Maria Kulikova

Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations

Objectives We examined the utility of circulating total and IgG4+ plasmablasts as biomarkers of diagnosis and disease activity in IgG4-related disease (IgG4-RD). Materials methods We evaluated patients with active, untreated, biopsy-proven IgG4-RD affecting various organs. Flow cytometry was used to measure total plasmablast and IgG4+ plasmablast counts by gating peripheral blood for CD19lowCD38+CD20−CD27+ cells and CD19lowCD38+CD20−CD27+IgG4+ cells. Serum IgG4 concentrations were measured by nephelometry. We compared 37 IgG4-RD patients to 35 controls, including healthy individuals (n=14) and patients with other inflammatory diseases before treatment (n=21). Results The IgG4-RD patients’ mean age was 59, and 68% were male. Fourteen patients (38%) had three or more organs involved. The IgG4-RD patients had substantially elevated total plasmablast counts (median 4698/mL, range 610–79524/mL) compared to both untreated disease controls (median 592/mL, range 19–4294/mL; p < 0.001) and healthy controls (median 94/mL, range 1–653/mL; p < 0.001). Thirteen IgG4-RD patients (36%) had normal serum IgG4 concentrations (mean 60 mg/dL, range 5–123 mg/dL, normal <135 mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations (3784/mL) compared to those with elevated serum IgG4 (5155/mL) (p = 0.242). Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6356/mL (range 1123–41589/mL), declining to 1419/mL (range 386/mL–4150/mL) during remission (p < 0.01). Conclusions Circulating plasmablasts are elevated in active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the appropriate time for re-treatment.

IgG4-Related Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients

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.

B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease

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 (R2=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.

Predictors of disease relapse in IgG4-related disease following rituximab

OBJECTIVE IgG4-related disease (IgG4-RD) is a relapsing-remitting condition responsible for fibroinflammatory 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.

IgG4‐related disease: Clinical and laboratory features in 125 patients

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.

IgG4-Related Disease: Baseline clinical and laboratory features in 125 patients with biopsy-proven disease

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.

OP0204 Clonal Expansion of CD4+ Cytotoxic T Lymphocytes in IGG4-Related Disease

Background IgG4-related disease (IgG4-RD) is a systemic condition of unknown etiology, characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates rich in IgG4+ plasma cells and CD4+ T cells (1). Given the longstanding history of atopy that characterizes a proportion of patients with IgG4-RD, it has been suggested that TH2 cytokines contribute to the pathogenesis of this condition (2). However, we recently demonstrated that allergic manifestations are not increased in patients with IgG4-RD compared to the general population (3). Similarly, CD4+TH2 cells are expanded only in the peripheral blood of IgG4-RD patients with concomitant atopy, questioning the hypothesis of IgG4-RD as a TH2 driven condition (4). Objectives We aimed to characterize CD4+ T cell subsets in IgG4-RD subjects. Methods We used flow cytometry to identify CD4+ effector/memory T cells as well as Th1, Th2, and T regulatory cells in a cohort of 101 IgG4-RD patients. Gene expression analysis was used to further characterize expanded cells. Results were validated by flow cytometry. Next-generation sequencing of the T cell receptor β chain gene was performed on CD4+ T cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined using quantitative multi-color imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype (cytotoxic T lymphocytes (CTLs)) were expanded in IgG4-RD patients compared to healthy controls. Next-generation sequencing revealed prominent clonal expansions of these CD4+CTLs but not of CD4+GATA3+ memory TH2 cells in subjects with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4+CTLs that expressed granzyme A and perforin. Clinical remission induced by rituximab-mediated B cell depletion was associated with a reduction in disease-associated CD4+ CTLs. Conclusions IgG4-RD is prominently linked to clonally-expanded CD4+ CTLs in peripheral blood as well as in inflammatory tissue lesions. A TH2 signature might be primarily linked to a concomitant atopic diathesis. CD4+ CTLs might be of pathogenic importance in other fibrotic conditions including IgG4-RD. References Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015 Aug;181(2):191–206. Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol. 2009 Oct;21(10):1136–39. Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Allergy. 2014 Feb;69(2):269–72. Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai S. Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy. 2014 Mar;69(3):399–402. Disclosure of Interest None declared

IgG4-Related Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients: CLINICAL AND LABORATORY FEATURES OF IgG4-RELATED DISEASE

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.

