Enfermedad relacionada con IgG4: reporte de un caso y revisión de la literatura / IgG4-related disease: a case report and literature review

Immunoglobulin G4 (IgG4-RD) -related disease is a regional or systemic fibroinflammatory disease of unknown etiology. It has a characteristic histopathological appearance of dense lymphoplasmacytic infiltrates with abundant IgG4 positive plasma cells, storiform fibrosis and obliterative phlebitis with the appearance of inflammatory swelling or swollen lesions. This entity frequently affects the pancreas, salivary glands, and lymph nodes, but it can compromise almost any structure in the human anatomy. This new disease entity includes a wide variety of diseases such as Mikulicz disease, autoimmune pancreatitis, Riedel's thyroiditis, interstitial nephritis, and retroperitoneal fibrosis. Glucocorticoid therapy can resolve clinical and pathologic abnormalities and impaired organ function. IgG4-RD was internationally recognized in 2011, and new evidence has accumulated on its pathogenesis, clinical characteristics, and treatment. However, much is still unknown about the behavior of IgG4 in vivo, the participation of this molecule in disease, and whether its role in IgG4-related disease is primary or secondary. The text below is based on a brief review of the most recent literature on this entity in relation to a clinical case.

Enfermedad relacionada con IgG4, según criterios ACR/EULAR 2019 sin evidencia de IgG4 en sangre / IgG4-related disease according to ACR/EULAR 2019 criteria without evidence of IgG4 in blood

INTRODUCCIÓN. La enfermedad relacionada con IgG4 es una patología fibroinflamatoria multiorgánica, de origen desconocido, que simula trastornos malignos, infecciosos e inflamatorios. Los criterios del American College of Rheumatology y la European League against Rheumatism 2019, son útiles para el diagnóstico diferencial de ésta enfermedad cuando se no se cuenta con evidencia de inmunoglobulina G4 en sangre. CASO CLÍNICO. Paciente hombre de 45 años de edad, nacido en Ambato-Ecuador, con ingreso en noviembre del 2017, en emergencias del Hospital de Especialidades Carlos Andrade Marín, con presencia de tos con hemoptisis leve, febrícula, astenia, pérdida de peso e hiporexia de dos semanas de evolución. Se realizó múltiples exámenes, tras observar infiltrados pulmonares intersticiales, con elevación de inmunoglobulina G en suero, negativas para malignidad; se sospechó de enfermedad relacionada a inmunoglobulina G4. Se ampliaron los estudios para descartar otras patologías más prevalentes y cuyo diferencial es primordial. Se inició tratamiento con prednisona y micofenolato con buena respuesta clínica; durante dos años. DISCUSIÓN. La evidencia científica registró que el hallazgo más importante en la enfermedad relacionada con inmunoglobulina G4 fue un aumento de sus niveles séricos. La recurrencia de la enfermedad en un órgano afectado o la aparición de un nuevo órgano involucrado pudo conducir al diagnóstico en el caso presentado. CONCLUSIÓN. La enfermedad relacionada con inmunoglobulina G4 al ser una patología heterogénea, inmunomediada, al simular otras afecciones puede retrasar el diagnóstico; se debe tener una alta sospecha clínica, si al excluir otros procesos infecciosos, autoinmunes y/o eoplásicos, hay evidencia de patología fibroesclerosante multiorgánica sin causa establecida.

