IgG4-related Disorder Research Articles

Bessel's disease-the first report of an IgG4-related disorder.

Many aspects of IgG4-related diseases were initially described during the late 19th and early 20th century. Avariety of clinical presentations caused by this common pathology have been named after the researchers who first described the disorders, such as Mikulicz, Küttner, Riedel or Ormond. However, the initial description of retroperitoneal fibrosis dates back to even 50years earlier, when in 1846, the Prussian private practitioner Raphael Jakob Kosch described ahitherto unknown constellation of symptoms and pathological findings in afamous patient. This celebrity was the mathematician and astronomer Friedrich Wilhelm Bessel, aclose friend of Alexander von Humboldt and Carl Friedrich Gauss.

The value of PLA2R antigen and IgG subclass staining relative to anti-PLA2R seropositivity in the differential diagnosis of membranous nephropathy

BackgroundThe diagnostic performance of PLA2R and IgG subclass staining of kidney biopsies relative to anti-PLA2R seropositivity in the differentiation of primary and secondary membranous nephropathy (pMN, sMN) was examined. Besides PLA2R staining – which has a lower specificity than anti-PLA2R antibody serology – there is insufficient knowledge to decide which IgG1-4 subtype immunohistological patterns (IgG4-dominance, IgG4-dominance/IgG1-IgG4-codominance or IgG4-dominance/IgG4-codominance with any IgG subtype) could be used to distinguish between pMN and sMN.Methods87 consecutive Hungarian patients (84 Caucasians, 3 Romas) with the biopsy diagnosis of MN were classified clinically as pMN (n = 63) or sMN (n = 24). The PLA2R and IgG subclass staining was part of the diagnostic protocol. Anti-PLA2R antibodies were determined by an indirect immunofluorescence test in 74 patients with disease activity.ResultsFor pMN, the sensitivity of anti-PLA2R seropositivity was 61.1%, and the specificity was 90.0%; and similar values for PLA2R staining were 81.0%, and 66.7%, respectively. In all stages of pMN, IgG4-dominance was the dominant subclass pattern, while the second most frequent was IgG3/IgG4-codominance. The sensitivity and specificity scores were: IgG4-dominance 52.2% and 91.7%, IgG4-dominance/IgG3-IgG4-codominance 76.2% and 87.5%, IgG4-dominance/IgG1-IgG4-codominance 64.2% and 75%, and IgG4-dominance/codominance with any IgG subclass 92.1% and 70.8%, respectively. Anti-PLA2R seropositivity, glomerular PLA2R, and IgG4-dominance/codominance significantly correlated with each other. The IgG4 subclass was rarely encountered in sMN.ConclusionIn our series, IgG4-dominance had the highest specificity in the differentiation of MN, just as high as that for anti-PLA2R seropositivity. The specificity values of PLA2R staining and IgG4-dominance/codominance with any IgG subclass or IgG4-dominance/IgG1-IgG4 codominance were ≤ 75%. Apart from IgG4 dominance, IgG4-dominance/IgG3-IgG4-codominance also had good statistical value in differentiating pMN from sMN. As IgG subclass switching during the progression of pMN was not the feature of our cohort, pMN in Hungarian patients is presumed to be an IgG4-related disorder right from the start. Although anti-PLA2R seropositivity has become the cornerstone for diagnosing pMN, if a kidney biopsy evaluation is conducted, besides the staining of PLA2R antigen, the evaluation of IgG subclasses provides relevant information for a differential diagnosis. Even in cases with IgG4-dominance, however, malignancy should be thoroughly checked.

Ultrasound and Sialogram Correlates to Parotid Immunoglobulin G4-Related Disease.

Immunoglobulin G4 (IgG4)-related disease is an immune-mediated disorder that commonly manifests in the salivary glands. As a recently described disorder, the description and classification of IgG4-related disease is an ongoing process. Diagnosis of IgG4-related disease requires integration of clinical history, histopathology, and radiographic findings, including ultrasonography and sialography. In this case report, we correlate parotid ultrasonographic and sialographic findings in a patient with proven IgG4-related disorder confirmed from analysis of previous submandibular gland resections. We aim to highlight the utility of multimodality imaging in the diagnosis of IgG4-related disease.

An Update on Idiopathic Hypertrophic Cranial Pachymeningitis for the Headache Practitioner.

