Classification Criteria For IgG4-related Disease Research Articles

A Rare Manifestation of IgG4-Related Disease and Secondary Hypereosinophilic Syndrome: A Case Report.

We report a case of IgG4-related disease with marked eosinophilia. A 79-year-old woman was admitted due to diarrhea, and weight loss. Cervical lymphadenopathy, bilateral submandibular glands swelling, anemia (Hb8.5g/dl), hypereosinophilia (9,750/μL), and elevated serum creatinine (1.57 mg/dL), pancreatic amylase (191 IU/L), and IgG4 (3,380 mg/dL) were found. Diffusion-weighted image on MRI showed high intensity signals inside of both the pancreas and the kidney. The echogram of submandibular glands revealed cobblestone pattern. Kidney biopsy revealed acute tubulointerstitial nephritis. Biopsies of lip, gastrointestinal tract and bone marrow showed infiltration of lymphoplasmacytic cells and IgG4 positive plasma cells (30-67/HPF). Gastrointestinal and bone marrow biopsies also showed eosinophilic infiltration. Adrenal insufficiency, rheumatic disease, tuberculosis, parasite infection, drug induced eosinophilia, and eosinophilic leukemia were all ruled out. We started treatment with 40mg of prednisolone and her general condition rapidly improved. The eosinophil count, serum IgG4, and serum creatinine decreased. We gradually tapered prednisolone and maintained 5mg/day. During the 5 years of treatment, she had no recurrence of the symptom. According to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease, eosinophils > 3000/μL is one of the exclusion criteria. If we comply this criterion, the diagnosis of IgG4-related disease should be avoided. However, our case fit the diagnostic criteria of type I autoimmune pancreatitis, IgG4-related sialadenitis and global diagnosis of IgG4-related disease. We finally diagnosed our case as IgG4-related disease with secondary hypereosinophilic syndrome. This case suggests that IgG4-related disease with eosinophils > 3000/μL does exist in the real world.

Performance of the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease in a Large Chinese Cohort.

The purpose of this research was to ascertain the effectiveness of the newly established criteria for classifying IgG4-related disease (IgG4-RD), as applied to a large Chinese cohort in real-world clinical settings. Patient data were procured from the digital health records of 4 prominent academic hospitals. The criterion standard for identifying IgG4-RD patients was from a seasoned rheumatologist. The control group consisted of individuals with other ailments such as cancer, other forms of pancreatitis, infectious diseases, and illnesses that mimic IgG4-RD. A total of 605 IgG4-RD patients and 760 mimickers were available for analysis. The 2019 EULAR/ACR criteria have a sensitivity of 69.1% and a specificity of 90.9% in this large Chinese cohort. IgG4-RD had a greater proportion of males (55.89% vs 36.25%, p < 0.001), an older average age at diagnosis (54.91 ± 13.44 vs 48.91 ± 15.71, p < 0.001), more pancreatic (29.59% vs 6.12%, p < 0.001) and salivary gland (63.30% vs 27.50%, p < 0.001) involvement, and a larger number of organ involvement (3.431 ± 2.054 vs 2.062 ± 1.748, p < 0.001) compared with mimickers. The 2019 EULAR/ACR criteria are effective in classifying IgG4-RD in Chinese patients, demonstrating high specificity and moderate sensitivity.

Update on respiratory lesions in patients with IgG4-related autoimmune pancreatitis.

We previously reported respiratory involvement in 25 patients with autoimmune pancreatitis, a pancreatic manifestation of IgG4-related disease that responds well to glucocorticoid treatment. However, whether all respiratory lesions in patients with autoimmune pancreatitis have genuine respiratory involvement is unclear. This study aimed to update respiratory lesions' clinical and radiological characteristics in patients with autoimmune pancreatitis. We retrospectively reviewed the clinical and radiological data of 74 consecutive patients diagnosed with autoimmune pancreatitis at Shinshu University Hospital and treated with glucocorticoid. Clinical features and chest high-resolution computed tomography findings before and after therapy were reviewed. Fifty-one patients (68.9%) had respiratory lesions. In 65 of the 74 patients, chest high-resolution computed tomography results were evaluated before and after treatment. Patients with IgG4-related disease and respiratory lesions showed significantly higher serum IgG4 levels and hypocomplementemia than those without respiratory lesions; they also had more affected organs. While most abnormal thoracic findings improved, 4 cases of 7 with reticular opacities and all 11 cases with emphysema did not improve. Therefore, these lesions with poor response to glucocorticoid treatment should not be considered due to respiratory involvement of autoimmune pancreatitis based on the current classification criteria for IgG4-related disease. Patients with autoimmune pancreatitis and respiratory lesions exhibited higher disease activity than those without. Most chest high-resolution computed tomography lesions were responsive to glucocorticoid treatment, whereas reticular opacities and emphysema were poorly responsive.

