Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease

Objectives: This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD.

Methods: We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD.

Results: We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4?+?PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138?+?cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not.

Conclusions: These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD.     

The diagnostic utility of labial salivary gland biopsy in IgG4-related disease

Objective: For the definitive diagnosis of IgG4-related disease (IgG4-RD), biopsies of local lesions are recommended so as to exclude other diseases, including lymphoma and cancer. However, performing biopsies of underlying organs is technically difficult. In this study, we examined the diagnostic utility of labial salivary gland (LSG) biopsy as a less invasive procedure.

Methods: Sixty-six patients with suspected IgG4-RD by clinical findings or high serum IgG4 underwent LSG biopsy. We examined the relationship between the number of IgG4-positive plasma cells in LSG and clinical findings.

Results: The final diagnosis was 45 patients with IgG4-RD, 12 with Sjögren’s syndrome, four with suspected Sjögren’s syndrome, three with malignant lymphoma, one with systemic lupus erythematosus, and one with Warthin’s tumor. The sensitivity, specificity, and accuracy of LSG biopsy were 55.6%, 100.0%, and 70.0%, respectively. Forty-five IgG4-RD patients were divided into two groups: 1) 25 with lesions of salivary glands (IgG4-RD S+) and 2) 20 without these lesions (IgG4-RD S?). Seventeen of 25 (68.0%) IgG4-RD S?+?and 8 of 20 (40.0%) IgG4-RD S???patients were positive for LSG biopsy. In the IgG4-RD S???patients, the mean number of affected organs and serum IgG4 in the positive cases for LSG biopsy were significantly higher than in the negative cases.

Conclusion: A solo LSG biopsy is insufficient for the diagnosis of IgG4-RD because of its low sensitivity. However, LSG biopsy combined with clinical findings, including serum IgG4 and number of affected organs, may contribute towards a diagnosis of IgG4-RD patients with affected underlying organs.     

Clinical features of patients with IgG4-related disease complicated with perivascular lesions

Abstract

Objective. To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions.

Methods. The clinical features of seven patients with IgG4-RD and perivascular lesions diagnosed at the University of Tsukuba Hospital between October 2008 and October 2013, were analyzed, including clinical background, results of imaging studies, satisfaction of the 2011 comprehensive diagnostic criteria (CDC) for IgG4-RD, laboratory data, distribution of perivascular lesions, involvement of other organs, and response to steroid therapy.

Results. We studied six men and one woman with a mean age of 66.9 ± 6.7 years (± SD). Six of seven patients were diagnosed as definite IgG4-RD, while the seventh was considered possible IgG4-RD, based on the CDC for IgG4-RD. Serum IgG4 levels at diagnosis were higher than 135 mg/dl in all seven patients (mean, 933 ± 527). Serum C-reactive protein (CRP) levels were elevated in two only (mean, 1.42 ± 3.56 mg/dl). The perivascular lesions were located in the pulmonary artery (n = 1), thoracic aorta (n = 2), abdominal aorta (n = 6), coronary (n = 1), celiac (n = 1), superior mesenteric (n = 1), renal (n = 2), inferior mesenteric (n = 5), and iliac (n = 3) arteries. In addition to perivascular lesions, six patients showed involvement of other organs. All seven patients were treated with prednisolone (0.6 mg/kg/day), which rapidly improved the perivascular and other organ lesions in six patients (the other one patient have not yet been evaluated due to the short follow-up).

Conclusion. Perivascular lesions show wide distribution in patients with IgG4-RD. Serum CRP levels are not necessarily elevated in these patients. Steroid therapy is effective in IgG4-RD and results in resolution of lesions.     

Ophthalmic manifestations of IgG4-related disease: Single-center experience and literature review

