Elevated Serum IgG4 Concentrations Research Articles

Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease

BackgroundIgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition, characterised by an elevated serum IgG4 concentration and abundant IgG4-positive plasma cells in the involved organs. An important question is whether the...

IgG-related disease in a patient with prior pancreatic cancer and splenopancreatectomy

IgG4-related disease is a newly recognised fibro-inflammatory condition characterised by a tendency to form tumefactive lesions in multiple sites; characteristic histopathological appearance with dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis; and, often but not always, elevated serum IgG4 concentrations. We present a case of 69-year-old male with a past history of treated, recurrent mucinous carcinoma of the pancreas who presented with retroperitoneal, axillary and mediastinal lymphadenopathy and a renal mass. Axillary node excisional biopsy showed reactive changes with marked interfollicular increase in IgG4+ plasma cells, along with scattered non-necrotising granulomata. Core biopsies of the renal mass showed polymorphous infiltrate of lymphocytes and predominant plasma cells that stained IgG4. IgH and TCR gene rearrangements were polyclonal. Full blood count was normal other than eosinophilia. Serum IgG4 and IgE were significantly elevated at 11.70 g/L and 258 IU/mL respectively; CRP, ESR, IL-2 and IL-6 were normal. An infectious screen was also negative. The patient was diagnosed with IgG4-related disease and treated, with an excellent response, with prednisolone 0.6 mg/kg. IgG4-related disease is a newly recognised fibro-inflammatory condition characterised by a tendency to form tumefactive lesions in multiple sites; characteristic histopathological appearance with dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis; and, often but not always, elevated serum IgG4 concentrations. We present a case of 69-year-old male with a past history of treated, recurrent mucinous carcinoma of the pancreas who presented with retroperitoneal, axillary and mediastinal lymphadenopathy and a renal mass. Axillary node excisional biopsy showed reactive changes with marked interfollicular increase in IgG4+ plasma cells, along with scattered non-necrotising granulomata. Core biopsies of the renal mass showed polymorphous infiltrate of lymphocytes and predominant plasma cells that stained IgG4. IgH and TCR gene rearrangements were polyclonal. Full blood count was normal other than eosinophilia. Serum IgG4 and IgE were significantly elevated at 11.70 g/L and 258 IU/mL respectively; CRP, ESR, IL-2 and IL-6 were normal. An infectious screen was also negative. The patient was diagnosed with IgG4-related disease and treated, with an excellent response, with prednisolone 0.6 mg/kg.

Severe IgG4-Related Disease in a Young Child: A Diagnosis Challenge.

Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized syndrome that can appear with multiple organ involvement, typically with tumor-like swelling, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and elevated serum IgG4 concentrations. We report the case of a 22-month-old female child with failure to thrive and recurrent respiratory tract infections since 8 months of age. Physical examination was normal except for pulmonary auscultation with bilateral crackles and wheezes. Laboratory tests revealed elevated erythrocyte sedimentation rate, and elevated serum IgG and IgG4 with polyclonal hypergammaglobulinemia. Thoracic CT and MRI showed multiple mediastinal lymphadenopathies and a nodular posterior mediastinal mass in right paratracheal location with bronchial compression. Initial fine needle aspiration biopsy was compatible with reactive lymphadenopathy but after clinical worsening a thoracoscopic partial resection of the mass was performed and tissue biopsy revealed lymphoplasmacytic infiltrate and increased number of IgG4-positive plasma cells and a ratio of IgG4/IgG positive cells above 40%. Glucocorticoids therapy was started with symptomatic improvement, reduction in the size of the mass, and decrease of serum IgG4 levels after 6 weeks. There are very few reports of IgG4-RD in children. Long-term follow-up is necessary to monitor relapses and additional organ involvement.

Clinical review of pulmonary manifestations of IgG4-related disease.