INTRODUCTION. IgG4-related disease is a multiorgan fibroinflammatory pathology of unknown origin that mimics malignant, infectious, and inflammatory disorders. The criteria of the American College of Rheumatology and the European League against Rheumatism 2019 are useful for the differential diagnosis of this disease when there is no evidence of immunoglobulin G4 in blood. CLINICAL CASE. 45-year-old male patient, born in Ambato-Ecuador, with admission in November 2017, in the emergency room of the Hospital de Especialidades Carlos Andrade Marín, with the presence of cough with mild hemoptysis, fever, asthenia, weight loss and hyporexia of two weeks of evolution. Multiple tests were performed, after observing interstitial pulmonary infiltrates, with elevated serum immunoglobulin G, negative for malignancy; immunoglobulin G4-related disease was suspected. Studies were extended to rule out other more prevalent pathologies whose differential is paramount. Treatment with prednisone and mycophenolate was started with good clinical response; for two years. DISCUSSION. The scientific evidence recorded that the most important finding in immunoglobulin G4-related disease was an increase in its serum levels. Recurrence of the disease in an affected organ or the appearance of a new involved organ could have led to the diagnosis in the presented case. CONCLUSION. Immunoglobulin G4-related disease, being a heterogeneous, immune-mediated pathology, by simulating other conditions may delay diagnosis; a high clinical suspicion should be maintained if, when other infectious, autoimmune and/or neoplastic processes are excluded, there is evidence of multiorgan fibrosclerosing pathology without established cause.

Review of a novel disease entity, immunoglobulin G4-related disease

Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related disease (IgG4-RD), which has been recognized as a single diagnostic entity for less than 15 years. Histopathologic examination is critical for diagnosis of IgG4-RD. CD4+ T and B cells, including IgG4-expressing plasma cells, constitute the major inflammatory cell populations in IgG4-RD and are thought to cause organ damage and tissue fibrosis. Patients with IgG4-RD who have active, untreated disease exhibit significant increase of IgG4-secreting plasmablasts in the blood. Considerable insight into the immunologic mechanisms of IgG4-RD has been achieved in the last decade using novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploring the interactions between CD4+ T cells and B lineage cells is critical for understanding the pathophysiology of IgG4-RD. Establishment of pathogenic T cell clones and identification of antigens specific to these clones constitutes the first steps in determining the pathogenesis of the disease. Herein, the clinical features and mechanistic insights regarding pathogenesis of IgG4-RD were reviewed.

IgG4-related Mikulicz disease: a case report and literature review / 口腔疾病防治

Objective@#To explore the etiology, clinical manifestations, diagnosis and treatment of IgG4-related Mikulicz disease and to provide a reference for clinical diagnosis and treatment. @*Methods @#Case data from a patient with IgG4-related Mikulicz disease occurring in the submandibular gland and the literature were retrospectively analyzed.@*Results @# IgG4-related Mikulicz disease is a rare autoimmune disease. Its typical features include lacrimal gland and salivary gland swelling, a significant increase in the serum IgG4 level (> 1.35 g/L), and IgG4-positive plasma cell infiltration into a large number of pathological tissues. The disease can easily recur. Treatment is mainly symptomatic, including surgical resection and administration of glucocorticoid and other drug treatment. Long-term follow-up is required after the operation. @*Conclusion@#IgG4-related Mikulicz disease has no specific clinical features. The diagnosis relies mainly on pathological examination and serum IgG4 examination. The main treatment methods are surgery and the use of glucocorticoids, which require long-term follow-up.

Values of serum IgG4, IgG4/IgG ratio,and IgG4/IgG1 ratio in the diagnosis of Mikulicz′s disease / 中华检验医学杂志