ObjectivesIgG4-related disease (IgG4-RD) is an inflammatory disorder responsible for fibrosing, tumefactive lesions that can involve the lacrimal gland as well as the extraocular muscles, orbital soft tissues, sclera, and local nerves. We reviewed IgG4-related ophthalmic disease (IgG4-ROD), including the natural history, pathology, and treatment, based on our center's experience and that reported in the literature.MethodsWe identified 27 patients with orbital manifestations from our IgG4-RD registry; six were excluded because no pathology was available for review. All 21 cases included had histopathologically confirmed diagnoses of IgG4-RD, 11 of which were of the orbital tissue. Other data were obtained by a retrospective medical records review. MEDLINE and PubMed literature searches in English were conducted to identify articles for a literature review on the topic.ResultsPatients with IgG4-ROD were predominantly male (57%) and had an average age at symptom onset of 50 years (range: 21–79 years). The lacrimal gland was the most commonly involved structure (62%). Most patients (71%) had bilateral disease and extra-orbital involvement (71%); these patients also had elevated serum IgG4 concentrations compared to those with unilateral disease and no extra-orbital disease. Ten patients improved following rituximab treatment.ConclusionsOphthalmic involvement is a common manifestation of IgG4-RD and can affect nearly every orbital structure. Consideration of IgG4-RD and accurate diagnosis by biopsy have important implications for prognosis and treatment following the distinction of this condition from the Sjögren syndrome (SjS), granulomatosis with polyangiitis (GPA, formerly Wegener's), sarcoidosis, lymphoma, infection, and other disorders. Rituximab holds promise as an effective steroid-sparing agent or therapy for steroid-resistant cases.     

Clinicopathological features of IgG4-related disease complicated with orbital involvement

Abstract

Objective. IgG4-related disease (IgG4-RD) is characterized by IgG4-positive plasmacytic infiltration and fibrosis in various organs. Orbital involvement in IgG4-RD includes lacrimal glands, extra-ocular muscles, trigeminal nerve and other parts of the orbit. Immunohistochemical staining is used to diagnose IgG4-RD in patients with orbital inflammation. The purpose of this retrospective study was to clarify the clinicopathological features of IgG4-RD complicated with orbital involvement.

Methods. We examined the clinical features, pathological findings and response to treatment in nine patients with IgG4-RD who underwent orbital tissue biopsy between April 2010 and August 2012 at the University of Tsukuba Hospital.

Results. Among the nine patients, eight had dacryoadenitis, one had infraorbital nerve swelling, and another one had IgG4-related orbital inflammation. Involvement of other organs was identified in all patients, including involvement of the salivary glands, lymph nodes, lung, kidney and para-aorta. In all patients, biopsy samples from orbital tissues showed lymphoplasmacytic infiltration and fibrosis, and IgG4-positive/IgG-positive plasmacyte ratio of > 40%. All patients were treated with prednisolone (0.6 mg/kg/day) and responded well in early phase, although relapse was noted in two patients following tapering of prednisolone, evident by swelling of lacrimal glands.

Conclusion. Patients with IgG4-RD complicated with orbital involvement often present with involvement of other organs. The histopathological findings of orbital tissue match the characteristic features of IgG4-RD. Corticosteroid is effective for orbital and systemic involvement in IgG4-RD.     

Ophthalmic manifestations of IgG4-related disease: Single-center experience and literature review

Objectives

IgG4-related disease (IgG4-RD) is an inflammatory disorder responsible for fibrosing, tumefactive lesions that can involve the lacrimal gland as well as the extraocular muscles, orbital soft tissues, sclera, and local nerves. We reviewed IgG4-related ophthalmic disease (IgG4-ROD), including the natural history, pathology, and treatment, based on our center's experience and that reported in the literature.

Methods

We identified 27 patients with orbital manifestations from our IgG4-RD registry; six were excluded because no pathology was available for review. All 21 cases included had histopathologically confirmed diagnoses of IgG4-RD, 11 of which were of the orbital tissue. Other data were obtained by a retrospective medical records review. MEDLINE and PubMed literature searches in English were conducted to identify articles for a literature review on the topic.

Results

Patients with IgG4-ROD were predominantly male (57%) and had an average age at symptom onset of 50 years (range: 21–79 years). The lacrimal gland was the most commonly involved structure (62%). Most patients (71%) had bilateral disease and extra-orbital involvement (71%); these patients also had elevated serum IgG4 concentrations compared to those with unilateral disease and no extra-orbital disease. Ten patients improved following rituximab treatment.

Conclusions

Ophthalmic involvement is a common manifestation of IgG4-RD and can affect nearly every orbital structure. Consideration of IgG4-RD and accurate diagnosis by biopsy have important implications for prognosis and treatment following the distinction of this condition from the Sjögren syndrome (SjS), granulomatosis with polyangiitis (GPA, formerly Wegener's), sarcoidosis, lymphoma, infection, and other disorders. Rituximab holds promise as an effective steroid-sparing agent or therapy for steroid-resistant cases.     

Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population

Objective: This study was performed to better know diagnosis associated with serum IgG4 concentration, and to explore the possibility for development of a serum IgG4 for IgG4-related disease (IgG4-RD) in Chinese populations.

Methods: We studied retrospectively 497 IgG4 serum subclass measurements from Peking Union Medical College Hospital during the four-year period, including 242 IgG4-RD, 130 other diseases and 125 healthy individuals.

Results: Serum IgG4 concentrations were significantly higher in IgG4-RD than in other pathologies (1662.9?±?3760.9?mg/L, p?<?0.001) and healthy individuals (538.2?±?458.6?mg/L, p?<?0.001). There were no significant differences in serum IgG4 level between other pathologies group and healthy individuals (p?=?0.075). Among the 242 IgG4-RD patients analyzed, serum IgG4 concentrations were normal in 46 patients (19.0%). We found 32 patients (24.6%) with elevated serum IgG4 levels among the 130 patients who suffered from other pathologies. There were seven (5.6%) with serum IgG4 over 1350?mg/L in healthy individuals. The ROC curve analysis revealed that the optimal sensitivity and specificity were 80.0% and 88.2%, respectively, at the concentration of 1575?mg/L for Chinese patients.

Conclusions: Our study demonstrated that serum IgG4 elevation was not specific of IgG4-RD. Further studies are needed to define the sensibility and specificity of IgG4 values for the diagnosis of IgG4-RD.     

Immune complexome analysis of antigens in circulating immune complexes isolated from patients with IgG4-related dacryoadenitis and/or sialadenitis

Objectives. IgG4-related disease (IgG4-RD) is characterized by various serological abnormalities. Some patients with IgG4-RD present with hypergammaglobulinemia, hypocomplementemia, and autoantibodies recognizing rheumatoid factors and nuclear factors. However, whether IgG4-RD is an autoimmune disease remains unclear.

Methods. Here, we used immune complexome analysis to comprehensively identify constituent antigens of circulating immune complexes isolated from 10 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-RDS) which is one condition associated with IgG4-RD.

Results. We detected each of 125 distinct antigens in independent samples from two or more patients with IgG4-RDS. Of them, 17 antigens were found to be specific to patients with IgG4-RDS by comparing 125 antigens with all the antigens found in other connective tissue diseases (antineutrophil cytoplasmic antibody-associated vasculitis, Takayasu's arteritis, mixed connective tissue disease, dermatomyositis, Sjögren's syndrome, systemic scleroderma, and systemic lupus erythematosus) or healthy donors. The number of disease-specific antigens associated with IgG4-RDS was comparable to those autoimmune diseases.

Conclusions. Studies of the 17 IgG4-RDS-specific antigens might lead to a better understanding of the pathogenesis of IgG4-RD, but further study of the prevalence of these CIC-associated antigens that involves a selective and sensitive assay will be needed to determine their potential as diagnostic or pathogenic biomarkers.     

Serum soluble interleukin-2 receptor as a biomarker in immunoglobulin G4-related disease

Objectives: Serum soluble interleukin-2 (IL-2) receptor (sIL-2R) might reflect disease activity in immunoglobulin G4-related disease (IgG4-RD). We aimed to elucidate the clinical significance of blood markers, including sIL-2R, in patients with IgG4-RD.

Methods: We enrolled 59 patients with IgG4-RD and investigated the association between blood markers (white blood cells, C-reactive protein, sIL-2R, IgG, IgG4, IgE, total hemolytic complement), and clinical indices.

Results: At baseline, serum sIL-2R (Rs?=?0.532, p?p?Conclusion: The serum sIL-2R level is a potential biomarker for IgG4-RD that may reflect the number of involved organs and may predict patients requiring glucocorticoid treatment.     

Role of interleukin-32 in the mechanism of chronic inflammation in IgG4-related disease and as a predictive biomarker for drug-free remission

Objectives: In immunoglobulin (Ig) G4-related disease (IgG4-RD), the mechanism of chronic inflammation and predictive factors for drug-free remission is still unclear. To examine the issues, we focused on tuberculosis, a chronic infection, and on the role of interleukin (IL)-32.

