‐RD). Glucocorticoids represent the first‐line therapeutic approach in patients with IgG4‐RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4‐RD. Methods: Expression of CD8α, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM ) and CD45RA+ effector memory T (TEMRA ) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4‐RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next‐generation sequencing of the T cell receptor α‐ and β‐chain gene was performed on circulating CD4+ CTLs from patients with IgG4‐RD before and after treatment and in affected tissues. Results: Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4‐RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4‐RD patients. Within CD4+SLAMF7+ TEM cells, CD8α− cells but not CD8αlow cells were elevated in IgG4‐RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlow CD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlow CD4+SLAMF7+ TEM cells decreased following glucocorticoid‐induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4‐RD. This TEM cell population contracts following glucocorticoid‐induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]- Published
- 2018
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6. Medical mirroring: granulomatosis with polyangiitis (formerly Wegener's) mimicking immunoglobulin‐G4 related disease.
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Kaushik, Prashant, Stone, John H., Anderson, James T., Dugar, Shaifali, Mathew, Roy, Nikolic, Boris, and Patel, Raina
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GRANULOMATOSIS with polyangiitis , *IMMUNOGLOBULINS , *COMPUTED tomography , *LYMPHADENITIS , *RETROPERITONEUM - Abstract
Abstract: Granulomatosis with polyangiitis (GPA; formerly Wegener's) can present with clinical and histopathological features similar to those of immunoglobulin‐G4 related disease (IgG4‐RD), a recently described fibro‐inflammatory condition. The ability of these two distinct entities to mimic each other closely creates significant pitfalls in diagnosis. We present a unique case in which GPA presented as a peri‐aortic fibrotic mass in the retroperitoneum. The patient's other clinical features also overlapped with classic IgG4‐RD disease manifestations, but the histopathology in two organs and the serological data confirmed the diagnosis of GPA. Rigorous histopathological review remains the gold standard for the diagnosis of GPA and the distinction of this entity from IgG4‐RD and other mimickers. [ABSTRACT FROM AUTHOR]
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- 2018
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7. Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies.
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Perugino, Cory A., Mattoo, Hamid, Mahajan, Vinay S., Maehara, Takashi, Wallace, Zachary S., Pillai, Shiv, and Stone, John H.
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AUTOIMMUNE disease diagnosis ,AUTOIMMUNE disease treatment ,AUTOIMMUNE diseases ,IMMUNOGLOBULINS ,SYMPTOMS - Abstract
The article discusses IgG4-related disease (IgG4-RD), which is multiorgan disorder, and discusses latest treatment models in rheumatology. Topics include distinguishing autoimmune pancreatitis from other diseases of pancreatic and biliary tract; abundance of IgG4-expressing plasma cells within affected tissues; and use of conventional disease-modifying antirheumatic drugs such as azathioprine, methotrexate, and mycophenolate mofetil in IgG4.
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- 2017
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8. Association of Serum Calprotectin (S100A8/A9) Level With Disease Relapse in Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Pepper, Ruth J., Draibe, Juliana B., Caplin, Ben, Fervenza, Fernando C., Hoffman, Gary S., Kallenberg, Cees G. M., Langford, Carol A., Monach, Paul A., Seo, Philip, Spiera, Robert, William St.Clair, E., Tchao, Nadia K., Stone, John H., Specks, Ulrich, Merkel, Peter A., and Salama, Alan D.
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DISEASE relapse ,ANTIGENS ,BIOMARKERS ,CALCIUM-binding proteins ,CONFIDENCE intervals ,CYTOPLASM ,ENZYME-linked immunosorbent assay ,GLUCOCORTICOIDS ,IMMUNOGLOBULINS ,MEDICAL cooperation ,NEUTROPHILS ,OXIDOREDUCTASES ,PROBABILITY theory ,PROTEOLYTIC enzymes ,RESEARCH ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,VASCULITIS ,RITUXIMAB ,DATA analysis ,MULTIPLE regression analysis ,RANDOMIZED controlled trials ,PROPORTIONAL hazards models ,BLIND experiment ,RECEIVER operating characteristic curves ,CYCLOPHOSPHAMIDE ,DATA analysis software ,AZATHIOPRINE ,DESCRIPTIVE statistics ,KAPLAN-Meier estimator ,MANN Whitney U Test ,FRIEDMAN test (Statistics) - Abstract
Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group ( P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 ( P = 0.0043) and baseline and month 6 ( P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse ( P = 0.028). Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. [ABSTRACT FROM AUTHOR]
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- 2017
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9. Association of IgG4-Related Disease With History of Malignancy.
