Elevated Serum IgG4 Levels Research Articles

Clinicoserological factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease

PurposeTo investigate the factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease (ROD).MethodsTwenty-eight patients with biopsy-proven IgG4-ROD treated between March 2010 and January 2017...

Combined membranous nephropathy and tubulointerstitial nephritis as a rare renal manifestation of IgG4-related disease: a case-based literature review.

IgG4-related disease (IgG4-RD) is a newly recognized immune-mediated multisystemic disease characterized by a fibro-inflammatory condition with tissue infiltration of IgG4-positive plasma cells and often associated with elevated serum IgG4 levels. Typical renal involvement of IgG4-RD presents as tubulointerstitial nephritis (TIN), membranous or membranoproliferative nephropathy. We are presenting a case with combined IgG4 membranous nephropathy and TIN, as well as a literature review on pathophysiology, diagnosis and treatment of IgG4-RD. A 62-year-old man presented with weight loss and fatigue. Labs showed significant proteinuria and hematuria with elevated serum creatinine (2.5mg/dL). CT/PET scan found scattered lymphadenopathy without increased FDG uptake. Kidney biopsy showed glomerular lesions as well as severe interstitial fibrosis and tubular atrophy. Immunohistochemistry study was negative for anti-phospholipase A2 receptor antibodies and showed interstitial lymphocytic infiltration with IgG4 positive plasma cells. Patient also had elevated serum IgG4 level and IgG4 to total IgG ratio. Prednisone treatment was initiated soon after the diagnosis was made, patient responded well with proteinuria and hematuria both resolved. IgG4-related disease (IgG4-RD) is a newly increasingly recognized immune-mediated multisystemic disease; IgG4-related membranous nephropathy should be included in the differential diagnosis for patients with proteinuria.

Delivery of Helicobacter pylori HpaA to gastrointestinal mucosal immune sites using Lactococcus lactis and its immune efficacy in mice.

To develop a safe and effective oral vaccine against Helicobacter pylori using its HpaA protein expressed in Lactococcus lactis. The gene encoding HpaA was obtained by PCR and ligated to pNZ8110-lysM following digestion with NaeI+SphI. The recombinant plasmid was transferred into E. coli for multiplication, and then into L. lactis. The recombinant L. lactis was induced to express HpaA, resulting in two products of 29 and 25kDa, both of which yielded positive immunoreaction with mouse antisera against H. pylori, as confirmed by immunoblot assays. The 29kDa product constituted 12% of the cell lysates. Oral inoculation with the engineered L. lactis evoked significantly elevated serum IgG level in mice (P<0.05). A novel engineered L. lactis strain was developed that efficiently produces whole HpaA protein with desired antigenicity and potent immunogenicity. It provides a basis for approaches to L. lactis-delivered anti-H. pylori vaccination.

Predicting therapeutic response in IgG4-related disease based on cluster analysis

To bring the clinical practice of immunoglobulin (Ig)G4-related disease (IgG4-RD) close to personalized medicine, we classified the patient groups and clarified the therapeutic responses of each group. A total of 147 patients enrolled in our registry were classified into four groups by cluster analysis with the software. The therapeutic responses and prognosis of each group were examined. The cluster analysis classified the subjects into four groups: Cluster 1, patients who presented with prominent hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia; Cluster 2, patients who presented with eosinophilia, elevated concentrations of serum IgG, IgG4, and IgE, and in whom CRP tended to be positive; Cluster 3, patients with younger onset and serum levels of IgG, IgG4, and IgE and peripheral eosinophil counts lower than the other clusters; and Cluster 4, patients with elder onset and low peripheral eosinophil counts. The amounts of glucocorticoid for maintenance treatment were from 5 to 7 mg/d in all groups, but the amounts were significantly greater in Cluster 1 (patients with hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia) than in Cluster 4 (elder onset patients, relatively low concentrations of peripheral eosinophils). With regard to the use of immunosuppressants and the relapse rate, there were high frequencies in Cluster 1 and Cluster 3 (younger onset patients who presented with mild elevations of serum IgG and IgG4). On the other hand, Cluster 4 showed a low rate of relapse and often could discontinue steroids. The present results suggest that personalized medicine could be provided in IgG4-RD by classifying patients based on their clinical features.