Objective To evaluate values of Serum IgG 4,IgG4/IgG ratio,and IgG4/IgG1 ratio for distinguishing Mikulicz′s disease(MD)from primary Sj?gren′s syndrome(pSS).Methods It retrospectively analyzed 186 patients subjected to serum IgG subclass testing to differentiate MD from primary Sj?gren′s syndrome(pSS)at Peking University People′s Hospital from July 2012 to July 2016.This sample included 42 MD patients and 144 pSS patients.Serum IgG subclass concentrations were measured using Siemens reagents with nephelometry and BNⅡinstrument.In partial patients,serum antinuclear antibodies (ANA)were detected by indirect immunofluorescence assay, and serum anti-SSA antibodies and anti-SSB antibodies were detected by Western blot.Serum IgG subclass test results,ANA test results,serum anti-SSA antibody,and anti-SSB antibody test results were collected.The quantitative data were represented by median(quantile range).The Mann-Whitney U test was used to compare the medians between the two groups.Categorical variables were analyzed with a χ2test and were shown as percentages.The ROC curve was constructed to identify the optimal cut-off values and the area under the curve(AUC)values of the serum IgG4,IgG4/IgG ratio,and IgG4/IgG1 ratio for distinguishing MD patients from pSS patients.Results The medians of serum IgG4, IgG4/IgG ratio and IgG4/IgG1 ratio in MD patients were 11 200 mg/L(17 330),0.444(0.314)and 1.318(1.920), as compared with 329 mg/L(490),0.016(0.025)and 0.023(0.039)respectively in pSS patients(Z=-9.368, -9.560, and -9.571, respectively, P<0.001).For distinguishing MD from pSS, the optimal cut-off values of serum IgG4, IgG4/IgG ratio, and IgG4/IgG1 ratio were 1 870 mg/L,0.111, and 0.206, respectively.The corresponding AUC values were 0.976,0.985,and 0.986,respectively.Comparison of the ROC curves showed that there was no significant difference between AUC of serum IgG4/IgG ratio and IgG4/IgG1 ratio(Z=0.283, P=0.777).But AUC of serum IgG4/IgG ratio and IgG4/IgG1 ratio were significantly higher than AUC of serum IgG 4(Z=2.360 and 1.975,repectively,P=0.018 and 0.048,respectively).The positive rates of serum ANA in MD and pSS group were 10%and 85.8%,respectively(χ2=71.340,P<0.001).The positive rates of anti-SSA antibody and anti-SSB antibody in MD were 6.7%and 0%,respectively.Compared to 72.3%and 38.3%in pSS group, they were lower(χ2=44.773 and 16.792, P<0.001).Conclusions Measurements of serum IgG4 concentration,IgG4/IgG ratio, and IgG4/IgG1 ratio were of important values in differentiating MD from pSS.Serum IgG4/IgG ratio or IgG4/IgG1 ratio was superior to serum IgG4.

Mikulicz's Disease with Progressively Transformed Germinal Centers-type Immunoglobulin G4-related Lymphadenopathy Mimicking Sjogren's Syndrome

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease, and lymphadenopathy is frequently observed in these patients. Among the 5 subtypes of IgG4-related lymphadenopathy, progressively transformed germinal centers (PTGC)-type IgG4-related lymphadenopathy possesses a unique characteristic that differentiates it from the other 4 subtypes. Here, we report on a rare case of PTGC-type IgG4-related lymphadenopathy accompanying Mikulicz's disease. A 39-year-old female complained of a left cervical mass and bilateral upper eyelid hypertrophy. The serum level of IgG4 was elevated, and computed tomography showed enlargement of the bilateral lacrimal and submandibular glands and left cervical lymph node. Excisional biopsy of a submandibular gland and cervical lymph node was performed, and the histopathologic findings revealed Mikulicz's disease accompanied by PTGC-type IgG4-related lymphadenopathy. After treatment of the patient with oral prednisolone and azathioprine, the patient's appearance improved. To the best of our knowledge, no case of PTGC-type IgG4-related lymphadenopathy has been previously reported in Korea.

Poor positive predictive value of serum immunoglobulin G4 concentrations in the diagnosis of immunoglobulin G4-related sclerosing disease

BACKGROUND: Immunoglobulin G4 (IgG4)-related sclerosing disease is a recently described clinicopathological entity with diverse manifestations including, amongst others, autoimmune pancreatitis, sclerosing cholangitis, sclerosing sialadenitis and retroperitoneal fibrosis. Elevated serum IgG4 concentration has been described as the hallmark of this condition with reported good sensitivity and specificity. OBJECTIVE: We sought to establish the utility of serum IgG4 concentrations in the diagnosis of IgG4-related sclerosing disease by determining how many serum samples with elevated IgG4 from an unselected population would originate from patients who fulfilled criteria for this diagnosis. METHODS: The clinical features and laboratory characteristics of patients whose serum IgG4 concentration was greater than 1.30 g/L were analysed retrospectively from a total of 1,258 IgG subclass measurements performed in a tertiary hospital diagnostic laboratory. RESULTS: Eighty patients (6.4%) had elevated IgG4 concentrations greater than 1.30 g/L. Nine of 61 patients had the diagnosis of IgG4-related sclerosing disease, giving a poor positive predictive value of 15%. The median serum IgG4 concentrations of those with and without IgG4-related sclerosing disease were 2.16 g/L and 1.86 g/L, respectively (p = 0.22). CONCLUSION: Serum IgG4 concentration has poor positive predictive value in the diagnosis of IgG4-related sclerosing disease and, therefore, the clinical significance of elevated serum IgG4 concentration alone must be interpreted with caution.