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Wallace, Zachary S., Wallace, Carly J., Lu, Na, Choi, Hyon K., and Stone, John H.
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TUMOR risk factors ,AGE distribution ,CONFIDENCE intervals ,FISHER exact test ,IMMUNOGLOBULINS ,INFLAMMATION ,PROBABILITY theory ,SEX distribution ,T-test (Statistics) ,LOGISTIC regression analysis ,DISEASE prevalence ,DATA analysis software ,MANN Whitney U Test - Abstract
Objective IgG4-related disease (IgG4-RD) is a fibroinflammatory disease of unclear etiology. Some studies suggest that IgG4-RD predisposes patients to malignancy or is a forme fruste of cancer, but we have frequently observed IgG4-RD patients who have a history of malignancy preceding the clinical onset of IgG4-RD. This study was undertaken to characterize IgG4-RD in the setting of previous malignancy diagnosis. Methods We identified IgG4-RD patients with a history of invasive malignancy from a well-defined cohort of 125 patients and compared their malignancy history to those of 2 reference groups. First, we calculated a standardized prevalence ratio against general US population estimates from the Surveillance, Epidemiology, and End Results (SEER) database. Second, we identified up to 5 age- and sex-matched controls for each case and calculated the odds of malignancy among those with IgG4-RD compared to controls, using conditional logistic regression. Results The mean ± SD age at IgG4-RD onset was 50.3 ± 14.9 years, and 61% of the patients were male. Twenty (16%) had been diagnosed as having malignancies (total 21 malignancies) before the diagnosis of IgG4-RD. The observed prevalence of malignancy in this cohort was 2.5 times higher (95% confidence interval [95% CI] 1.1-3.6) than expected compared to the SEER database. Compared to matched controls, the frequency of history of malignancy was >3-fold higher in IgG4-RD patients (95% CI 1.6-6.2). Conclusion Our findings suggest that, in a subset of patients with IgG4-RD, malignancy may be associated with subsequent IgG4-RD development. Potential explanations include shared risk factors for both IgG4-RD and cancer, the triggering by cancer of autoantigen expression leading to IgG4-RD, and an increased risk of IgG4-RD resulting from cancer treatment. [ABSTRACT FROM AUTHOR]
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- 2016
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10. Predictors of disease relapse in IgG4-related disease following rituximab.
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Wallace, Zachary S., Mattoo, Hamid, Mahajan, Vinay S., Kulikova, Maria, Lu, Leo, Deshpande, Vikram, Hyon K. Choi, Pillai, Shiv, and Stone, John H.
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DISEASE relapse ,AUTOIMMUNE diseases ,BIOMARKERS ,CONFIDENCE intervals ,FISHER exact test ,IMMUNOGLOBULINS ,LONGITUDINAL method ,RESEARCH funding ,T-test (Statistics) ,RITUXIMAB ,TREATMENT effectiveness ,DISEASE remission ,PROPORTIONAL hazards models ,RETROSPECTIVE studies ,DISEASE progression ,LABORATORY test panels ,DATA analysis software ,DESCRIPTIVE statistics ,KAPLAN-Meier estimator ,LOG-rank test - Abstract
Objective. IgG4-related disease (IgG4-RD) is a relapsing-remitting condition responsible for fibroinflam-matory lesions that can lead to organ damage and life-threatening complications at nearly any anatomical site. The duration of remission following treatment varies and predictors of relapse are unclear. The objectives of this study were to review our experience with rituximab as remission induction in IgG4-RD, to clarify the duration of efficacy and to identify predictors of flare following treatment. Methods. In this retrospective cohort study, all patients were treated with two doses of rituximab (1 g) separated by 15 days. Clinical, radiographic and laboratory data pertaining to rituximab response and disease relapse were collected from the electronic medical record. Kaplan-Meier curves were constructed to estimate the time to disease relapse. Log-rank analyses were performed to compare times to relapse among subgroups. Potential relapse predictors were evaluated with Cox regression analysis. Results. Fifty-seven of 60 patients (95%) had clinical responses to rituximab. Forty-one patients (68%) were treated without glucocorticoids. Twenty-one patients (37%) experienced relapses following treatment at a median time from the first infusion of 244 days. Baseline concentrations of serum IgG4, IgE and circulating eosinophils predicted subsequent relapses, with hazard ratios of 6.2 (95% CI: 1.2, 32.0), 8.2 (95% CI: 1.4, 50.0) and 7.9 (95% CI: 1.8, 34.7), respectively. The higher the baseline values, the greater the risk of relapse and the shorter the time to relapse. Only 10% of the patients had elevations of all three major risk factors, underscoring the importance of measuring all three at baseline. Conclusion. Baseline elevations in serum IgG4, IgE and blood eosinophil concentrations all predict IgG4-RD relapses independently. [ABSTRACT FROM AUTHOR]
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- 2016
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11. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease.
