Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19+CD24−CD38hi was increased in patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD). A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19+CD24−CD38hi plasmablasts/plasma cells, CD19+CD24+CD38− memory B cells, CD19+CD24intCD38int naive B cells, and CD19+CD24hiCD38hi regulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19+CD24−CD38hi plasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array. In untreated patients with IgG4-RD, the peripheral CD19+CD24−CD38hi plasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19+CD24−CD38hi plasmablasts/plasma cells from patients with IgG4-RD. Furthermore, CD19+CD24−CD38hi plasmablasts/plasma cells secreted more IgG4 than other B-cell populations. Circulating CD19+CD24−CD38hi plasmablasts/plasma cells are elevated in active IgG4-RD and decreased after glucocorticoid treatment. This IgG4-secreting plasmablast/plasma cell population might be a potentially useful biomarker for diagnosis and assessing response to treatment.

Circulating plasmablasts/plasma cells: a potential biomarker for IgG4-related disease.

Objectives This randomized, controlled clinical trial aims to compare the efficacy and safety of glucocorticoid combined with MMF and glucocorticoid monotherapy for patients with IgG4-related disease. Methods Sixty-nine patients newly diagnosed with IgG4-related disease were randomly divided into two groups (35 patients in Group I and 34 patients in Group II). Patients in Group I received glucocorticoid monotherapy (0.6-0.8 mg/(kg·day) and tapered gradually); patients in Group II received glucocorticoid combined with MMF therapy (1-1.5 g/day). All the patients were followed up at 1, 3, 6 and 12 months. The primary endpoint was response rate in 12 months and the secondary endpoints were relapse, remission rate and adverse reactions. Results Group I and Group II shared almost the same efficacy at the 1 month treatment, but during the follow-up, the complete response rate in Group II was much higher than that in Group I at different time points, and the cumulative relapse rate during 1 year of therapy was much higher in Group I than that in Group II (40.00 vs 20.59%). The remission rate was lower in Group I (51.42 vs 76.47%). Relapses were more likely to happen in lung, lacrimal gland, salivary gland, paranasal sinus and kidney. MMF could reduce relapse, especially organs recurrence. No serious adverse reactions occurred in the two groups. Conclusion Combination treatment with glucocorticoid and MMF was more effective than the monotherapy, and the relapse of IgG4-related disease might be associated with the elevated levels of serum IgG4 and the low glucocorticoid maintenance dose. Trial registration ClinicalTrials.gov, www.clinicaltrials.gov, NCT02458196.

Efficacy and safety of low dose Mycophenolate mofetil treatment for immunoglobulin G4-related disease: a randomized clinical trial.

The aim of this study was to assess the outcomes of remission induction in patients with IgG4-related disease (IgG4-RD) in our cohort, and to investigate the characteristics, prognosis, and risk factors in the patients failed of remission induction. We prospectively enrolled 215 newly diagnosed patients with IgG4-RD, who were initially treated with glucocorticoid (GC) alone or in combination with immunosuppressive agents (IM), and had at least 6 months of follow up. The therapeutic goals of remission induction were defined as fulfilling each of the following after the 6-month remission induction stage: (1) ≥ 50% decline in the IgG4-RD responder index (RI); (2) GC tapered to maintenance dose; and (3) no relapse during GC tapering. The patients not achieving the therapeutic goals were considered to have failed of remission induction. There were 26 patients in our cohort who failed of remission induction, including 16 (20.8%) on GC monotherapy, and 10 (7.2%) on combination therapy comprising GC and IM. The lacrimal gland and lung were most common sites of remission induction failure. Among the patients who relapsed during remission induction stage, 52.9% had secondary relapse during follow-up. Eosinophilia, higher baseline RI, more than five organs involved and dacryoadenitis were risk factors for remission induction failure with GC monotherapy, and the incidence of remission induction failure was 71.4% in the patients with more than three risk factors. After 6-month treatment, the patients who failed of remission induction had significantly higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and IgG4. In our cohort, 20.8% of patients failed of remission induction with GC monotherapy, while 7.2% of patients failed of remission induction with combination therapy comprising GC and IM.

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Failure of remission induction by glucocorticoids alone or in combination with immunosuppressive agents in IgG4-related disease: a prospective study of 215 patients

Objectives To study the impact of sex on the clinical presentation of IgG4-related disease (IgG4-RD). Methods We prospectively enrolled 403 newly diagnosed IgG4-RD patients. We compared the demographic features, clinical manifestations, organ involvement, laboratory tests and treatment outcomes between female and male patients. The organs involved were divided into superficial organs (salivary glands, lacrimal glands, orbit, sinus and skin) and internal organs (all the other organs). The patients treated with glucocorticoids with or without additional immunosuppressants were included in the assessment of treatment outcomes, and potential confounding factors were corrected by propensity score matching or multivariate Cox regression analysis. Results Female patients showed younger age at both symptom onset and diagnosis, and a longer interval between symptom onset and diagnosis. Allergy history, Mikulicz's disease and thyroiditis were more common in female patients, while autoimmune pancreatitis, sclerosing cholangitis and retroperitoneal fibrosis were more common in male patients. In accordance, female patients more frequently presented with superficial organ involvement, while male patients more frequently had internal organ involvement, and the discrepancy was more prominent in the patients with older age. Male sex was associated with higher peripheral eosinophils, CRP and IgG4 levels at baseline. In response to glucocorticoid-based therapies, male sex was associated with a higher IgG4-RD responder index during follow-up as well as a greater risk of relapse (hazard ratio 3.14, P = 0.003). Conclusion Our study revealed the sex disparities in clinical characteristics of IgG4-RD, and indicated that male sex was independently associated with worse prognosis in response to glucocorticoid-based therapies.

Sex disparities in clinical characteristics and prognosis of immunoglobulin G4-related disease: a prospective study of 403 patients.

The most representative kidney lesion of IgG4-related disease (IgG4-RD) is plasma cell-rich tubulointerstitial nephritis (TIN) with distinctive imaging findings including multiple low-density lesions on contrast-enhanced computed tomography. In addition, membranous glomerulonephritis is a representative glomerular lesion of this disease. Recent advances have clarified that inflammation with IgG4-positive plasma cell infiltrates is not restricted to the renal parenchyma, but can be seen in outside the renal capsule, around medium-sized arteries such as lobar arteries, around nerves, and in the renal pelvis and periureter. Hypocomplementemia is a very important feature of IgG4-TIN, and serum complement level might serve as a convenient biomarker to predict relapse. Although good responsiveness to glucocorticoid has been considered characteristic of IgG4-RD, delayed start of treatment is associated with partial scarring in the kidneys on imaging study. Therefore, steroid therapy should be immediately initiated as soon as the diagnosis of IgG4-TIN is made. Future analyses of pathogenesis will be needed to more precisely define the optimal therapeutic strategies for the various subsets of Ig4-RD patients.

IgG4-related kidney disease and retroperitoneal fibrosis: An update.

Background:
Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic disease that can involve multiple organs and various clinical phenotypes. The purpose of this study was to analyze different types of organ involvement in IgG4-RD patients in China.

Yang Shi

Papers

Types of Organ Involvement in Patients with Immunoglobulin G4-related Disease.