Clinical Characteristics of Patients with Autoimmune Pancreatitis with or without Mikulicz's Disease and Mikulicz's Disease Alone

BACKGROUND/AIMS: The objective of this study was to compare the clinical characteristics of patients with autoimmune pancreatitis (AIP) with or without Mikulicz's disease (MD) and with MD alone. METHODS: We investigated the clinical findings in 15 AIP patients with MD (group A+M), 49 AIP only patients (group A), and 14 MD only patients (group M). RESULTS: The male-female ratio was significantly higher in group A+M (73%, p<0.05) and group A (78%, p<0.01) than group M (21%). Serum immunoglobulin G (IgG) levels were significantly higher in group A+M than in group A (p<0.01) and group M (p<0.05). Serum IgG4 levels were significantly higher in group A+M than in group A (p<0.01). Other organ involvement was observed in 73% (11/15) of patients in group A+M. The number of patients with diabetes mellitus was significantly higher in group A+M (66%, p<0.01) and group A (51%, p<0.05) than in group M (7%). All of the patients responded well to steroid therapy, but the relapse rate in group A+M (33%) was significantly higher than that in group A (3%, p<0.01). Salivary gland function was impaired in all groups compared with the control group, but the degree of dysfunction was less in group A compared with group A+M and group M. CONCLUSIONS: The relapse rate of AIP in MD patients was significantly higher than that of AIP in patients without MD.

A Case of Immunoglobulin G4-Related Sialadenitis and Dacryoadenitis / 대한이비인후과학회지

Hypertrophy of salivary gland was developed by sialadenitis, sialolithiasis, autoimmune diasease and other tumorous conditions. Mikulicz's disease has been used to describe symptomless hypertrophy of the salivary gland and lacrimal gland. In the past, it was thought that Mikulicz's disease is included within the diagnosis of Sjogren's syndrome. However, Mikulicz's disease represents Immunoglobulin G4 (IgG4)-related hypertrophy of salivary gland and lacrimal gland by an elevated level of IgG4 in the serum of the patient and good responsiveness to glucocorticoid, eventually leading to recovery of gland function. We have experienced a case of IgG4-related sialadenitis and dacryoadenitis with bilateral hypertrophy of parotid, submandibular and lacrimal glands. We report this case with a brief review of the literature.

A Case of IgG4-Related Sclerosing Disease Involving the Optic Nerve

PURPOSE: To report a case of IgG4-related sclerosing dacryoadenitis masquerading for a long period as a. CASE SUMMARY: A 59-year-old man with visual acuity loss and proptosis in the left eye was referred to our hospital. Ten years prior, the patient was diagnosed with lymphoma and underwent chemotherapy at another hospital. However, the patient spontaneously stopped treatment and took steroids for the relief of periorbital swelling. Magnetic resonance imaging revealed diffuse infiltrative lesions involving both optic nerves and extraocular muscles. Incisional biopsies of the lacrimal gland's posterior side and the lateral rectus muscle's lateral side were performed. Staining for IgG4 via immunochemistry showed infiltration of IgG4-positive lymphoplasmacytic cells. Under the diagnosis of IgG4-related sclerosing disease, the patient underwent high-dose steroid pulse therapy.