SAT0528 IgG4-Related Disease: Baseline Clinical and Laboratory Features in 125 Patients

Background IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ (1). No detailed clinical and laboratory assessments have been reported in large numbers of patients with IgG4-RD diagnoses established by strict clinicopathological correlation (2-4). Objectives To describe a single center cohort of 125 patients with biopsy-proven disease. Methods We reviewed the baseline features of 125 patients with biopsy-proven disease. The diagnosis was confirmed by pathology review according to consensus diagnostic criteria (5). Disease activity and damage were assessed by the IgG4-RD Responder Index (RI) (6). Flow cytometry was used to assess levels of circulating plasmablasts (7, 8). Results Of the 125 patients, 103 had active disease and 86 were on no treatment. 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 RI, a greater number of organs involved, lower complement levels, a higher absolute eosinophil count, and higher IgE levels compared to those with active disease but normal serum IgG4 (P<0.01 for all comparisons). The correlation between IgG4+ plasmablast level and RI (R=0.45, P=0.003) was stronger than that of total plasmablasts and RI. Seventy-six (61%) of the patients were male, but no significant differences according to gender were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Glucocorticoids failed to produce sustained remission in the majority of patients. Conclusions Nearly 50% of this patient cohort with biopsy-proven, clinically-active IgG4-RD had normal serum IgG4 concentrations. Serum IgG4 elevation identify a subset with more inflammatory features. IgG4+ plasmablasts correlate well with disease activity. References Stone JH, Zen Y, Deshpande V. IgG4-related disease. NEJM 2012; Feb 9;366(6):539-51. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol 2010; Dec;34(12):1812-9. Ebbo M, Daniel L, Pavic M, Seve P, Hamidou M, Andres E, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore) 2012; Jan;91(1):49-56. Chen H, Lin W, Wang Q, Wu Q, Wang L, Fei Y, et al. IgG4-related disease in a Chinese cohort: a prospective study. Scand J Rheumatol 2014;43(1):70-4. Deshpande V. Consensus Statement on IgG4-RD Diagnosis. Modern Pathology 2012; 25(9):1181. Carruthers MN, Stone JH, Deshpande V, Khosroshahi A. Development of an IgG4-RD Responder Index. Int J Rheumatol 2012;2012:259408. Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis 2015; 74(1):190. Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG-related disease. J Allergy Clin Immunol 2014;134(3):679. Disclosure of Interest None declared

SAT0527 Predictors of Disease Relapse in IgG4-Related Disease

Background IgG4-related disease (IgG4-RD) is a relapsing-remitting condition responsible for fibroinflammatory lesions that can lead to organ damage and life-threatening complications at nearly any anatomic site (1). The duration of remission following treatment varies and predictors of relapse are unclear (2, 3). Objectives To evaluate potential predictors of relapse in 60 patients treated with rituximab for active, biopsy-proven IgG4-RD. Methods In this retrospective cohort study, all patients were treated with two doses of rituximab (1g) 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 Of the 60 patients included, 57 (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 (95% CI 158-330 days). Baseline concentrations of serum IgG4 and IgE and circulating eosinophil levels were predictors of disease relapses, with hazard ratios (HR) of 6.2 (95% CI 1.2-32.0), 8.2 (1.4-50.0), and 7.9 (1.8-34.7), respectively. Conclusions Rituximab is an effective steroid-sparing agent but relapses following remission are common. Baseline elevations in serum IgG4 and IgE concentrations and blood eosinophil levels predict subsequent disease relapses. Measurement of these variables at baseline may assist in longitudinal management decisions for these patients. References Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012; Feb 9;366(6):539-51. Hart PA, Kamisawa T, Brugge WR, Chung JB, Culver EL, Czako L, et al. Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis. Gut 2013; Dec;62(12):1771-6. Yamamoto M, Nojima M, Takahashi H, Yokoyama Y, Ishigami K, Yajima H, et al. Identification of relapse predictors in IgG4-related disease using multivariate analysis of clinical data at the first visit and initial treatment. Rheumatology (Oxford) 2015; Jan;54(1):45-9. Disclosure of Interest None declared