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Della-Torre, Emanuel, Feeney, Eoin, Deshpande, Vikram, Mattoo, Hamid, Mahajan, Vinay, Kulikova, Maria, Wallace, Zachary S., Carruthers, Mollie, Chung, Raymond T., Pillai, Shiv, and Stone, John H.
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AUTOIMMUNE diseases ,B cells ,BIOPSY ,CELLULAR immunity ,FIBROBLASTS ,IMMUNOGLOBULINS ,IMMUNOHISTOCHEMISTRY ,RESEARCH funding ,FIBROSIS ,DISEASE progression - Abstract
Objectives: Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid.Methods: Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab.Results: The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition.Conclusions: The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions. [ABSTRACT FROM AUTHOR]- Published
- 2015
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12. IgG4-related disease and the kidney.
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Cortazar, Frank B and Stone, John H
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KIDNEY disease diagnosis , *KIDNEY disease treatments , *IMMUNOGLOBULINS , *KIDNEY diseases , *DISEASE complications , *PARAPROTEINEMIA , *DIAGNOSIS , *THERAPEUTICS - Abstract
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent manifestations in the kidney—IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4(+) T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches. [ABSTRACT FROM AUTHOR]
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- 2015
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13. IgG4-Related Disease.
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Wallace, Zachary S., Deshpande, Vikram, Mattoo, Hamid, Mahajan, Vinay S., Kulikova, Maria, Pillai, Shiv, and Stone, John H.
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THERAPEUTIC use of glucocorticoids ,ACADEMIC medical centers ,AGE distribution ,AUTOIMMUNE diseases ,BIOPSY ,BLOOD testing ,STATISTICAL correlation ,FISHER exact test ,FLOW cytometry ,IMMUNOGLOBULINS ,RESEARCH funding ,SEX distribution ,STATISTICS ,T-test (Statistics) ,DATA analysis ,SEVERITY of illness index ,DATA analysis software ,DESCRIPTIVE statistics ,MANN Whitney U Test - Abstract
Objective. IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. Prior studies have focused on individual cases of IgG4-RD or small case series. This study was undertaken to report detailed clinical and laboratory findings in a larger group of patients with IgG4-RD whose diagnosis was established by strict clinicopathologic correlation. Methods. The baseline features of 125 patients with biopsy-proven IgG4-RD were reviewed. The diagnosis was confirmed by pathologists' review, based on consensus diagnostic criteria and correlation with clinicopathologic features. Disease activity and damage were assessed using the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts. Results. Of the 125 patients, 107 had active disease and 86 were not receiving treatment for IgG4-RD. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher IgG4-RD RI score, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 concentrations (P < 0.01 for all comparisons). The correlation between IgG41 plasmablast levels and the IgG4-RD RI of disease activity (Spearman's r50.45, P50.003) was stronger than the correlation between total plasmablast levels and the IgG4-RD RI. Seventy-six (61%) of the patients were male, but no significant differences according to sex were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Treatment with glucocorticoids failed to produce sustained remission in 77% of patients. Conclusion. Nearly 50% of this patient cohort with biopsy-proven, clinically active IgG4-RD had normal serum IgG4 concentrations. Elevations in the serum IgG4 concentration appeared to identify a subset of patients with a more severe disease phenotype. In addition, the levels of IgG41 plasmablasts correlated well with the extent of disease activity. [ABSTRACT FROM AUTHOR]
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- 2015
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14. Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Grayson, Peter C., Carmona‐Rivera, Carmelo, Xu, Lijing, Lim, Noha, Gao, Zhong, Asare, Adam L., Specks, Ulrich, Stone, John H., Seo, Philip, Spiera, Robert F., Langford, Carol A., Hoffman, Gary S., Kallenberg, Cees G. M., St.Clair, E. William, Tchao, Nadia K., Ytterberg, Steven R., Phippard, Deborah J., Merkel, Peter A., Kaplan, Mariana J., and Monach, Paul A.