IgG4-Unrelated Type 1 Auto Immune Pancreatitis Manifesting with Pancreatic Head Mass Mimicking Cancer

Auto immune pancreatitis (AIP) is an uncommon form of chronic pancreatitis that has been divided into type 1 and type 2 which have distinct histopathology and clinical features. Type 1 AIP seems to be the pancreatic manifestation of an IgG4-related systemic disease, characterized by elevated IgG4 serum levels, infiltration of IgG4-positive plasma cells and extrapancreatic lesions. When manifesting as a focal disease in the pancreas, it can be challenging to differentiate it from pancreatic cancer (PC). Because AIP is typically responsive to steroid therapy without the need for resection, differentiation between these two diseases is critical. We report the case of a 56-year-old man with initial suspect of PC, and final diagnosis of type 1 AIP according to the International Consensus Diagnostic Criteria (ICDC) without elevated levels of serum IgG4 or need for a histology sample. We take a review of literature in order to improve the diagnostic accuracy of AIP and describe clinical and imaging features to differentiate it from PC and avoid unnecessary surgery due to misdiagnosis.

Evaluation of IgG4+ Plasma Cell Infiltration in Patients with Systemic Plasmacytosis and Other Plasma Cell-infiltrating Skin Diseases

Systemic plasmacytosis is a rare skin disorder characterized by marked infiltration of plasma cells in the dermis. IgG4-related disease is pathologically characterized by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, accompanied by elevated levels of serum IgG4. Reports of cases of systemic plasmacytosis with abundant infiltration of IgG4+ plasma cells has led to discussion about the relationship between systemic plasmacytosis and IgG4-related disease. This study examined IgG4+/IgG+ plasma cell ratios in 4 patients with systemic plasmacytosis and 12 patients with other skin diseases that show marked infiltration of plasma cells. Furthermore, we examined whether these cases met one of the pathological diagnostic criteria for IgG4-related disease (i.e. IgG4+/IgG plasma cells ratio of over 40%). Only one out of 4 patients with systemic plasmacytosis met the criterion. These results suggest that systemic plasmacytosis and IgG4-related disease are distinct diseases.

IgG4-related disease: why is it so important?

IgG4-related disease (IgG4-RD) is a recently defined systemic inflammatory and fibrous condition of unknown etiology and multiple clinical presentations. Characteristic features include elevated serum IgG4 levels in approximately 70% of patients; diffuse lymphoplasmocytic infiltrates rich in IgG4(+) cells; a “storiform” fibrosis pattern; and obliterative phlebitis affecting various organs. The disease responds well to corticosteroid treatment, with a second-line therapy involving B-cell-directed immunosuppressive biologic agents. Despite intense studies, the pathogenesis of IgG4-RD remains unclear. The inflammatory infiltrates present in affected tissues contain also multiple polyclonal T and B cells, plasma cells, and – often – eosinophils. Cytokines secreted by type 2 helper T-cells and regulatory T-cells are known to cause B-cell differentiation into IgG4-producing plasma cells. On the other hand, large numbers of IgG4(+) plasma cells can be observed in nonspecific chronic inflammatory conditions, areas adjacent to neoplastic lesions with an inflammatory response, and in autoimmune inflammatory infiltrates. Thus, the fundamental question about the role of IgG4(+) cells in the pathogenesis of inflammation, tissue damage, and fibrosis in IgG4-RD still remains unanswered: does IgG4 stimulate or rather – which is more consistent with its natural properties – play a regulatory function in the inflammatory process?

IgG4-Related Disease with lymphadenopathy Presenting as a Cervical lymph node enlargement

During the course of evaluation and management of neck masses, consideration for Immunoglobulin G4-related disease (IgG4-RD) should be given. IgG4-RD is relatively a new growing entity of immune-mediated origin, characterized by a mass-forming lesion, the infiltration of IgG4-positive plasma cells and occasionally elevated serum IgG4. The most common manifestations are parotid and lacrimal swelling, lymphadenopathy and autoimmune pancreatitis.A previously healthy 72-year-old man was referred to our clinic with a 2-month history of left cervical lymph node enlargement without systemic manifestations . A cervical lymph node biopsy was planned because of elevated serum IgG4 levels. Pathological findings showed prominent infiltration of IgG4-postive plasma cells in the lymph node. After steroid therapy, a computed tomography scan revealed a decrease in the cervical lymph node size.This case illustrates the importance of including IgG4-RD in the differential diagnosis of a cervical lymph node enlargement.

Clinical features and prognostic factors of ten patients with renal failure caused by IgG4-related retroperitoneal fibrosis.

