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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.

A medical eponym honours a scientist’s accomplishment in discovering a disease, symptom, anatomical part, procedure or principle.1 Many of them are firmly embedded in our terminology, such as Hodgkin’s disease, Babinski’s sign, Meckel’s diverticulum or Billroth’s surgery, respectively. Eponyms can be very helpful for professional communication, because they evoke characteristic images in every medical student or doctor and are usually easier to memorise than designations based on pathophysiology or their acronyms. However, the use of eponyms also has disadvantages. They may become outdated, because a progress in knowledge requires a new terminology, or worse, the name belongs to a person, whose acts or views are not in accordance with the social ethos of medical literature.1 2 Therefore, many medical eponyms that once were popular have become outdated over the course of time. In rheumatology, we are currently witnessing a rare phenomenon: an eponymous designation for a disease, which 100 years ago was frequently used in the literature, then became almost forgotten and now reappears in the context of a new immunopathology: ‘Mikulicz’s syndrome’. Jan Mikulicz-Radecki (from 1899 Johann Freiherr von Mikulicz-Radecki) was born in 1850 in Cernivci (then part of the Austro-Hungarian Empire, today Ukraine) as son of a Polish forest and construction official (figure 1). Initially pursuing a career in music, he began his medical training at the University of Vienna in 1869. After finishing his studies in 1875, he became voluntary assistant and later a close friend of the famous surgeon Theodor Billroth. Mikulicz’s contributions to surgery are numerous. He was the first to perform endoscopies of oesophagus and stomach and described achalasia as sphincter dysfunction. He …

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect various organs. The kidney is one of the organs most frequently affected and IgG4-related tubulointerstitial nephritis (TIN) is the most dominant feature.1 However, several radiologically characteristic lesions within the kidney have also been shown to be diagnostic for IgG4-RD affecting the kidney, in the setting of definitively diagnosed IgG4-related lesions in extrarenal organs.2 Therefore the term ‘IgG4-related kidney disease (IgG4-RKD)’ has been proposed as a comprehensive term for the renal lesions associated with IgG4-RD.2 3 In 2011, the IgG4-RKD working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD.4 Recently, we validated those criteria in a Japanese kidney cohort and developed a revised version.5 On the other hand, the 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-RD (the ACR/EULAR criteria) were proposed in 2019.6 According to the latter criteria, exclusion criteria should be applied first to any potential IgG4-RD case. Then, inclusion criteria consisting of eight weighted domains are applied to any case that does not satisfy any of the exclusion criteria, and if …

In their insightful correspondence, Akiyama et al 1 focus on a peculiar feature of eosinophilic granulomatosis with polyangiitis (EGPA), that is, the involvement of salivary and lacrimal glands, which mimics the Mikulicz disease, a common manifestation of IgG4-related disease (IgG4-RD). Given that EGPA shows high serum IgG4 levels (particularly in its active phases),2 and that IgG4-RD often features allergy, eosinophilia and respiratory tract involvement, the differential diagnosis between these two disorders may be challenging. The observation that patients with EGPA can present with Mikulicz-like salivary and lacrimal gland involvement enhances the difficulty in the differential diagnosis with …

ObjectiveIgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.MethodsWe used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.ResultsIn the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, pConclusionWe identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

We read the paper by Vaglio et al in your journal with great interest.1 They reported that patients with eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, showed high serum IgG4 levels, correlating with disease activity and the extent of organ involvement.1 Since then, the association between EGPA and IgG4-related disease has been discussed by researchers.2–4 EGPA is one of the systemic vasculitis and is typically preceded by bronchial asthma, allergic rhinitis and/or sinusitis and followed by peripheral blood eosinophilia and eosinophil infiltration into organs. IgG4-related disease is an emerging disease entity characterised by high serum IgG4 levels and marked IgG4-positive plasma cell infiltration at lesions. Mikulicz disease, a prototype of IgG4-related disease, presents with enlarged lacrimal and salivary glands and often has allergic features such as asthma and chronic sinusitis. Pathogenically, T helper …

We read with much interest the 2019 classification criteria for IgG4-related disease by the American College of Rheumatology and the European League Against Rheumatism.1 This new classification driven by scientific evidence and research provides a substantial amount of new information, which will considerably improve the identification and management of patients with IgG4-related disease. Despite the fact that radiology is integrated into the diagnostic criteria, only CT and/or positron emission tomography-CT are mentioned. We humbly suggest that the use of ultrasonography and/or MRI …