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ACADEMIC medical centers ,ENZYME-linked immunosorbent assay ,FISHER exact test ,GENE expression ,IMMUNOGLOBULINS ,MULTIVARIATE analysis ,NEUTROPHILS ,POLYMERASE chain reaction ,REGRESSION analysis ,RESEARCH funding ,STATISTICS ,VASCULITIS ,LOGISTIC regression analysis ,GENOMICS ,DATA analysis ,SEVERITY of illness index ,REVERSE transcriptase polymerase chain reaction ,DESCRIPTIVE statistics - Abstract
Objective To discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV. Methods The source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions. Results Differential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2,346 transcripts at the baseline visit ( P < 0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders ( P < 0.01) and during active disease than during remission ( P < 0.01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response ( P < 0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO. Conclusion In AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV. [ABSTRACT FROM AUTHOR]
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- 2015
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15. Clinical Manifestations of IgG4-Related Disease in the Pharynx: Case Series and Review of the Literature.
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Reder, Lindsay, Della-Torre, Emanuel, Stone, John H., Mori, Matthew, and Song, Phillip
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PHARYNGEAL diseases ,RITUXIMAB ,ACADEMIC medical centers ,BIOPSY ,EPIDEMIOLOGY ,IMMUNOGLOBULINS ,CASE studies ,PATHOLOGY ,LITERATURE reviews ,SOCIAL services case management ,DIAGNOSIS - Abstract
The article present case studies of three patients with laryngopharyngeal lesions, who were diagnosed with Immunoglobulin G4-related disease (IgG4-RD), manifested in the head and neck. The manner of diagnosis and effective treatment for the disease is discussed. Result suggests IgG4-related disease as a fibroinflammatory disorder, with the head and neck regions as among of the most common areas of involvement.
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- 2015
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16. Brief Report: Spuriously Low Serum IgG4 Concentrations Caused by the Prozone Phenomenon in Patients With IgG4-Related Disease.
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Khosroshahi, Arezou, Cheryk, Lynn A., Carruthers, Mollie N., Edwards, Judith A., Bloch, Donald B., and Stone, John H.
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AUTOIMMUNE diseases ,BIOPSY ,IMMUNOGLOBULINS ,SEVERITY of illness index - Abstract
Objective To determine the frequency of the prozone effect in patients with IgG4-related disease (IgG4-RD). Methods After identifying the prozone effect in an index patient with IgG4-RD, we examined additional samples to determine the frequency of this phenomenon. Thirty-eight serum samples obtained from patients with IgG4-RD whose results had been reported previously were retested. The serum IgG4 concentrations determined by this repeat analysis were compared with the originally reported values. Results In 10 (26%) of 38 patients, the originally reported IgG4 values were falsely low; the prozone effect was identified in each of these 10 samples. Correction of the prozone effect by sample dilution led to revision of the mean serum IgG4 concentration in the 10 samples, from 26 mg/dl to 2,008 mg/dl (normal range 2.4-121 mg/dl). All 10 patients whose samples were affected by the prozone effect had active IgG4-RD. Failure to detect the elevated serum IgG4 concentrations had a direct impact on the decision not to institute treatment in these patients. Conclusion The prozone effect may lead to major underestimations of IgG4 concentrations in patients with IgG4-RD and offers a potential explanation for the poor correlation observed between disease activity and serum IgG4 levels in some patients. This phenomenon should be considered if the serum IgG4 measurement appears discordant with the clinicopathologic diagnosis and the clinical assessment of disease activity. [ABSTRACT FROM AUTHOR]
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- 2014
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17. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations.