The external validation of the 2019 ACR/EULAR classification criteria for IgG4-related disease in a large cohort from China

ObjectiveTo externally validate the performance of the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-related disease (IgG4-RD) within a cohort from China and to compare the criteria with the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. MethodsThis study included 875 IgG4-RD and 302 non-IgG4-RD cases (213 mimickers and 89 patients with other diseases). Using expert clinical judgment as the gold standard for diagnosis of IgG4-RD, the performance (sensitivity, specificity, area under the curve (AUC) of the 2019 ACR/EULAR criteria for IgG4-RD was evaluated. We also compared it with the 2020 RCD criteria. ResultsThe 2019 ACR/EULAR classification criteria had a sensitivity of 76.6% (95% CI: 73.8% to 79.4%) and a specificity of 98.0% (96.0%-99.4%), an AUC of 0.873 (0.857–0.889) in the overall cohort. Those false negative cases under the 2019 ACR/EULAR classification criteria had significantly lower levels of serum IgG4, and fewer had pathological information, with a higher frequency in the involvement of those uncommon organs compared with the true positive cases. The cases judged as negative by the 2019 ACR/EULAR classification criteria yet judged as “definite” by the 2020 RCD criteria had more involvement of uncommon organs. ConclusionsThe 2019 ACR/EULAR classification criteria for IgG4-RD show outstanding specificity and good sensitivity in real-world clinical practice. The 2020 RCD criteria are helpful for the diagnosis of IgG4-RD in clinical scenarios where IgG4-RD presents as involving an isolated organ, especially the unusual sites.

Clinical value of 18F-FDG PET/CT in IgG4-related disease.

To investigate the clinical value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in IgG4-related disease (IgG4-RD). Seventy two patients diagnosed with IgG4-RD who underwent PET/CT were included. Correlations between clinical variables and PET/CT findings were analyzed by Spearman's correlation test. Conventional radiology was compared to PET/CT to evaluate detection discrepancies. The detection ability of insidious organ involvement by PET/CT at disease onset was investigated. The utility value of PET/CT for the 2019 ACR/EULAR classification criteria was analyzed with the multivariate logistic analysis and ROC curve. SUVmax of main involved organ was positively correlated with IgG4-RD Responder Index (IgG4-RD RI), serum and tissue IgG4 levels and IgG4/IgG ratio, serum eosinophils counts and number of involved organs, while negatively correlated with serum IgM levels. PET/CT was superior in detecting organ/tissue involvements including prostate, gastrointestinal tract and lung compared with conventional imaging. For patients with pancreato-hepato-biliary or head-neck involvements at onset, PET/CT showed superiority in detecting insidious lesions. Multivariate analysis showed that disease duration, multiple-organ involvement, SUVmax of main involved organ and mean SUVmax of all involved organs were significantly associated with the fulfillment of the 2019 ACR/EULAR classification criteria. ROC curves indicated that the cut-off value for SUVmax of main involved organ and mean SUVmax of all involved organs for fulfillment of the 2019 ACR/EULAR classification criteria for IgG4-RD were 4.1 and 3.5, respectively. 18F-FDG PET/CT has potential capacity to monitor disease activity, evaluate organ involvements and assist in the classification criteria in IgG4-RD.

American College of Rheumatology and the European League Against Rheumatism classification criteria for IgG4-related disease: an update for radiologists.

IgG4-related disease (IgG4-RD) is an immune-mediated, multiorgan, chronic inflammatory disease. The three-step classification criteria proposed in 2019 by the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) encompass a wide range of clinical, radiological, serological, and histopathological findings. The ACR/EULAR proposed a three-step classification process, i.e., entry step, exclusion step, and scoring system. Radiologists need to know that the radiological findings observed in the five domains of the lacrimal and salivary glands, chest, pancreas and biliary ducts, kidney, and retroperitoneum are independently weighted with different points in the scoring system. A total score < 20 points indicates that the patient should not be classified as having IgG4-RD; conversely, a total score ≥ 20 points indicates that the patient should be classified as having IgG4-RD. In this review, the 2019 ACR/EULAR classification criteria are discussed, focusing on the interpretation of each radiological item, with the aim of applying them to the diagnosis of IgG4-RD in clinical practice.

Abatacept in IgG4-related disease: a prospective, open-label, single-arm, single-centre, proof-of-concept study.

There is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report. We conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel. The subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept. Abatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.

Differences of clinicopathological features between IgG4‐related and non‐IgG4‐related idiopathic retroperitoneal fibrosis

To evaluate the clinical and pathological features of IgG4-related and non-IgG4-related idiopathic retroperitoneal fibrosis (IRF) according to the latest classification criteria for IgG4-related disease in 2019. Patients with IRF confirmed by histological examination from our hospital between 2000 and 2020 were selected in this study. Medical records of all patients were reviewed by independent researchers. Retroperitoneal specimens were obtained for hematoxylin & eosin staining, elastic-collagenous fiber staining, and immunohistochemical analysis. The clinical and pathological features between IgG4-related and non-IgG4-related IRF were analyzed. A total of 105 patients were included with 77 in the IgG4-related group and 28 in non-IgG4-related group. The ratio of male to female patients and the incidence of acute renal failure were significantly higher in the IgG4-related group than in the non-IgG4-related group. Elevated erythrocyte sedimentation rate and C-reactive protein were more common and the recurrence rate was significantly higher in the IgG4-related group than in the non-IgG4-related group. Radiographically, the ureter was more easily involved by retroperitoneal soft tissue in the IgG4-related group. Histologically, there were no significant differences in the incidence of dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis between the two groups except for the IgG4 staining. Idiopathic retroperitoneal fibrosis can be classified into IgG4-related and non-IgG4-related subtypes. There were no significant pathological differences between the two subtypes of IRF, except for the IgG4 staining. Patients with the IgG4 subtype tended to be more likely to be male, have a higher inflammatory index, and be more likely to have recurrence.