IgG4-related disease (IgG4-RD) is a recently recognized systemic disease characterized by tumefactive lesions in various organ systems. The list of organs that can be involved continues to expand, and recently computed tomography (CT) descriptions of the pulmonary lesions found in the disease have been described. The clinical symptoms are nonspecific and may include cough, dyspnea, chest pain, and fever. The appropriate clinical presentation along with elevated serum IgG4 concentrations and pathologic evidence of lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells and storiform fibrosis is consistent with the disease. Steroids are used to treat this disease in addition to immunosupressives such as cyclosporine or rituxumab for steroid refractory disease. The pulmonary manifestations and imaging features can often mimic malignancy, and as such knowledge of the diagnostic, clinicopathologic, and radiographic features of the disease is required in order to provide appropriate diagnostic workup and treatment.

Abstract 4977: Chronic mastitis in North Africa: Geographic overlap and a potential precursor comorbidity of inflammatory breast cancer

Abstract North African countries, such as Egypt and Morocco, have a high prevalence of non-infectious, chronic mastitis (up to 10% of patients presenting with breast problems) compared to less than 1% worldwide. This same geographic region also suffers from an unusually high prevalence of inflammatory breast cancer (IBC) - 10-15% of breast cancer cases - versus just 1-2% of cases in the U.S. IBC is a serious public health issue as it is the most lethal form of breast cancer because of the propensity for rapid onset of disseminated metastases, which are present in one-third of cases at diagnosis. It is our hypothesis that this geographic overlap is not coincidental, but that the high level of background chronic breast inflammation changes the mammary microenvironment making it more auspicious for the development of IBC. Here we report our work aimed at determining molecular and histologic criteria to classify mastitis into pathogenic groups in order to rationally guide treatment for this serious inflammatory illness, as well as study its possible role in the development of IBC. We identified 44 cases of chronic mastitis of unknown etiology. Cases were defined as any female patient with histopathological diagnosis of chronic mastitis seen at the 5 study hospitals in Egypt and Morocco from 2008-2011. Exclusion criterion was previous diagnosis of malignancy. Biopsy slides were analyzed by a pathologist and stained for IgG4 and IgG. Out of the 44 cases of chronic mastitis using consensus guidelines and our molecular IgG4 profiling, we identified 10 as idiopathic granulomatous mastitis (IGM) and 17 as breast manifestations of IgG4-related disease. IGM is a rare non-neoplastic, chronic, often severe inflammatory lesion of the breast that mimics carcinoma clinically and radiologically. Treatment strategies include watchful waiting, immunosuppressive therapy, wide local or other excisions, or combinations of the above. IgG4-related disease is a newly recognized fibro-inflammatory condition. It is characterized by the formation of tumefactive lesions, a dense lymphoplasmacytic infiltrate with many IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis and, frequently, elevated serum IgG4 concentrations. While no randomized clinical trials have been conducted, glucocorticoid treatment is the standard first line therapy and appears to be quite effective in the majority of patients. This series is the largest reported and is the first step toward changing the chronic breast inflammatory landscape in North Africa by classifying the chronic mastitis into pathogenic groups that can guide personalized treatment protocols. Further studies are needed to discern whether effective and timely treatment of these chronic inflammatory conditions may lower the incidence of IBC. Citation Format: Steven G. Allen, Hanna Oltean, Kathy Toy, Omar S. Omar, Tamer Youssef, Mehdi Karkouri, Azza Abdel-Aziz, Ahmad Hablas, Ali Tahri, Celina Kleer, Amr Soliman, Sofia D. Merajver. Chronic mastitis in North Africa: Geographic overlap and a potential precursor comorbidity of inflammatory breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4977. doi:10.1158/1538-7445.AM2014-4977

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

BackgroundImmunoglobulin 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.ObjectiveWe 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.MethodsThe 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.ResultsEighty 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).ConclusionSerum 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.