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Stone, John H., Khosroshahi, Arezou, Deshpande, Vikram, Chan, John K. C., Heathcote, J. Godfrey, Aalberse, Rob, Azumi, Atsushi, Bloch, Donald B., Brugge, William R., Carruthers, Mollie N., Cheuk, Wah, Cornell, Lynn, Castillo, Carlos Fernandez-Del, Ferry, Judith A., Forcione, David, Klöppel, Günter, Hamilos, Daniel L., Kamisawa, Terumi, Kasashima, Satomi, and Kawa, Shigeyuki
- Subjects
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CONFERENCES & conventions , *IMMUNOGLOBULINS , *RESEARCH funding , *RHEUMATISM , *TERMS & phrases - Abstract
The article offers recommendations reported by the organizing committee at the International Symposium on IgG4-related diseases held in Boston, Massachusetts on October 4–7, 2011, related to the terminology for overall disease, emphasizing on individual organ system manifestations. IgG4-related organ system nomenclature and the associated problems including the pancreatic manifestation of IgG4-related disease, ophthalmic disease and tubulointerstitial nephritis (TIN) are also discussed.
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- 2012
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18. In vivo accumulation of T cells in response to IL-2/anti-IL-2 mAb complexes is dependent in part on the TNF family ligand 4-1BBL.
- Author
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Lin, Gloria H Y, Stone, John C, Surh, Charles D, and Watts, Tania H
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T cells , *LYMPHOCYTES , *IMMUNOGLOBULINS , *KILLER cells , *GENOTYPE-environment interaction - Abstract
Immune complexes combining IL-2 with particular anti-IL-2 antibodies can be used to selectively expand regulatory T cells or memory T cells. Combining IL-2 with anti-IL-2 (Clone S4B6) greatly enhances the biological potency of IL-2 in vivo leading to selective expansion of CD8 memory T cells and NK cells compared with regulatory T cells. Here we show that in vivo administration of IL-2/anti-IL-2 mAb (IL-2/mAb) complexes induces 4-1BB expression on both adoptively transferred antigen-specific memory CD8 T cells as well as on endogenous memory phenotype cells. Remarkably, the accumulation of adoptively transferred memory CD8 T cells following in vivo IL-2/mAb-complex treatment was found to be dependent in part on the presence of 4-1BBL in the host. These effects were independent of IL-2-induced cell division, suggesting that 4-1BBL-induced survival signals contribute to IL-2/mAb-complex-induced T-cell accumulation in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
19. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis.
- Author
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Kelley, James M., Monach, Paul A., Ji, Chuanyi, Zhou, Yebin, Wu, Jianming, Tanaka, Sumiaki, Mahr, Alfred D., Johnson, Sharleen, McAlear, Carol, Cuthbertson, David, Carette, Simon, Davis, John C., Dellaripa, Paul F., Hoffman, Gary S., Khalidi, Nader, Langford, Carol A., Seo, Phillip, Clair, E. William St., Specks, Ulrich, and Stone, John H.
- Subjects
KIDNEY diseases ,FUNCTIONAL genomics ,GRANULOMATOSIS with polyangiitis ,FC receptors ,IMMUNOGLOBULINS - Abstract
Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ~30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's). [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