IgG4-related retroperitoneal fibrosis (IgG4-RPF) is a newly recognized entity which often mimics cancer. We aimed to investigate the clinical features and the causes of renal failure, as well as to explore the factors affecting the prognosis of renal function by analysis of the clinical data of patients with IgG4-RPF. We reviewed clinical features of 10 patients with renal failure caused by IgG4-RPF, which was confirmed by pathology review and clinic-pathologic correlations. All patients were male, and the mean age at onset was 64.2 ± 10.0 years. Five patients were revealed with acute renal failure (ARF), while the other five ones with ARF on chronic kidney disease (CKD) (A on C) at diagnosis. Initial favorable responses obtained in 90% of the patients who underwent steroid therapy. The serum creatinine (SCr) level returned to normal in six patients including five with ARF and one with A on C, while those of the rest four patients with A on C restored to baseline levels (GFR remained below 60 ml/min/1.73 m2 however) after therapy. These four unrecovered patients had a history of CKD, a longer period of persistently elevated SCr, a thinner total renal parenchyma thickness, and continuous elevated serum IgG4 levels after steroid therapy, compared with those recovered patients (P < 0.05). We concluded that recovery and long-term prognosis of the disease were primarily associated with timely diagnosis and proper treatment.

IgG4-related disease: with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis.

In 2011, chronic fibroinflammatory processes occurring simultaneously or metachronously in various organs and associated with elevated IgG4 serum levels and/or tissue infiltration with IgG4-positive plasma cells have been recognized as manifestations of a systemic disorder called IgG4-related disease (IgG4-RD). The histologic key findings are lymphoplasmacytic infiltration rich in IgG4-positive plasma cells combined with storiform fibrosis and obliterative phlebitis. Among the organs mainly affected by IgG4-RD are the pancreas and the extrahepatic bile ducts. The pancreatic and biliary alterations have been described under the terms autoimmune pancreatitis (AIP) and sclerosing cholangitis, respectively. These diseases are currently more precisely called IgG4-related pancreatitis (or type 1 AIP to distinguish it from type 2 AIP that is unrelated to IgG4-RD) and IgG4-related sclerosing cholangitis (IgG4-related SC). Clinically and grossly, both diseases commonly imitate pancreatic and biliary adenocarcinoma, tumors that are well known for their dismal prognosis. As IgG4-RD responds to steroid treatment, making a resection of a suspected tumor unnecessary, a biopsy is often required to establish the preoperative diagnosis. This review discusses the morphologic spectrum of IgG4-related pancreatitis and IgG4-related SC and focuses on the biopsy relevant histologic features for the diagnosis and differential diagnosis of these diseases.

New clues to the nature of immunoglobulin G4-related disease: a retrospective Japanese multicenter study of baseline clinical features of 334 cases

BackgroundThe aim was to further characterize immunoglobulin G4-related disease (IgG4-RD) by a large-scale multicenter study of its clinical and laboratory features conducted by multidisciplinary physicians of IgG4-RD in Japan.MethodsVarious specialists retrospectively evaluated IgG4-RD patients diagnosed between 1996 and 2015 in five hospitals by analyzing their baseline clinical features, laboratory, imaging, and pathological test findings, and treatment.ResultsOf the 334 patients listed, 205 were male and median age at diagnosis was 65 years. The mean number of organs involved was 3.2 at diagnosis. The most frequently affected organs were the salivary glands, followed by the lacrimal glands, lymph nodes, pancreas, retroperitoneum/periaorta, kidneys, and lungs. The mean serum level of IgG4 was 755 mg/dl, and more than 95% of patients had elevated serum IgG4 levels. The median serum level of C-reactive protein (CRP) was 0.1 mg/dl and the level was less than 1 mg/dl in 90% of patients. A total of 34.7% of patients had low serum levels of C3. Serum levels of C3 and non-IgG4 IgG, calculated as the total IgG minus IgG4, showed an inverse correlation in patients with kidney lesions, while serum IgG4 levels were not correlated with serum C3 levels. Corticosteroid was administered in 78.0% of patients, and was effective in all.ConclusionsThe serum CRP level is generally low and the serum IgG4 level is elevated in most Japanese IgG4-RD patients, in contrast to western patients. These original findings suggest that these two parameters in IgG4-RD differ in some interesting ways from those hitherto reported in western populations. Additional studies, especially international comparative ones, are needed to elucidate the extent and significance of these differences between populations. Attention will also have to be paid to whether the existence of such differences requires consideration when devising international classification criteria.