The diagnostic utility of serum IgG4 concentrations in IgG4-related disease

ObjectivesWe evaluated the sensitivity, specificity and positive and negative predictive values of elevated serum IgG4 concentrations for the diagnosis of IgG4-RD.MethodsBetween 2001 and 2011, 190 unique patients had elevated serum...

IgG4-Related Disease: A Multispecialty Condition.

IgG4-related disease (IgG4-RD) is a recently recognized group of conditions, characterized by tumor-like swelling of involved organs, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, variable degrees of fibrosis, and elevated serum IgG4 concentrations. Currently IgG4-RD is recognized as a systemic condition that can affect several organs and tissues. Herein we report the case of a 34-year-old male patient who was admitted to our hospital with diffuse abdominal pain, weight loss, and painful stiffness in his neck. He had a history of tumoral mass of the left maxillary region, right palpebral ptosis with protrusion of the eyeball, and chronic dry cough for about 6 years. Laboratory tests revealed polyclonal hypergammaglobulinemia and increased serum IgG4 levels. Immunohistochemical staining of the maxillary biopsy was compatible with IgG4-RD. He had an excellent response to corticosteroid therapy. This case highlights that IgG4-RD should be included in the differential diagnosis with multisystem diseases.

IgG4-related disease: diagnostic methods and therapeutic strategies in Japan.

This review describes methods utilized in Japan to diagnose and treat patients with IgG4-related disease. A diagnosis of IgG4-related disease is based on elevated serum IgG4 concentration and an increased number of IgG4(+) plasma cells. Differentiating IgG4-related disease from other disorders, especially malignancy, is quite important. Consensus treatment in Japan consists of an initial dose of prednisolone at 0.5-0.6 mg/kg/day, followed by careful and gradual dose reduction. Most patients require maintenance treatment at 5 to 10 mg/day. Patients refractory to glucocorticoids are either truly refractory or have been misdiagnosed, therefore requiring reassessment.

Brief Report: Spuriously Low Serum IgG4 Concentrations Caused by the Prozone Phenomenon in Patients With IgG4‐Related Disease

To determine the frequency of the prozone effect in patients with IgG4-related disease (IgG4-RD). After identifying the prozone effect in an index patient with IgG4-RD, we examined additional samples to determine the frequency of this phenomenon. Thirty-eight serum samples obtained from patients with IgG4-RD whose results had been reported previously were retested. The serum IgG4 concentrations determined by this repeat analysis were compared with the originally reported values. In 10 (26%) of 38 patients, the originally reported IgG4 values were falsely low; the prozone effect was identified in each of these 10 samples. Correction of the prozone effect by sample dilution led to revision of the mean serum IgG4 concentration in the 10 samples, from 26 mg/dl to 2,008 mg/dl (normal range 2.4-121 mg/dl). All 10 patients whose samples were affected by the prozone effect had active IgG4-RD. Failure to detect the elevated serum IgG4 concentrations had a direct impact on the decision not to institute treatment in these patients. The prozone effect may lead to major underestimations of IgG4 concentrations in patients with IgG4-RD and offers a potential explanation for the poor correlation observed between disease activity and serum IgG4 levels in some patients. This phenomenon should be considered if the serum IgG4 measurement appears discordant with the clinicopathologic diagnosis and the clinical assessment of disease activity.

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.

Immunoglobulin G4-Related Disease of the Heart Causing Aortic Regurgitation and Heart Block

Immunoglobulin (Ig) G4-related disease is a novel disease entity characterized by diffuse lymphoplasmacytic infiltrates and the presence of abundant IgG4-positive plasma cells in extensive fibrosis, frequently associated with tumorous swelling lesion and elevated serum IgG4 concentrations. Immunoglobulin G4-related disease has been described in almost every organ system but rarely affects the heart. We describe a rare case of IgG4-related disease of the heart causing aortic regurgitation and heart block in a 59-year-old woman. The excised lesion revealed a high ratio of IgG4-positive to IgG-positive plasma cells, providing a definite diagnosis of IgG4-related disease. The aortic valve was replaced using Manouguian technique, resulting in a favorable outcome.