20. Antiproteinase 3 Antineutrophil Cytoplasmic Antibodies and Disease Activity in Wegener Granulomatosis.
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Finkielman, Javier D., Merkel, Peter A., Schroeder, Darrell, Hoffman, Gary S., Spiera, Robert, St. Clair, E. William, Davis Jr., John C., McCune, W. Joseph, Lears, Andrea K., Ytterberg, Steven R., Hummel, Amber M., Viss, Margaret A., Peikert, Tobias, Stone, John H., and Specks, Ulrich
- Subjects
MEDICAL research ,GRANULOMATOSIS with polyangiitis ,IMMUNOGLOBULINS ,DISEASE relapse ,ENZYME-linked immunosorbent assay ,IMMUNOSUPPRESSIVE agents - Abstract
Background: The utility of antineutrophil cytoplasmic antibody (ANCA) levels to guide the management of patients with Wegener granulomatosis remains controversial. Objective: To determine whether pro-proteinase 3 (PR3)-ANCA levels are a better measure of disease activity than mature-PR3- ANCA levels, whether decreases in either level are associated with shorter time to remission, and whether increases are followed by relapse. Design: Prospective, observational cohort study. Setting: 8 United States medical centers that participated in a treatment trial for Wegener granulomatosis. Patients: 156 patients with Wegener granulomatosis enrolled during periods of active disease. Measurements: PR3-ANCA levels (by capture enzyme-linked immunosorbent assay) and disease activity (by the Birmingham Vasculitis Activity Score for Wegener granulomatosis). Results: The ANCA levels were only weakly associated with disease activity across patients. The longitudinal association within patients was stronger, but changes in ANCA levels explained less than 10% of the variation in disease activity. Decreases in mature- and pro-PR3-ANCA levels were not statistically significantly associated with shorter time to remission, and increases in mature-PR3-ANCA levels (adjusted hazard ratio, 0.8 [95% CI, 0.4 to 1.9]; P =0.67) and pro-PR3-ANCA levels (adjusted hazard ratio, 1.0 [CI, 0.5 to 2.1]; P = 0.99) were not associated with relapse. The proportion of patients who had relapse within 1 year of an increase in PR3-ANCA levels was 40% for mature-PR3 (CI, 18% to 56%) and 43% for pro-PR3 (CI, 22% to 58%). Limitations: Samples were collected approximately every 3 months. Sensitivity and specificity of ANCA levels for detecting remission and relapse could not be calculated because each patient had different follow-up times. Conclusion: Pro-PR3-ANCA is no better than mature-PR3-ANCA as a measure of Wegener granulomatosis activity. Decreases in PR3-ANCA levels are not associated with shorter time to remission, and increases are not associated with relapse. These findings suggest that ANCA levels cannot be used to guide immunosuppressive therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2007
21. The antineutrophil cytoplasmic antibody–associated vasculitides
- Author
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Seo, Philip and Stone, John H.
- Subjects
- *
IMMUNOGLOBULINS , *VASCULITIS , *PATHOLOGY , *INFECTION - Abstract
Wegener''s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome are small- to medium-vessel vasculitides linked by overlapping pathology and the presence of antineutrophil cytoplasmic antibodies (ANCA). Commonly referred to as the ANCA-associated vasculitides, these diseases are challenging to diagnose and to treat. Distinguishing the ANCA-associated vasculitides from other forms of vasculitis or nonvasculitic processes (such as infection) can be particularly difficult. This review describes the clinical and pathologic hallmarks of the ANCA-associated vasculitides, discusses the role of ANCA assays in diagnosis and treatment, and outlines an approach to the evaluation and management of these diseases. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
22. Reply.
- Author
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Perugino, Cory A. and Stone, John H.
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ACUTE phase proteins , *AMYLOIDOSIS , *AUTOIMMUNE diseases , *BLOOD sedimentation , *C-reactive protein , *IMMUNOGLOBULINS , *INFLAMMATION - Published
- 2018
- Full Text
- View/download PDF
23. Reply.
- Author
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Khosroshahi, Arezou, Cheryk, Lynn A., Bloch, Donald B., and Stone, John H.
- Subjects
AUTOIMMUNE diseases ,CALIBRATION ,IMMUNOGLOBULINS - Abstract
A response from the authors of the article "Spuriously Low Serum IgG4 Concentrations Caused by the Prozone Phenomenon in Patients With IgG4-Related Disease," published in a previous 2014 issue is presented.
- Published
- 2014
- Full Text
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24. Reply.
- Author
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Stone, John H. and Khosroshahi, Arezou
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AUTOIMMUNE disease diagnosis , *CALIBRATION , *IMMUNOGLOBULINS ,RESEARCH evaluation - Abstract
The article presents a reply to the corroboration of the authors' findings by Drs. N. Urquhart and A. Mattman on the emergence of IgGr-RD as an entity that often enters into the differential diagnoses of rheumatic disease elevates the importance of accuracy in diagnostic assays of IgG4. It notes that while their algorithm may constitute an effective solution to the problem of the prozone effect in assays for IgG4, it may be difficult for commercial laboratories to implement such a solution.
- Published
- 2014
- Full Text
- View/download PDF
25. Reply.
- Author
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Carruthers, Mollie N., Miloslavsky, Eli M., and Stone, John H.
- Subjects
IMMUNOGLOBULINS ,CASE studies ,PHARYNGITIS - Abstract
A response from the authors of the article "Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations" in the 2012 issue is presented.