Utility of the “2019 ACR/EULAR classification criteria” for the management of patients with IgG4-related disease

BackgroundThe 2019 ACR/EULAR Classification Criteria for IgG4-related disease (IgG4-RD) represent a fundamental tool for patient enrollment in research studies and in clinical trials but their usefulness in daily clinical practice remains unknown. ObjectiveTo validate the 2019 ACR/EULAR Classification Criteria for IgG4-RD in a real-life setting and to anticipate their utility for orienting disease diagnosis and patient management. MethodsFour experts were asked to classify 200 patients diagnosed with IgG4-RD according to the 2019 ACR/EULAR Classification Criteria for IgG4-RD. Agreement between experts was calculated and the Classification score of each patient was correlated with the following variables and outcomes: serum IgG4 and IgE; inflammatory markers; eosinophils; plasmablasts; IgG4-RD responder index; diabetes, osteoporosis, relapses; and use of rituximab. ResultsAmong the 157/200 cases equally rated by at least three experts, 94 (59.9%) achieved IgG4-RD classification and 63 (40.1%) did not. Strong agreement among IgG4-RD experts was observed in classifying patients (k = 0.711, p<0.0001). Clinical presentations not included in the classification algorithm and lack of informative histology were the most common reasons for not achieving classification. In patients achieving classification, the Classification score did not correlate with variables of disease activity and was not associated with specific outcomes. ConclusionsThe ACR/EULAR Classification Criteria represent a replicable instrument for classifying patients and a useful framework for orienting diagnosis but are of limited utility for assessing IgG4-RD activity, for predicting disease outcomes, and for defining personalized therapeutic approaches.

Positive disease-specific autoantibodies have limited clinical significance in diagnosing IgG4-related disease in daily clinical practice.

The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.

The new 2019 American college of rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-related disease

This paper considers the new 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease, discusses essential differences with IgG4-RD comprehensive diagnostic criteria (Umehara H., 2011) and comments their potential use in clinical practice.

Maladie associée aux IgG4 : des critères « diagnostiques » aux critères de classification ACR/EULAR 2019

The concept of IgG4-related disease (IgG4-RD) has recently been individualized in the early 2000s, but most of the organ involvements are known since more than 100 years. IgG4-RD is a non-malignant fibroinflammatory disorder, characterized by peculiar immunological and pathological abnormalities, which can affect virtually all organs or tissues. Diagnostic criteria have been proposed and have evolved rapidly, with general or organ specific criteria. An international and multidisciplinary group assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) has recently developed and validated a set of classification criteria called 2019 ACR/EULAR classification criteria for IgG4-related disease. The objective of this review is to discuss the evolution from organ specific and general diagnostic criteria toward the 2019 ACR/EULAR classification criteria, as well as respective benefits and limits of these criteria. The use of the 2019 ACR/EULAR classification criteria will help to better define homogeneous group of IgG4-RD patients in future clinical, epidemiological and basic science research studies on the disease.

Performance of the 2019 ACR/EULAR classification criteria for IgG4-related disease and clinical phenotypes in a Spanish multicentre registry (REERIGG4).

Several IgG4-related disease (IgG4-RD) phenotypes have been proposed and the first set of classification criteria have been recently created. Our objectives were to assess the phenotype distribution and the performance of the classification criteria in Spanish patients as genetic and geographical differences may exist. We performed a cross-sectional multicentre study (Registro Español de Enfermedad Relacionada con la IgG4, REERIGG4) with nine participating centres from Spain. Patients were recruited from November 2013 to December 2018. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria (AECC) were used. We included 105 patients; 88% had Caucasian ethnicity. On diagnosis, 86% met the international pathology consensus while 92% met the Japanese comprehensive criteria. The phenotype distribution was head and neck 25%, Mikulicz and systemic (MS) 20%, pancreato-hepato-biliary (PHB) 13%, retroperitoneal and aorta (RA) 26%. Sixteen per cent had an undefined phenotype. Seventy-seven per cent of the cases met the AECC. From the 24 patients not meeting the AECC, 33% met exclusion criteria, and 67% did not get a score ≥20 points. Incomplete pathology reports were associated to failure to meet the AECC. The PHB phenotype was rare among Spanish IgG4-RD patients. The MS phenotype was less frequent and the RA phenotype was more prevalent than in other, Asian patient series. An undefined phenotype should be considered as some patients do not fall into any of the categories. Three quarters of the cases met the 2019 AECC. Incomplete pathology reports were the leading causes of failure to meet the criteria.