Editorial: IgG4-related Inflammatory Disease - a New Entity

IgG4-related inflammatory disease represents a new entity of unknown aetiology with a fribro-inflammatory condition associated with dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and often but not always elevated serum IgG4 concentration. This condition has been recently reviewed in the New England Journal of Medicine [1]. Auto-immune pancreatitis, described in 2001, was one of the first manifestations of the disease.

Autoimmune pancreatitis: current concepts

Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis with unique clinical, pathological, serological, and imaging features. AIP usually presents with obstructive jaundice. Imaging studies often reveal enlargement of the pancreas with a pancreatic mass and strictures of the main pancreatic duct. Two subtypes of AIP have recently been identified. Type I AIP is more prevalent in elderly Asian males and is characterized by lymphoplasmacytic sclerosing pancreatitis, obliterative phlebitis, and infiltration of large numbers of IgG4-positive plasma cells. Type II AIP is more prevalent in Caucasians and is characterized by granulocyte epithelial lesions. Most patients with type I AIP have a significantly elevated serum IgG4 concentration, which is an important feature for diagnosis and for differentiating between AIP and other conditions such as pancreatic cancer. Extrapancreatic complications are common, such as sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis in type I AIP, and ulcerative colitis in type II AIP. A rapid response to glucocorticoids treatment is suggestive of AIP, but the relapse rate is high, warranting the use of immunosuppressant treatment. B-cell depletion with rituximab may be a promising therapy. The prognosis of AIP is generally benign if treated promptly, and spontaneous remission occurs in a proportion of patients.

IgG4-Related Disease

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by an elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4-RD encompasses a wide variety of diseases, formerly diagnosed as Mikulicz's disease (MD), autoimmune pancreatitis (AIP), hypophysitis, Riedel thyroiditis, tubulointerstitial nephritis, prostatitis, retroperitoneal fibrosis, inflammatory aortic aneurysm and inflammatory pseudotumor. However, like a crow flying on a dark night, IgG4-RD passed through the history of medicine, until the concept of an overarching of these systemic disorders was established in Japan at the beginning of the present century. In addition, most clinical practitioners are not yet familiar with IgG4-RD, and thus one cannot diagnose what one does not know. The purpose of the book [1] is to raise awareness of this disease and its diagnostic pitfalls. Another goal was to delineate the characteristic features of individual organs in IgG4-RD radiologically and histopathologically with many color photographs. Most of the authors are members of the IgG4 team of the Japanese the Ministry of Health, Labor and Welfare (MHLW), and experts who have published numerous important papers in the field. Thus, this book will be useful to physicians in various disciplines such as gastroenterology, rheumatology, ophthalmology, otolaryngology, urology, hematology, respiratory medicine and oral medicine, not only as a textbook but also as an authoritative and comprehensive reference work.

Renal disease masquerading as pyrexia of unknown origin

Pyrexia of unknown origin is a challenging clinical problem. Infections, malignancies, and connective tissue diseases form the major etiologies for this condition. We report a case of a 57-year-old diabetic male who presented with fever of unknown origin for several months. The course of investigations led to a kidney biopsy which clinched the cause of his fever as well as the underlying diagnosis. The light microscopy findings of expansile storiform fibrosis with a dense inflammatory infiltrate suggested the diagnosis which was confirmed by positive staining of Immunoglobulin G4, the dense lympho-plasmacytic infiltrate and elevated serum IgG4 concentrations. A course of steroids followed by mycophenolate mofetil as maintenance immunosuppression rendered the patient afebrile with improvement of renal function.