Intérêt de la TEP-FDG dans le syndrome d’hyper-IgG4 : à propos d’un cas et revue de la littérature

Hyper-IgG4 syndrome, or IgG4-related systemic disease (IgG4-RSD), is a recently described entity of fibro-inflammatory systemic damage. Multiorgan lesions can occur synchronously or metachronously in a same patient. The common histological features include a lymphoplasmacytic infiltration (especially to IgG4), and fibrosis. Elevated serum level of IgG4 is also often present. The main concerned organs are: pancreas, biliary ducts, mediastinal lymph nodes, peritoneum, lacrimal and salivary glands. We report a case of an unusual location of this disease at the nasophyrnx in a patient of 84years for which the diagnosis was made through immunolabelling with IgG4 in lesions biopsied, and we illustrate the potential role of PET-FDG in this systemic disease.

Pulmonary schistosomiasis mimicking IgG4‐related lung disease

IgG4‐related disease (IgG4‐RD) is a systemic fibroinflammatory disease characterized by tumefactive lesions in various organ systems, including the lungs. Clinical and radiological manifestations of IgG4‐RD are relatively non‐specific, and we report a case highlighting the importance of histopathological confirmation in cases of suspected IgG4‐related lung disease. A 44‐year‐old male with significantly elevated serum IgG4 levels, patchy consolidation on thoracic CT imaging, and cough was referred with suspected IgG4‐related lung disease. However, surgical lung biopsy revealed an unexpected diagnosis of pulmonary schistosomiasis, and following treatment with praziquantel, cough resolved and IgG4 levels significantly declined. This case highlights the potentially diverse array of conditions that may mimic IgG4‐related lung disease and the importance of comprehensive evaluation including histopathological confirmation where possible.

Thoracic involvement in IgG4-related disease in a UK-based patient cohort.

IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder with classical histopathological findings, often in the context of elevated serum IgG4 levels. The thoracic manifestations of IgG4-RD are numerous and can mimic several common and better known conditions. The objective of this study was to outline the frequency and nature of thoracic involvement in a prospective cohort of IgG4-RD patients who met defined diagnostic criteria. Over 40% of IgG4-RD patients had clinicoradiological and/or histological evidence of thoracic involvement, predominantly mediastinal lymphadenopathy, the majority associated with multi-system disease outside the chest. Thoracic involvement was associated with a higher serum IgG4 level, potentially representing greater disease activity or spread. Our data highlight the diverse nature of thoracic IgG4-RD, and the importance of knowledge and recognition of the condition among respiratory physicians who are likely to encounter this disease entity on an increasing basis.

IgG4-Related Systemic Disease Lymphadenopathy Masquerading as Renal Cell Cancer Recurrence: A Surprising Turn of Events

SESSION TITLE: Pulmonary Manifestations of Systemic Disease 4 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Immunoglobulin G4 Related Disease (IgG4-RD) has been recognized in pulmonary and extra-pulmonary inflammatory states. IgG4-RD encompasses a multitude of diseases once thought to be separate entities unto themselves. We herein present a case of IgG4-RD in a 72-year-old man, which was thought to be a recurrence of his distant renal cell carcinoma. CASE PRESENTATION: A 72-year-old man presented to his pulmonologist’s office for an incidental finding of pulmonary opacities with an adjacent axillary solitary lymphadenopathy on a cancer follow-up screening CT of the chest. Further testing with a PET/CT revealed uptake in the both the lymph node and affected lung tissue. Due to concern for distant metastatic disease, an excisional biopsy was performed. Tissue sampling revealed florid reactive follicular hyperplasia with intrafollicular histiocytes and an abundance of IgG4-positive plasma cells, which is the hallmark of IgG4-RD. The patient received corticosteroids, which caused resolution of the pulmonary opacities. The patient returned to the hospital three months later with severe abdominal pain and was diagnosed with acute pancreatitis. At first, he was managed with conservative medical therapy, but his condition worsened. He was then given a course of corticosteroids and his symptoms began to slowly resolve. DISCUSSION: IgG4-RD was termed in 2010 for a systemic fibroinflammatory disease, which presents with tumefactive lesions. A definite diagnosis of IgG4-RD depends on clinical findings such as masses, hematological findings of elevated serum IgG4 levels, and histopathologic findings of lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Treatment is recommended initially with steroids, and other immunosuppressants such as rituximab can be used as steroid sparing treatment. IgG4-RD has many organ system involvements, among them are autoimmune pancreatitis, Mikulicz’s disease, Riedel’s thyroiditis, multi-organ inflammatory pseudotumors, Ormond’s disease, idiopathic hypocomplementemic tubulointersitital nephritis, and multifocal fibrosclerosis. Pulmonary parenchymal involvement frequently presents radiographically as a mass-like, focal opacity, which may mimic a neoplasm, and may show uptake on PET/CT. CONCLUSIONS: IgG4-RD closely resembles malignancies, and has a favorable response to treatment. Therefore, heightened awareness of IgG4-RD and its early diagnosis may significantly improve patients’ morbidity. Reference #1: Campbell SN, Rubio E, Loschner AL. Clinical review of pulmonary manifestations of IgG4-related disease. Ann Am Thorac Soc 2014;11:1466-75. Reference #2: Wolfson AR, Hamilos DL. Recent advances in understanding and managing IgG4-related disease. F1000Res 2017;6 Reference #3: Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. United States 2011:57-66. DISCLOSURE: The following authors have nothing to disclose: Shimshon Wiesel, Anna Gutman, Paul Catella, Phyllis Suen, Abdul Siddiqui, Ali Abou Yassine, Dany El-Sayegh No Product/Research Disclosure Information