- Published
- 2013
- Full Text
- View/download PDF
26. IgG4-Related Disease.
- Author
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Stone, John H., Chan, John K. C., Deshpande, Vikram, Kazuichi Okazaki, Hisanori Umehara, and Yoh Zen
- Subjects
- *
IMMUNOLOGIC diseases , *IMMUNOGLOBULINS , *ANTIBODY diversity , *ANTIGENS , *ALLERGIES - Published
- 2013
- Full Text
- View/download PDF
27. B-cell depleting agents for ANCA vasculitides: A new therapeutic approach
- Author
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Gómez-Puerta, José A., Quintana, Luis F., Stone, John H., Ramos-Casals, Manuel, and Bosch, Xavier
- Subjects
- *
B cells , *VASCULITIS , *GLOMERULONEPHRITIS , *IMMUNOGLOBULINS , *GENE expression , *CYCLOPHOSPHAMIDE - Abstract
Abstract: Vasculitides associated with anti-neutrophil cytoplasmic antibody (ANCA) serum positivity affecting small and medium-sized vessels are defined as ANCA-associated vasculitis (AAV). Glomerulonephritis in AAV is characterized by focal necrosis, crescent formation, and few or no immunoglobulin deposits. In vitro and animal evidence suggests that ANCA play a pathogenic role in AAV. Specific gene expression signatures are reported to predict long-term prognosis in AAV, suggesting the possibility of individualizing therapy and identifying new therapeutic targets. Although immunosuppressants and glucocorticoids are the cornerstone of AAV therapy, results from two recent randomized controlled trials have shown the non-inferiority of rituximab, compared with cyclophosphamide, for the induction of remission in patients with severe AAV. In fact, in April 2011, the US Food and Drug Administration (FDA) approved rituximab, combined with glucocorticoids, as a front-line therapy for adult patients with granulomatosis with polyangiitis (GPA; Wegener''s granulomatosis) or microscopic polyangiitis. This new indication for rituximab provided the first ever FDA-approved therapy for these two diseases and the first alternative to cyclophosphamide for the treatment of severe disease in almost 40years. However, issues regarding the use of maintenance therapy after rituximab, the concurrent use of cyclophosphamide and the toxicity of rituximab remain unanswered and should be clarified in ongoing and future randomized controlled trials. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
28. IgG4-Related Kidney Disease: Clinical and Laboratory Features
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Nishi, Shinichi, Saeki, Takako, Saito, Takao, editor, Stone, John H., editor, Nakashima, Hitoshi, editor, Saeki, Takako, editor, and Kawano, Mitsuhiro, editor
- Published
- 2016
- Full Text
- View/download PDF
29. ANCA Are Detectable in Nearly All Patients with Active Severe Wegener’s Granulomatosis
- Author
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Finkielman, Javier D., Lee, Augustine S., Hummel, Amber M., Viss, Margaret A., Jacob, Gregory L., Homburger, Henry A., Peikert, Tobias, Hoffman, Gary S., Merkel, Peter A., Spiera, Robert, St. Clair, E. William, Davis, John C., McCune, W. Joseph, Tibbs, Andrea K., Ytterberg, Steven R., Stone, John H., and Specks, Ulrich
- Subjects
- *
IMMUNOGLOBULINS , *ENZYME-linked immunosorbent assay , *IMMUNOFLUORESCENCE , *FLUORESCENCE microscopy - Abstract
Abstract: Background: The pathogenic significance of antineutrophilic cytoplasmic antibodies (ANCA) in Wegener’s granulomatosis is controversial. Their presence is influenced by the extent, severity, and activity of the disease at the time of sampling. The objective of this study was to determine the frequency of ANCA in patients with active Wegener’s granulomatosis and to assess the influence of disease severity on test results. Methods: Baseline serum samples from the 180 participants in a multicentric prospective trial were tested for ANCA by indirect immunofluorescence, direct enzyme-linked immunosorbent assay (ELISA), and capture ELISA. Disease activity was measured using the Birmingham Vasculitis Activity Score for Wegener’s granulomatosis. All patients had active disease at enrollment. Patients were categorized as having severe (n=128) or limited (n=52) Wegener’s granulomatosis. Results: When all ANCA detection methods were combined, 166 patients (92%) were ANCA positive, including 96% with severe disease and 83% with limited disease. Conclusion: ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis, but approximately 1 of 5 patients with active limited disease are ANCA negative. Immunofluorescence and both direct and capture ELISAs are required for optimal detection, suggesting that ANCA are not recognized equally well by all testing methods. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
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