A Case of IgG4-Related Sclerosing Disease Involving the Optic Nerve

PURPOSE: To report a case of IgG4-related sclerosing dacryoadenitis masquerading for a long period as a. CASE SUMMARY: A 59-year-old man with visual acuity loss and proptosis in the left eye was referred to our hospital. Ten years prior, the patient was diagnosed with lymphoma and underwent chemotherapy at another hospital. However, the patient spontaneously stopped treatment and took steroids for the relief of periorbital swelling. Magnetic resonance imaging revealed diffuse infiltrative lesions involving both optic nerves and extraocular muscles. Incisional biopsies of the lacrimal gland's posterior side and the lateral rectus muscle's lateral side were performed. Staining for IgG4 via immunochemistry showed infiltration of IgG4-positive lymphoplasmacytic cells. Under the diagnosis of IgG4-related sclerosing disease, the patient underwent high-dose steroid pulse therapy.

The expression of IgG4 in salivary glands and the clinical analysis of 58 cases of Sj(o)gren's syndrome / 中华风湿病学杂志

Objective Mikulicz's disease (MD) was considered to be a subtype of Sj(o)gren's syndrome (SS) due to the clinical and histological similarities between them.Evidence had shown that there were differences between MD and typical SS.The purpose of this study was to investigate the correlation between MD and SS,by means of analyzing the expression of IgG4 in salivary glands and the clinical characteristics of patients who were previously considered as SS.Methods The paraffin sections of salivary glands from SS patients were stained with monoclonal antibodies to IgG4 and CD38.Patients were divided into two groups based on the pathological results.Analysis of the symptoms,the signs and the laboratory results were carried out in these patients.The difference in laboratory parameters and histopathological gradings in the two groups was analyzed.Normal and abnormal distributed data comparison was conducted using random independent samples t-test and rank sum test respectively.Two-sample rates were compared with Chi-square test.Results Based on immunohistochemistry of IgG4 distribution,the 58 patients with SS were divided into two groups:IgG4 related (9 cases) and non-IgG4 related (49 cases).Histopat-hologically,IgG4 related cases showed IgG4+ plasma cells/IgG+ plasma cells infiltration and there were more IgG4 related monoclonal antibody expressed when compared to IgG4 unrelated cases.In addition,there were also significant differences in clinical features between the two groups.IgG4 related disease was associated with male gender,higher level of plateletconnt,lymphocytes [(2.4±0.8)×109/L vs (1.4±0.7) ×109/L] count and CRP [(52±60) mg/L vs (15±17) mg/L] levels and lower titer of IgM [(1.2±0.7) g/L vs (1.8±0.8) g/L],antinuclear antibody (56％ vs 87％) and anti-SSB antibodies (13％ vs 54％) (P＜0.05),when compared with IgG4-unrelated cases.There was no significant difference in other indicators (P＞0.05).Conclusion The present study has demonstrated that some of the MD patients misdiagnosed as SS.Some of the laboratory tests such as the level of platelet and lymphocyte count,serum level of CRP,IgM,antinuclear antibody,anti-SSB antibodies,the serum levels of IgG4 and the histopathological presentations in the salivary gland are different between these two disorders.Because of good response to steroid in MD,so laboratory tests and pathological examinations for IgG4 can help to avoid misdiagnosis.

Corticosteroid Sparing Effect of Hachimijiogan in Mikulicz's Disease : A Case Report / 日本東洋医学雑誌

A 65-year-old woman suffered from swollen parotid and submandibular glands in July 2005, and sicca of the eyes and oral cavity arose in October 2005. We diagnosed her as having Mikulicz's disease based on magnetic resonance imaging of the head, gallium scintigraphy, and a lip biopsy in June 2006. After prednisolone 10 mg/day was commenced, her salivary glands shrank slightly. Although the amount of prednisolone had been tapered to 7 mg/day by May 2007, her serum IgG rebounded. In January 2008, hachimijiogan extract granules 7.5 g/day were introduced. Swelling of the salivary glands disappeared and her serum IgG level decreased. In May 2008, the amount of prednisolone was tapered successfully to 6 mg/day. Mikulicz's disease is a corticosteroid-sensitive disease, but in this case steroid resistance made treatment difficult. Based on this case, we performed functional assays of P-glycoprotein with calcein-AM, which demonstrated that hachimijiogan can reverse drug resistance.