We read with great interest the article from Simpson et al on the clinical efficacy of dupilumab in a patient with IgG4-related disease (IgG4-RD).1 Glucocorticoid is currently the first-line induction therapy for IgG4-RD.2 Since it generally suppresses acquired immune cells, we could not know the therapeutic targets in IgG4-RD. So far, the efficacy of rituximab, targeting B cells, has been discussed,3 but we reconfirm that type 2 helper T (Th2) cells can be one of the therapeutic targets in IgG4-RD by this article. Tanaka et al previously disclosed that the expression of Th2 cytokine mRNA was elevated in the labial glands from patients with IgG4-RD, compared with the patients with Sjogren’s syndrome and healthy controls.4 We have shown that the levels of serum interleukin (IL)-5 were elevated according to the disease …

We read the manuscript reported by Simpson et al with great interest.1 They showed remarkable effectiveness of dupilumab, a monoclonal antibody targeting the interleukin-4 (IL-4) receptor alpha, in immunoglobulin G4-related disease (IgG4-RD) complicated with retroperitoneal fibrosis for the first time. Considering the frequent relapse in patients with IgG4-RD during glucocorticoid tapering and the difficulty in glucocorticoid withdrawal,2 it is of great value that their patient could discontinue prednisone within 2 months after starting dupilumab and even remain stable without any relapse for 12 months.1 They also showed no significant adverse effects of dupilumab for the duration. We have previously revealed that IL-4 plays an important role in the pathogenesis of IgG4-RD.3–5 In particular, IL-4-producing follicular helper T cells contribute to IgG4 class-switching and plasmablast differentiation in the disease.3–5 The case reported by Simpson et al connects the basic research findings with the translational application and …

IgG4-related disease (IgG4-RD) is a systemic disorder characterised by elevated serum IgG4 levels, tissue infiltration by IgG4+ plasma cells and severe fibrosis.1 2 However, biomarkers for IgG4-RD disease activity are lacking.3 A recent report demonstrated that CC-chemokine ligand 18 (CCL18) was a substantial biomarker for fibrotic diseases.4 Here, we investigated the correlation between serum CCL18 levels and clinical features of patients with IgG4-RD. Written informed consent was obtained from all patients and healthy controls. Twenty-eight consecutive patients with active, untreated IgG4-RD diagnosed based on the 2011 comprehensive diagnostic criteria5 and 16 healthy controls were enrolled. Diagnosis of IgG4-RD was biopsy proven in 26 patients (93%). Disease activity was assessed using the IgG4-RD responder index (IgG4-RD RI).6 Healthy controls had no autoimmune diseases, atopic diseases or active infections at enrolment. Serum CCL18 levels were measured using a human CCL18/PARC Quantikine ELISA Kit (R&D Systems, Minneapolis, Minnesota, USA). Characteristics of patients are shown in table 1. The mean age of patients with IgG4-RD and healthy controls was 59.7 and 47.3 years, and the proportion of females were 50% (14/28) and 69% (11/16), respectively. View this table: Table 1 Characteristics of patients with IgG4-related disease Serum CCL18 levels in patients …

We read with great interest the editorial by Fox and Fox1 describing the use of serum immunoglobulin G4 (IgG4) concentrations as a marker for IgG4-related disease (IgG4-RD). IgG4-RD is a fascinating clinical entity including a wide variety of diseases, formerly diagnosed as Mikulicz’s disease, autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis.2 ,3 However, universal criteria for IgG4-RD have not yet been established at present, making its diagnosis in some patients ambiguous leading to many IgG4-RD mimickers. A 3-year investigation by the Japanese IgG4 team, organised by the Ministry of Health, Labour and Welfare (MHLW) of Japan, has reached a consensus, in that IgG4-RD can occur in various organs, with clinical symptoms depending on lesion location. Characteristics common to all forms of IgG4-RD include elevated serum IgG4 concentration and tissue infiltration by IgG4-positive plasma cells, accompanied by tissue fibrosis and sclerosis.2 In 2011, the Japanese IgG4 team published comprehensive diagnostic (CD) criteria for IgG4-RD,4 with the major characteristics being serum IgG4 concentration >135 mg/dL, the infiltration of >10 IgG4+ cells …

ObjectivesTo date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease.MethodsIn this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data.ResultsUsing combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4+ cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions.ConclusionFAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.