We aim to review idiopathic hypertrophic cranial pachymeninigitis (IHCP), describe common head pain patterns and features associated with the disorder, suggest potential classification of head pain syndromes based on the recently published International Classification of Headache Disorders-3, explore pathophysiology found to be associated with cases of IHCP, and indicate common treatment for the disorder. It is suggested that a subset of IHCP is an IgG4-related autoimmune disorder. Patients with IHCP were found to have elevated cerebrospinal fluid (CSF) protein and lymphocytic pleocytosis. Corticosteroids are a mainstay of treatment. Other immunosuppressive agents and steroid sparing agents as add-on therapy may have utility in the treatment of cases refractory to corticosteroids alone. Clinical manifestations of IHCP depend upon the location of the inflammatory lesions and compression of the adjacent nervous system structures. Headache and loss of cranial nerve function were the most common presenting features of hypertrophic cranial pachymeninigitis. Several headache diagnoses may result from IHCP. Gadolinium-enhanced MRI is the standard imaging modality for diagnosing. Although the pathophysiology is poorly understood, many cases of hypertrophic pachymeninigitis (HP) are thought to be closely related to inflammatory disorders. Cases of HP previously thought to be idiopathic may have IgG4 pathophysiology. CSF and serological studies are helpful. Treatment involves immunosuppressive agents. Advancement in neuroimaging, assays, tests, and further delineation of inflammatory disorders affecting the nervous system may provide further insight to the etiology of cases of HP previously considered and diagnosed as idiopathic.

IgG4-Related Disorder Masquerading as an Indurated Skin Lesion

IgG4-related disorder (IgG4-RD) is a recently defined systemic disorder characterized by a unique fibro-inflammatory response that involves multiple organs including lymph nodes, salivary, lacrimal glands, and the pancreas as well as other endocrine organs. These organs display lymphoplasmacytic infiltrate with positive staining for IgG4 and high levels of circulating IgG4. We present an unusual case of IgG4-RD in a 55-year-old African-American female, who presented with an isolated chronic indurated painful mass in the thigh with a normal IgG4. Increased awareness with variable manifestations of IgG4-RD will facilitate the diagnosis of this condition. J Hematol. 2016;5(3):113-115 doi: http://dx.doi.org/10.14740/jh287w

Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature

IgG4-related disorders (IgG4-RD) are a new entity of multi-organ disorders that share common fibro-inflammatory histopathologic characteristics and elevated IgG4 levels in serum and tissue. Autoimmune pancreatitis and Mikulicz syndrome are major entities, however many syndromes are part of IgG4-RD including eosinophilic angiocentric fibrosis, fibrosing mediastinitis, hypertrophic pachymeningitis, inflammatory pseudotumour, multifocal fibrosclerosis (commonly affecting the orbits, thyroid gland, retroperitoneum, mediastinum, and other tissues and organs), periaortitis and peri-arteritis, inflammatory aortic aneurysm, retroperitoneal fibrosis (Ormond’s disease), Riedel’s thyroiditis, and sclerosing mesenteritis. In this review we detail the link between IgG4-RD and endocrine disorders and then examine the link between diabetes and IgG4-RD. We study the increased risk of IgG4-RD after using dulaglutide. We concluded that IgG4-RD should be suspected in patients with progressive thyroiditis with mass effect and very high antibody titers. The relationship between IgG4-RD and diabetes is still controversial.

IgG4-related cardiovascular disorders.

Immunoglobulin4 (IgG4)-related disease is a systemic inflammatory disease characterized by elevation of serum IgG4. It involves various organs such as the pancreas (autoimmune pancreatitis), lacrimal gland (Mikulicz's disease), retroperitoneum (retroperitoneal fibrosis), aorta (aortic aneurysm and aortitis), heart (constrictive pericarditis), and pseudotumors around the coronary arteries. These disorders often coexist in accordance with progression of the disease. Because IgG4-related cardiovascular disorder affects the patient's prognosis, early detection and treatment is important. Coronary CT imaging and echocardiography accidentally detect IgG4-related disorders and (18)FDG-PET imaging can identify active inflammation in the lesions. Measurement of serum IgG4 levels and tissue biopsy are necessary for diagnosis. Minor salivary gland biopsy is recommended even though (18)FDG uptake is not detected when it is difficult to obtain a biopsy specimen from IgG4-related cardiovascular lesions. The first-line treatment is high-dose corticosteroid therapy, however, relapse is often reported. Corticosteroids suppress the development of active inflammatory diseases such as aortitis, pericarditis, and pseudotumors, but already-developed lesions do not respond. A large developed aneurysm can rupture even during or after corticosteroid therapy, therefore, additional surgical treatment may be needed. Treatment of IgG4-related cardiovascular disorders might require higher doses of corticosteroids than IgG4-related extracardiovascular disorders. The adequate dose of corticosteroid, type and dose of immunosuppressant, and surgical intervention should be carefully considered on a case-by-case basis.

Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case

IgG4-related lung disease is commonly associated with autoimmune pancreatitis. Recently, isolated IgG4-related interstitial lung disease (ILD) without other organ involvement has newly been reported in two cases with clinical features of nonspecific interstitial pneumonitis (NSIP).We report the first case of an isolated IgG4-related ILD in a 78-year-old man with dry cough and dyspnea, whose clinical findings proved to be different from NSIP. Serum IgG4 levels were increased. Chest CT scan revealed bilateral consolidations especially in the lower lobes, enlarged mediastinal and hilar lymph nodes and pleural effusions. Video-assisted thoracoscopic (VATS) lung biopsy revealed a pattern similar to usual interstitial pneumonia (UIP) and an abundant IgG4-positive plasma cell infiltration. He was effectively treated by steroid therapy.Increasing recognition of IgG4 related diseases has led to a growing number of new entities. The novel concept of isolated IgG4-related ILD as a pulmonary manifestation of a systemic IgG4-related disorder should be taken into account as a possible differential diagnosis of ILD and mass-forming lesions, even when no other organ manifestation is clinically apparent at the time of diagnosis. Lung specific diagnostic criteria and algorithms are required to enhance diagnostic accuracy in cases of possible IgG4-related ILD.

Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case

IgG4-related lung disease is commonly associated with autoimmune pancreatitis. Recently, isolated IgG4-related interstitial lung disease (ILD) without other organ involvement has newly been reported in two cases with clinical features of nonspecific interstitial pneumonitis (NSIP). We report the first case of an isolated IgG4-related ILD in a 78-year-old man with dry cough and dyspnea, whose clinical findings proved to be different from NSIP. Serum IgG4 levels were increased. Chest CT scan revealed bilateral consolidations especially in the lower lobes, enlarged mediastinal and hilar lymph nodes and pleural effusions. Video-assisted thoracoscopic (VATS) lung biopsy revealed a pattern similar to usual interstitial pneumonia (UIP) and an abundant IgG4-positive plasma cell infiltration. He was effectively treated by steroid therapy. Increasing recognition of IgG4 related diseases has led to a growing number of new entities. The novel concept of isolated IgG4-related ILD as a pulmonary manifestation of a systemic IgG4-related disorder should be taken into account as a possible differential diagnosis of ILD and mass-forming lesions, even when no other organ manifestation is clinically apparent at the time of diagnosis. Lung specific diagnostic criteria and algorithms are required to enhance diagnostic accuracy in cases of possible IgG4-related ILD.

Otologic Manifestation in IgG4-Related Systemic Disease

IgG4-related systemic disease, including autoimmune pancreatitis, is a multi-organ disorder characterized by elevated serum immunoglobulin G4 (IgG4) concentration and IgG4-positive plasma cell infiltration. We report a case of a 66-year-old woman with IgG4-related hearing disorder, presenting with fluctuating mixed hearing loss with middle ear effusion. The serum IgG4 level was elevated and pathological examination revealed dense infiltration of IgG4-positive lymphocyte in the renal parenchyma, lung tissue and lacrimal gland. With intravenous methylprednisolone at a dose of 60 mg daily, improvement of hearing loss were observed. No recurrence was observed for 6 months with mainternance of prednisolone and methotrexate.

Ocular adnexal marginal zone B cell lymphoma infiltrated by IgG4-positive plasma cells

AimsTo report the clinicopathological characteristics of patients with ocular adnexal marginal zone B cell lymphoma (MZBL) with IgG4-positive plasma cells.Methods114 biopsy samples of ocular adnexal MZBLs were analysed. MZBLs with...

Paratesticular fibrous pseudotumor—an IgG4-related disorder?

Paratesticular fibrous pseudotumor (nodular periorchitis, inflammatory pseudotumor of the spermatic cord) is a rare, benign condition of unknown etiology characterized by solitary or multiple intrascrotal nodules composed of dense fibrous tissue with a variable, sometimes sparse inflammatory infiltrate. Based on certain similarities to other fibroinflammatory disorders characterized by infiltrates of IgG4-expressing plasma cells and recently subsumed under the heading of IgG4-mediated diseases, we investigated the plasma cell distribution and immunoglobulin isotypes in three cases of paratesticular fibrous and inflammatory pseudotumor. All three cases showed a high number of IgG4-positive plasma cells with an IgG4 to IgG ratio of 44-48%. This finding indicates that paratesticular fibrous pseudotumor might belong to the growing list of IgG4-related diseases, which by now includes such diverse entities as retroperitoneal fibrosis, sclerosing pancreatitis and cholangitis, Riedel's thyroiditis, or sclerosing sialadenitis.

Castleman's Disease of the Retroperitoneum : With Special Reference to IgG4-Related Disorder

Localized Castleman's disease (CD) has been divided two types, the classical hyaline vascular (HV) type and the rare plasma cell (PC) type. Recently, we have reported two cases of IgG4-related disorder of the retroperitoneum showing PC type of CD. To further clarify the clinicopathological findings of CD of the retroperitoneum, eight such cases have been studied. A single lesion was located in the retroperitoneum (n=3), ureter (n=2) and renal hilum (n=2). One case had bilateral ureter lesions. The HV type of CD accounts for approximately 90% of cases. However, 50% (n=4) of our cases were the PC type of CD. Three of the four lesions of HV type had lymph node lesions, whereas all four PC type of CD were soft tissue masses. These clinicopathologic findings appear quite different from previous descriptions. Immunohistochemical study demonstrated numerous IgG4(+) plasma cells accounting for more that 50% of IgG4(+) cells in three cases of the four PC type of CD. Moreover, serum IgG4 concentration was increased in two of the four cases of PC type of CD that were examined. The serum interleukin-6 levels were within the normal range in two cases of PC type that were examined. The present study suggests that a majority of the PC type of CD arising in the retroperitoneum appears to be an IgG4-related disorder.

IgG4-Related Disorder of the Retroperitoneum Resembling Castleman’s Disease Plasma Cell Type: A Report of 2 Cases

This study reports 2 cases of IgG4-related disorder of the retroperitoneum resembling plasma cell type of Castleman's disease. A single lesion was located in the renal hilum and ureter, respectively, in these 2 cases. Histologically, both lesions were characterized by reactive follicular hyperplasia with active germinal centers and a sheet of polyclonal mature plasma cells in the interfollicular area. The prominent sclerosis and/or fibrosis, which were characteristic histological findings of IgG4-related disorders, were absent. However, immunohistochemical study demonstrated numerous IgG4+ plasma cells accounting for more than 50% of IgG+ cells. The phlebitis that occurs with early lesions of obliterative phlebitis is one of the characteristic histological findings of IgG4-related disorders and was noted in one case. Serum IgG4 concentration was increased in one case. The serum interleukin-6 level was within the normal range in one case that was examined. From a therapeutic perspective, it is important to discriminate IgG4-related disorder from plasma cell type of Castleman's disease.

The Relationship Between Autoimmune Pancreatitis and IgG4-Related Systemic Disorder in Japanese Patients

The Relationship Between Autoimmune Pancreatitis and IgG4-Related Systemic Disorder in Japanese Patients

De novo autoimmune hepatitis after living donor liver transplantation is unlikely to be related to immunoglobulin subtype 4‐related immune disease

Recently, we reported that immunoglobulin subtype 4 (IgG4) is involved in autoimmune hepatobiliary diseases, such as autoimmune hepatitis, sclerosing cholangitis, and pancreatitis. However, the association of IgG4 with autoimmune hepatic disease after living donor liver transplantation (LDLT) has not been investigated. Of the 72 LDLT recipients, four patients (5.6%) were suspected of having autoimmune-related hepatic disease after LDLT. The diagnosis was made based on a histological diagnosis following an examination of a biopsy liver specimen in three cases, while in one case a pemphigoid appeared in the flank with liver fibrosis of unknown cause. Human leukocyte antigen (HLA) mismatches were 3, 2, 2, and 2, respectively. The serum level of IgG4 in the patients was measured, and IgG4 immunohistochemical staining in the liver biopsy specimens was also performed. In all cases, steroid pulse therapy or recycle treatment and subsequent increased steroid dose as well as additional azathioprine or mycophenolate mofetil were effective. While a few positive-stained cells for IgG4 were observed in the liver of one case, negative staining for IgG4 was observed in the other cases. All serum subclasses of IgG4 were within normal limits. In our series of LDLT, IgG4-related immune disorder is unlikely to be involved in post-transplant, autoimmune-related liver disease.

Seronegative Sjögren syndrome with asymptomatic autoimmune sclerosing pancreatitis

We report two elderly patients with seronegative Sjögren syndrome who showed benign swelling of the pancreas on computed tomography. Immunostaining of the biopsied lip tissue or serum examination confirmed an increase in production of IgG4, leading to a diagnosis of autoimmune sclerosing pancreatitis (ASP) as a cause of the asymptomatic swelling of the pancreas. Sicca symptoms and ASP spontaneously improved in one patient, and the other responded well to oral prednisolone. Seronegative Sjögren syndrome and ASP can concurrently occur as a clinical manifestation of the IgG4-related systemic disorder, particularly in elderly subjects, and, in such a case, corticosteroid may be a potent therapeutic option.