Methods: We examined the positive rate of QuantiFERON TB-2G (QFT-2G) in 126 patients with IgG4-RD, and compared with the rate in the general population. Furthermore, specimens of submandibular glands from the maintenance treatment group and drug-free group of IgG4-RD and specimens of small salivary glands from primary Sjögren’s syndrome (SS) were stained with anti-IL-32 antibody and anti-protease-activated receptor 2 antibody, and the number of positive cells was compared between these groups.

Results: The positive rate of QFT-2G was 19.8% in IgG4-RD patients, which is higher than in the general population. The expression of IL-32 and PAR2 in the submandibular glands of the maintenance treatment group of IgG4-RD was significantly greater than that of the drug-free remission group and SS patients.

Conclusions: This study indicates the possibility that IL-32 is associated with chronic inflammation and that it can be a predictive factor for drug-free remission in IgG4-RD.     

Risk of malignancies in IgG4-related disease

Abstract

IgG4-related disease (IgG4-RD) is considered a systemic, chronic, and inflammatory disorder that is characterized by the enlargement of involved organs, elevated levels of IgG4, and abundant infiltration of plasmacytes with IgG4 and fibrosis in involved organs. It is necessary to differentiate IgG4-RD from malignant tumors. Recently we have looked at case reports of IgG4-RD with malignancy that was discovered at systemic screening. In this study, we analyzed the relationship between IgG4-RD and malignancies. The study subjects were 106 patients with IgG4-RD who had been referred to our hospital since April 1997. We analyzed the clinical characteristics of IgG4-RD patients who had cancer that was observed upon the initial diagnosis of IgG4-RD or that occurred during an average follow-up period of 3.1 years. Using data from national cancer registries that monitor cancer incidence in Japan, we evaluated the standardized incidence ratio (SIR) for malignancies in IgG4-RD. Malignancies were observed in 11 of the IgG4-RD patients (10.4%). The malignancies were all different and included lung cancer, colon cancer, and lymphoma. With the exception of the age at which the IgG4-RD diagnosis was made, there were no common features in patients with cancer and those without. The SIR for these malignancies in IgG4-RD was 383.0, which was higher than that for the general population. We should be cognizant of the possible existence of malignancies in patients with IgG4-RD at the time of diagnosis and during follow-up care.     

IgG4-related respiratory disease

Abstract

IgG4-related diseases (IgG4-RDs), such as autoimmune pancreatitis and IgG4-related Mikulicz disease, are often accompanied by intrathoracic lesions, which are called IgG4-related respiratory disease (IgG4-RRD). IgG4-RRD has few subjective symptoms, and is usually detected during workup of patients with extra-thoracic lesions of IgG4-RD. IgG4-RRD is characterized by various conditions, including masses, nodules, thickening, and infiltration at numerous sites in the thorax through lymphatic routes. Although elevated serum IgG4 concentrations and pathologic evidence of lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells are characteristic findings of IgG4-RD, other intrathoracic diseases, such as multicentric Castleman disease and malignancy, may present with similar findings. Developing diagnostic criteria for IgG4-RRD, including clinicoradiological and pathological characteristics, is necessary for its appropriate diagnosis.     

IgG4-related kidney disease and retroperitoneal fibrosis: An update

Abstract

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.     

Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: Results from the SMART database

Abstract

Objective. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a new disease entity that has only been identified this century. Clinical information is thus lacking. We established the Sapporo Medical University and Related Institutes Database for Investigation and Best Treatments of IgG4-related Disease (SMART) to clarify the clinical features of IgG4-RD and provide useful information for clinicians.

Methods. Participants comprised 122 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), representing lacrimal and/or salivary lesions of IgG4-RD, followed-up in December 2013. We analyzed the sex ratio, mean age at onset, organ dysfunction, history or complications of malignancy, treatments, rate of clinical remission, and relapse.

Results. The sex ratio was roughly equal. Mean age at diagnosis was 59.0 years. Positron emission tomography revealed that the ratio of other organ involvements was 61.4%. Complications of malignancy were observed in 7.4% of cases. Glucocorticoid was used to treat 92.1% of cases, and the mean maintenance dose of prednisolone was 4.8 mg/day. Rituximab was added in three cases, and showed good steroid-sparing effect. The clinical remission rate was 73.8%, and the annual relapse rate was 11.5%. Half of the cases experienced relapses within 7 years of initial treatment.

Conclusion. We analyzed the clinical features and treatments of IgG4-DS using SMART, providing useful information for everyday clinical practice.     

Total lesion glycolysis as an IgG4-related disease activity marker

Abstract

Objectives. 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was reported to be useful for monitoring immunoglobulin G4-related disease (IgG4-RD); however, a quantitative FDG-PET/CT analysis such as total lesion glycolysis (TLG) has not yet been conducted. This study aimed to investigate whether TLG would correlate with serum markers in IgG4-RD, and the utility of TLG for disease monitoring.

Methods. This retrospective study included 17 patients (12 men; median age, 62 years) who were followed up at Kyoto University Hospital and underwent FDG-PET/CT from April 2009 to November 2013. TLG was calculated for the involved lesions. Correlations between serum markers [IgG4, soluble IL-2 receptor (sIL-2R), lactate dehydrogenase (LDH), and C-reactive protein (CRP)] and TLG concomitant with FDG-PET/CT scans were investigated. Serial changes in TLG were assessed in patients who underwent follow-up FDG-PET/CT (n = 6).

Results. The calculated median (IQL) TLG value was 154.8 (63.7–324.4). A significant correlation was found between the sIL-2R level and TLG (P = 0.001, rs = 0.763). In contrast, no correlations were found between the IgG4, LDH, or CRP levels and TLG. Increased or decreased TLG corresponded with clinical disease improvement or worsening.

Conclusions. TLG correlated significantly with the serum sIL-2R level and may be useful for disease monitoring in IgG4-RD.     

Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment

Abstract

Objectives: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution.

Methods: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed.

Results: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group.

Conclusion: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.     

Utility of Serum IgG4 Levels in a Multiethnic Population

Background

IgG4-related disease (IgG4-RD) is a recently recognized condition defined by characteristic histopathologic findings in affected organs. Serum IgG4 concentration is often but not always elevated. The sensitivity and specificity of serum IgG4 vary greatly across studies and has been anecdotally associated to ethnicity. Our study was conducted to investigate the difference in serum IgG4 levels between Asian and non-Asian patients with IgG4-RD.

Comorbid case of IgG4-related disease and primary Sjögren's syndrome

Abstract

A 63-year-old man with enlargement of the bilateral submandibular glands visited with elevated serum IgG4. A biopsy specimen showed plasma cell infiltration with more than 50% IgG4/IgG staining, suggesting the existence of IgG4-related disease (IgG4-RD). Positive anti-SS-A/Ro antibody and the labial salivary gland's biopsy suggested existence of primary Sjögren's syndrome (pSS). Administration of glucocorticoid improved the serum IgG4 level while reducing the submandibular gland lesions. Positive TUNEL staining suggested the coexistence of IgG4-RD and pSS.     

Clinical and histological changes associated with corticosteroid therapy in IgG4-related tubulointerstitial nephritis

Abstract

Objectives This study aimed to investigate the clinicopathological changes induced by corticosteroid therapy in immunoglobulin (Ig)G4-related tubulointerstitial nephritis (TIN).

Methods We studied six IgG4-related TIN patients receiving renal biopsies before and after corticosteroid therapy. Their clinical data and histological findings were evaluated before and after therapy.

Results Elevated serum creatinine levels rapidly improved after corticosteroid therapy except for two patients, in whom it persisted. Abnormal radiological findings improved in all patients, although focal cortical atrophy persisted in three. Histologically, TIN-like dense lymphoplasmacytic infiltration, interstitial fibrosis, IgG4-positive plasma cell, CD4+CD25+ T cell, and Foxp3+ cell infiltration were characteristic before therapy. After therapy, the area with cell infiltration decreased and regional fibrosis became evident in the renal interstitium. The number of IgG4-positive plasma cells and Foxp3+ cells significantly diminished even in the early stage of therapy, whereas low to moderate numbers of CD4+ and CD8+ T cells still infiltrated where inflammation persisted in the later stage.

Conclusions Our study shows that persistent renal insufficiency associated with macroscopic atrophy and microscopic fibrosis is not so rare in IgG4-related TIN. Pathologically, the behavior of regulatory T cells during the clinical course is quite similar to that of IgG4-positive plasma cells, and the behavior pattern of those cells is distinctive.