IgG4-related disease (IgG4-RD) is a systemic and chronic inflammatory disorder that can affect every part of the body. The formation of tertiary lymphoid tissues (TLT) in the affected organs may be a ...key phenomenon in understanding the pathogenesis of this disease because T follicular helper (Tfh) 2 cells play an important role in IgG4 class switching within TLT in the affected organs or tissues. TLT formation leads to the formation of masses or swelling of the affected organs. Interleukin (IL)-4 and IL-10 are critical cytokines for IgG4-class switching and are produced in TLT. Other factors, such as CD4-positive (CD4+) cytotoxic T cells, M2 macrophages, and LAG3+ Tfh cells, have been identified as disease-specific contributors to lesion formation. In this review, I describe the current knowledge necessary to understand the pathogenesis of this disease and recent developments in treatment strategies beyond B-cell depletion therapy.
IgG4-related disease (IgG4-RD) is a fascinating clinical entity first reported in this century in Japan, and includes a wide variety of diseases, such as formerly named Mikulicz's disease (MD), ...autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. The Japanese IgG4 team organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan has published the first criteria, comprehensive diagnostic (CD) criteria for IgG-RD 2011. Thereafter, IgG4-RD has been accepted widely and many cases have been reported from all over the world. Several problems have arisen in clinical practice, however, including the difficulty obtaining biopsy samples, and the sensitivity and specificity in cut off level of serum IgG4 and impaired immunostaining of IgG4. Given these situations, the Japanese IgG4 team has updated the 2011 comprehensive diagnostic criteria for IgG4-RD and propose the 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD, which consists of 3 domains; 1) Clinical and radiological features, 2) Serological diagnosis and 3) Pathological diagnosis. In addition, the new pathological diagnosis is composed by three sub-items including storiform fibrosis and obliterative phlebitis.
IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be ...present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.
IgG4-related disease (IgG4-RD) is a fascinating clinical entity proposed by Japanese investigators, and includes a wide variety of diseases, formerly diagnosed as Mikulicz's disease (MD), autoimmune ...pancreatitis (AIP), interstitial nephritis, prostatitis, retroperitoneal fibrosis, etc. Although all clinicians in every field of medicine may encounter this new disease, a unifying diagnostic criterion has not been established. In 2011, the Japanese IgG4 team, organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan, published comprehensive diagnostic criteria for IgG4-RD. Several problems with these criteria have arisen in clinical practice, however, including the difficulty obtaining biopsy samples from some patients, and the sensitivity and the specificity of techniques used to measure serum IgG4 concentrations. Although serum IgG4 concentration is an important clinical marker for IgG4-RD, its diagnostic utility in differentiating IgG4-RD from other diseases, called IgG4-RD mimickers, remains unclear. This review describes the current optimal approach for the diagnosis of IgG4-RD, based on both comprehensive and organ-specific diagnostic criteria, in patients with diseases such as IgG4-related pancreatitis (AIP), sclerosing cholangitis, and renal, lung and orbital diseases.
Objective
IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. ...This work was undertaken to develop and validate an international set of classification criteria for IgG4‐RD.
Methods
An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included.
Results
A 3‐step classification process was developed. First, it must be demonstrated that a potential IgG4‐RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4‐RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4‐RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval 95% CI 97.2–99.8%) and a sensitivity of 85.5% (95% CI 81.9–88.5%). In the second, the specificity was 97.8% (95% CI 93.7–99.2%) and the sensitivity was 82.0% (95% CI 77.0–86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds.
Conclusion
ACR/EULAR classification criteria for IgG4‐RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.
The most representative kidney lesion of IgG4-related disease (IgG4-RD) is plasma cell-rich tubulointerstitial nephritis (TIN) with distinctive imaging findings including multiple low-density lesions ...on contrast-enhanced computed tomography. In addition, membranous glomerulonephritis is a representative glomerular lesion of this disease. Recent advances have clarified that inflammation with IgG4-positive plasma cell infiltrates is not restricted to the renal parenchyma, but can be seen in outside the renal capsule, around medium-sized arteries such as lobar arteries, around nerves, and in the renal pelvis and periureter. Hypocomplementemia is a very important feature of IgG4-TIN, and serum complement level might serve as a convenient biomarker to predict relapse. Although good responsiveness to glucocorticoid has been considered characteristic of IgG4-RD, delayed start of treatment is associated with partial scarring in the kidneys on imaging study. Therefore, steroid therapy should be immediately initiated as soon as the diagnosis of IgG4-TIN is made. Future analyses of pathogenesis will be needed to more precisely define the optimal therapeutic strategies for the various subsets of Ig4-RD patients.
Immunoglobin G (IgG) 4‐related sclerosing pancreatitis and cholangitis (autoimmune pancreato‐cholangitis AIPC) are recently recognized disease entities characterized by high serum IgG4 concentrations ...and sclerosing inflammation with numerous IgG4‐positive plasma cells, although the underlining immune mechanism remains only speculative. In this study, the immunopathogenesis of AIPC was examined with respect to the production of cytokines in situ and the possible involvement of regulatory T cells (Tregs) using fresh (5 cases) and formalin‐fixed (28 cases) specimens of AIPC and related extra‐pancreatobiliary lesions. Quantitative real‐time polymerase chain reaction revealed that AIPC and extra‐pancreatobiliary lesions had significantly higher ratios of interleukin (IL)‐4/interferon‐γ (IFN‐γ) (45.8‐fold), IL‐5/IFN‐γ (18.7‐fold), IL‐13/interferon (IFN)‐γ (20.7‐fold), IL‐10/CD4 (45.3‐fold), and tumor growth factor (TGF)‐β/CD4 (39.4‐fold) than did primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Lymphocytes with signals for IL‐4 and IL‐10 were frequently found in AIPC by in situ hybridization. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4+CD25+ Tregs, was significantly increased in AIPC and extra‐pancreatobiliary lesions in comparison to PSC and PBC (36.4‐fold). Immunohistochemically, CD4+CD25+Foxp3+ cells were frequently found in AIPC, while few were found in PSC and other disease controls. Taken together, AIPC could be characterized by the over‐production of T helper (Th) 2 and regulatory cytokines. Tregs might be involved in the in situ production of IL‐10 and TGF‐β, which could be followed by IgG4 class switching and fibroplasia. Conclusion: AIPC is a unique inflammatory disorder characterized by an immune reaction predominantly mediated by Th2 cells and Tregs. (HEPATOLOGY 2007.)
ABSTRACT
Recent advances in the management and understanding of immunoglobulin (Ig)G4-related kidney disease (RKD) have emphasized the importance of urgent treatment in IgG4-related ...tubulointerstitial nephritis. On the other hand, to avoid long-term glucocorticoid toxicity, strategies for early withdrawal of steroids or combination of immunosuppressants, such as rituximab, and the minimum dose of steroids have been pursued. However, disease recurrence after reducing or stopping steroid therapy hampers early withdrawal of glucocorticoid maintenance therapy. In addition, knowledge has accumulated in diagnostic approaches including differential diagnosis of anti-neutrophil cytoplasmic antibodies-associated vasculitis, idiopathic multicentric Castleman’s disease, and Rosai–Dorfman disease with kidney lesion, which leads to earlier and precise diagnosis of IgG4-RKD. This review summarizes recent progress in the differential diagnosis of IgG4-RKD and related treatment strategies and recent topics of hypocomplementaemia, membranous glomerulonephritis, and IgG4-related pyelitis and periureteral lesion.
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