IgG4-related sclerosing disease in the kidney – a case report

A 39-year-old man presented with a left renal mass. A CT scan showed a 4.5 cm enhancing solid central left renal mass engulfing the pelvicalyceal system and the hilar blood vessels. The patient underwent a left radical nephrectomy. Macroscopically the kidney showed a cream, solid, irregular lesion occupying the central hilar region of the kidney. No necrosis or haemorrhage was present. Microscopically, there was marked fibrosis centred in the renal hilum, and extending into the perihilar fat. Associated with the extensively sclerotic fibrous connective tissue, there was a prominent plasma cell infiltrate with scattered lymphoid collections and a focal obliterative phlebitis. Immuno-histochemical examination showed the plasma cells were reactive for kappa and lambda light chains and IgG4, consistent with IgG4-related sclerosing kidney disease. IgG4 related disease is a fibroinflammatory condition that affects virtually any organ system. It is characterised by a dense lymphoplasmacytic infiltrate rich in IgG4 positive plasma cells, storiform fibrosis and often elevated serum IgG4 concentrations. The histopathological features are similar, regardless of the site of the disease. Many conditions previously confined to single organs are now considered to be part of the spectrum of IgG4-related diseases.

Three cases of IgG4-related orbital inflammation presented as unilateral pseudotumor and review of the literature

IgG4-related disease is an emerging disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. In IgG4-related disease, tumor-like lesions develop in multiple organs, such as the lacrimal gland, salivary gland, lung, pancreas, kidney, and lymph nodes. We report here three cases of IgG4-related orbital inflammation that presented as unilateral pseudotumors. The patients all were men, with an age range of 65-75 years. The patients had been pointed out unilateral intra-orbital masses, and histopathological examinations revealed marked accumulation of IgG4-positive plasma cells (IgG4/IgG ratio: 51.1-71.6%) with fibrosis. But storiform fibrosis was seen in only one case, and no obliterative phlebitis was seen. The serum levels of IgG4 were increased to 178-670 mg/dL. The masses had well-defined homogeneous signal intensities, and they were hypo-intense on T1-weighted MR images and iso-intense on T2-weighted MR images. Gadolinium enhanced mass lesions in two cases. All orbital mass lesions responded well to corticosteroid treatment.

IgG4-Related Sclerosing Cholangitis Mimicking Cholangiocarcinoma

IgG4-related disease has gained increased attention worldwide. While the initial focus was on autoimmune pancreatitis which was first described in Asian populations and turned out to be of relevance in Western populations too, the scope has recently broadened towards a notion of a multi-systemic disease with very diverse manifestations such as autoimmune pancreatitis, IgG4-related sclerosing cholangitis (IgG4-SC), retroperitoneal fibrosis and tubulointerstitial nephritis. IgG4-SC (also known as IgG4-associated cholangitis, IAC) represents a rare but clinically challenging differential diagnosis in patients with obstructive jaundice and proximal extra- or intrahepatic biliary strictures which can be mistaken for cholangiocarcinoma (CC). We present the case of a 79-year-old male patient who presented with obstructive jaundice and biliary strictures at the hepatic duct bifurcation without any evidence for autoimmune pancreatitis and without elevation of serum IgG4-concentrations who underwent hemihepatectomy for suspected CC. However, on histological examination of the resection specimen CC could not be confirmed. It was only after several episodes of obstructive jaundice had reoccurred that the diagnosis of IgG4-SC could be established by reexamination of the surgical specimen which showed extensive infiltration with IgG4-positive plasma cells. Appropriate medical treatment with steroids and azathioprine led to complete remission of the disease. Early recognition of IgG4-SC can save patients from potential harmful and unnecessary surgical interventions. Here we describe the clinical features of this rare case of IgG4-SC with extensive liver tissue infiltration with IgG4-positive cells but without elevated serum IgG4 concentration or evidence of autoimmune pancreatitis. We describe diagnostic criteria for IgG4-SC and review recent insights in pathophysiology and treatment options.

Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011

IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells. Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established. Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists.Background: IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells. Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established. Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists.Methods: Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan. As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively. Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD.Results: Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135 mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10 cells/high powered field of biopsy sample. Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz’s disease (MD) and kidney disease (KD). In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP.Conclusion: Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists.