IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A ...framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4
T cells have also been investigated in detail; CD4
cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
2.
Trial of Tocilizumab in Giant-Cell Arteritis Stone, John H; Tuckwell, Katie; Dimonaco, Sophie ...
The New England journal of medicine,
07/2017, Volume:
377, Issue:
4
Journal Article
Peer reviewed
Open access
Treatment of giant-cell arteritis with tocilizumab, an interleukin-6 receptor alpha inhibitor, while prednisone was tapered over a 26-week period resulted in higher rates of sustained remission than ...prednisone tapering plus placebo and reduced the total prednisone dose.
Summary IgG4-related disease is a protean condition that mimics many malignant, infectious, and inflammatory disorders. This multi-organ immune-mediated condition links many disorders previously ...regarded as isolated, single-organ diseases without any known underlying systemic condition. It was recognised as a unified entity only 10 years ago. Histopathology is the key to diagnosis. The three central pathology features of IgG4-related disease are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The extent of fibrosis is an important determinant of responsiveness to immunosuppressive therapies. IgG4-related disease generally responds to glucocorticoids in its inflammatory stage, but recurrent or refractory cases are common. Important mechanistic insights have been derived from studies of patients treated by B-cell depletion. Greater awareness of this disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and even death. Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective
IgG4‐related disease (IgG4‐RD) is an immune‐mediated fibroinflammatory condition that can affect nearly any organ. Prior studies have focused on individual cases of IgG4‐RD or small case ...series. This study was undertaken to report detailed clinical and laboratory findings in a larger group of patients with IgG4‐RD whose diagnosis was established by strict clinicopathologic correlation.
Methods
The baseline features of 125 patients with biopsy‐proven IgG4‐RD were reviewed. The diagnosis was confirmed by pathologists’ review, based on consensus diagnostic criteria and correlation with clinicopathologic features. Disease activity and damage were assessed using the IgG4‐RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts.
Results
Of the 125 patients, 107 had active disease and 86 were not receiving treatment for IgG4‐RD. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher IgG4‐RD RI score, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 concentrations (P < 0.01 for all comparisons). The correlation between IgG4+ plasmablast levels and the IgG4‐RD RI of disease activity (Spearman's ρ = 0.45, P = 0.003) was stronger than the correlation between total plasmablast levels and the IgG4‐RD RI. Seventy‐six (61%) of the patients were male, but no significant differences according to sex were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Treatment with glucocorticoids failed to produce sustained remission in 77% of patients.
Conclusion
Nearly 50% of this patient cohort with biopsy‐proven, clinically active IgG4‐RD had normal serum IgG4 concentrations. Elevations in the serum IgG4 concentration appeared to identify a subset of patients with a more severe disease phenotype. In addition, the levels of IgG4+ plasmablasts correlated well with the extent of disease activity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease. Since its discovery nearly two decades ago, our understanding of its pathophysiology and clinical ...manifestations has grown substantially. Early diagnosis and treatment of this elusive disease can prevent substantial organ damage from end-stage fibrosis, emphasizing the need for prompt recognition and accurate characterization of IgG4-RD. The classification criteria endorsed by the American College of Rheumatology and the European Alliance of Associations for Rheumatology in 2019 provide a framework for establishing the diagnosis in the clinical setting. This process involves recognizing the typical manifestations of the disease and incorporating clinical, radiological, serological, and histopathological information as well as excluding disease mimickers. Glucocorticoids and rituximab are effective at inducing remission in IgG4-RD in most patients, but the optimal approach to long-term management of IgG4-RD remains an area of active clinical research.
IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This ...work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. 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 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. 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, epidemiological and basic science investigations.
We evaluated the sensitivity, specificity and positive and negative predictive values of elevated serum IgG4 concentrations for the diagnosis of IgG4-RD.
Between 2001 and 2011, 190 unique patients ...had elevated serum IgG4 measurements. We reviewed electronic medical records to determine the indication for IgG4 measurement and underlying clinical diagnosis. Additionally, we reviewed the records of 190 other randomly selected patients from a pool of 3360 with normal results, to evaluate test characteristics of the IgG4 measurement.
Among 380 patients analysed, 72 had either probable or definite IgG4-RD. Sixty-five of the 72 IgG4-RD patients had elevated serum IgG4 concentrations (mean: 405 mg/dL; range 140-2000 mg/dL), for a sensitivity of 90%. Among the 308 subjects without IgG4-RD, 125 had elevated IgG4 (mean: 234 mg/dL; range 135-1180 mg/dL) and 183 had normal IgG4 concentrations, for a specificity of 60%. The negative predictive value of a serum IgG4 assay was 96%, but the positive predictive value only 34%. Analysis of the serum IgG4/total IgG ratio did not improve these test characteristics. Doubling the cutoff for IgG4 improved specificity (91%) but decreased sensitivity to 35%.
Multiple non-IgG4-RD conditions are associated with elevated serum IgG4, leading to poor specificity and low positive predictive value for this test. A substantial subset of patients with biopsy-proven IgG4-RD do not have elevated serum IgG4. Neither doubling the cutoff for serum IgG4 nor examining the serum IgG4/IgG ratio improves the overall test characteristics for the diagnosis of IgG4-RD.
Background IgG4 -related disease (IgG4 -RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and ...accumulation of IgG4 -expressing plasma cells at disease sites. Objective The role of B cells and IgG4 antibodies in IgG4 -RD pathogenesis is not well defined. We evaluated patients with IgG4 -RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis. Methods B-cell populations from the peripheral blood of 84 patients with active IgG4 -RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy. Results Numbers of CD19+ CD27+ CD20− CD38hi plasmablasts, which are largely IgG4+ , are increased in patients with active IgG4 -RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive. Conclusions Clonally expanded CD19+ CD27+ CD20− CD38hi plasmablasts are a hallmark of active IgG4 -RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell–dependent responses by CD4+ T cells, likely driving a self-reactive disease process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PURPOSE OF REVIEWTo summarize the existing knowledge of various clinical presentations of IgG4-related systemic disease (IgG4-RSD) and to review the evolving list of organs affected by IgG4-RSD.
...RECENT FINDINGSThe term IgG4-RSD encompasses a variety of clinical entities once regarded as being entirely separate diseases. The list of organs associated with this condition is growing steadily. Tissue biopsies reveal striking histopathological similarity, regardless of which organ is involved, although subtle differences across organs exist. Diffuse lymphoplasmacytic infiltrates, presence of abundant IgG4-positive plasma cells and extensive fibrosis are the hallmark pathology findings. Tumorous swelling, eosinophilia, and obliterative phlebitis are other frequently observed features. Polyclonal elevations of serum IgG4 are found in most but not all patients.
SUMMARYIgG4-RSD is an underrecognized condition about which knowledge is now growing rapidly. Yet there remain many unknowns with regard to its cause, pathogenesis, various clinical presentations, approach to treatment, disease monitoring, and long-term outcomes. A wide variety of organs can be involved in IgG4-RSD. Clinicians should be aware of this entity and consider the diagnosis in the appropriate settings.
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