Elevated IgG4 serum levels in patients with cystic fibrosis.

ObjectiveSerum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients.MethodsIn a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL.ResultsOne hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations.ConclusionAn elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

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The clinical characteristics of 346 patients with IgG4-related disease

Objective: To analyze the clinical characteristics of IgG4-related disease (IgG4-RD)so as to improve the understanding of IgG4-RD in China. Methods: IgG4-RD patients were recruited from Peking Union Medical College Hospital between January 2011 and January 2016. All patients were followed-up for more than 6 months. The demographic characteristics, symptoms, organ involvements, laboratory examinations and treatment efficacy were evaluated and analyzed. Results: A total of 346 patients were finally enrolled, including 230 males (66.5%) and 116 females (33.5%). The mean age of disease onset was (53.8±14.2) years old. The mostly common involved organs were lymph nodes (56.4%) and submandibular glands (52.6%). Other affected organs and manifestations included: swelling of the lacrimal glands (46.5%), autoimmune pancreatitis (38.4%), pulmonary involvement (28.0%), sclerosing cholangitis (25.4%), naso-sinusitis (23.4%), parotid gland swelling (21.7%), retroperitoneal fibrosis (19.9%), large arteries involvement (9.5%), kidney involvement (obstructive nephropathy caused by retroperitoneal fibrosis was excluded) (6.9%), skin lesions (6.4%). Rare features consisted of thyroid glands, pituitary glands, gastrointestinal tract, pachymeningitis, pericardium, sclerosing mediastinitis and orchitis. The majority of patients had multi-organ involvement, such as 74.3% patients with 3 and more, 18.2% and 7.5% patients with 2 and single organ involvement respectively. The average IgG4-RD responder index (IgG4-RD RI) was 13.21±5.70. History of allergy was found in 172 (49.7%) patients. As to the laboratory tests, elevated serum IgG4 levels were confirmed in 285 (94.1%) patients, which was positively correlated with IgG4-RD RI. There were 33.5% patients receiving monotherapy of glucocorticoid, 52.6% treated with glucocorticoids combined with immunosuppressive agents, 4.9% patients with immunosuppressant only, and 9.0% patients with mild disease not receiving medication. The majority (336, 97.1%) patients improved the above regimens. Conclusion: IgG4-RD is a systemic fibro-inflammatory disease with multiple organ involvement. The mostly common involved organs include lymph node, submandibular glands, and pancreas. Glucocorticoids and immunosuppressive agents were effective for IgG4-RD.

IgG4-related disease; a unifying entity

IgG4-related disease (IgG4-RD) is characterized by dense lymphoplasmacytic infiltration of different organs and elevated serum IgG4 level. The disease involves different organs including pancreas, kidney, aorta, lung, thyroid, salivary and lacrimal glands. IgG4-RD mimics malignancies, infectious and inflammatory disorders. Many disorders previously regarded as isolated, single-organ diseases such as autoimmune pancreatitis type 1, Mikulicz disease, and Riedel thyroiditis are connected within the spectrum of IgG4-RD. Chronic interstitial nephritis (CIN) is the main type of renal involvement. Membranous nephropathy is another renal picture of IgG4-RD. Multiple, hypo-dense, cortical, round and wedge-shape lesions are the main renal ultrasound features. IgG4-RD during its inflammatory phase successfully responds to glucocorticoid therapy. Here we presented a case of IgG4-RD and then reviewed the existing literature.

Surgical management of isolated mesenteric autoimmune disease: addressing the spectrum of IgG4-related disease and sclerosing mesenteritis

IgG4-related disease (IgG4-RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG4 and tissue IgG4 levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid...