Spectrum Of IgG4-related Disease Research Articles

Coronary periarteritis and pericarditis are rare but distinct manifestations of heart involvement in IgG4-related disease: a retrospective cohort study

BackgroundThe heart can be involved in immunoglobulin (Ig)-G4-related disease (IgG4-RD). This study aimed to summarize the clinical features and efficacy of treatment for IgG4-RD patients with heart involvement.MethodsWe conducted a retrospective study enrolling 42 IgG4-RD patients with heart involvement from the IgG4-RD cohorts of the Peking Union Medical College Hospital and Beijing An Zhen Hospital, from 2010 to 2022. Clinical, laboratory, radiological data were collected, and treatment responses to glucocorticoids and immunosuppressants were analyzed.ResultsIgG4-related cardiac involvement is a rare part of the IgG4-RD spectrum. The incidences of coronary periarteritis and pericarditis were 1.2%(13/1075) and 3.1%(33/1075), respectively in our cohort. Valvular disease possibly related to IgG4-RD was detected in two patients. None of the patients with myocardial involvement were identified. The average age was 58.2 ± 12.8 years, with a male predominance (76.7%). Coronary artery CT revealed that mass-like and diffuse wall-thickening lesions were the most frequently observed type of coronary periarteritis. Pericarditis presented as pericardial effusion, localized thickening, calcification and mass. After treatment with glucocorticoid and immunosuppressants, all patients achieved a reduced IgG4-RD responder index score and achieved radiological remission. Two patients with coronary peri-arteritis experienced clinical relapses during the maintenance period.ConclusionsCardiac involvement in IgG4-RD is rare and easily overlooked since many patients are asymptomatic, and the diagnosis relies on imaging. Patients showed a satisfactory response to glucocorticoid based treatment.

Hypertrophic pachymeningitis due to IgG4-related disease (RD-IgG4). A case report

IntroductionHypertrophic pachymeningitis (HP) is a clinico-radiological entity characterized by a thickening of the dura mater that may be focal or diffuse and manifested by a variety of neurological syndromes. Aetiologically, it is classified as infectious, neoplastic, autoimmune, and idiopathic. Many of these formerly idiopathic cases have been shown to fall into the spectrum of IgG4-related disease. ObjectiveTo describe the case of a patient attended for neurological involvement due to hypertrophic pachymeningitis with initial diagnosis of inflammatory myofibroblastic tumour and final diagnosis of IgG4-related disease. CaseA 25-year-old woman with neurological symptoms of 3 years’ evolution characterized initially by right hypoacusis, evolving with headache and diplopia. Magnetic resonance imaging (MRI) of the encephalon showed pachymeningeal thickening with involvement of vasculo-nervous structures in the tip of the cerebellum, cavernous sinus, ragged foramen, and optic chiasm. The patient presented for consultation with the result of an incisional biopsy that reported a proliferative lesion combining fibrous elements of fascicular or swirling arrangement with collagenized streaks with dense, lymphoplasmacytic infiltrate and some macrophages, with negative staining for ALK 1, with a diagnosis of inflammatory myofibroblastic tumour.Due to suspicion of IgG4-related disease (IgG4-RD) the biopsy was sent for review and pertinent complementary studies were requested. Biopsy reviewNon storiform fibrosis, predominantly lymphoplasmacytic infiltrate, histiocytes, and polymorphonuclear infiltrate in sectors, without granulomas or atypia. Staining for germs negative. Immunohistochemistry with 50–60 IgG4+/HPF cells and range of 15%–20%, CD68+ in histiocytes, CD1a−, S100−.The patient presented deterioration of visual acuity due to ophthalmic nerve involvement, so glucocorticoid treatment was started in pulses and rituximab with regression of symptoms and imaging improvement of the lesions. ConclusionHP is a clinical imaging syndrome with variable symptoms and aetiologies that poses a diagnostic challenge.In this case the initial diagnosis was inflammatory myofibroblastic tumour, which is a neoplasm of variable behaviour, locally aggressive, and can metastasize; it is one of the main differential diagnoses of IgG4-related disease because they share anatomopathological features, including storiform fibrosis.IgG4-RD is an immune-mediated condition that can have single or multiple involvement. Its diagnosis is complex when it presents with single organ involvement or in non-typical organs (CNS, meninges) in which data are scarce, as in the case of our patient with single organ involvement of the CNS.Although there are classification criteria to guide non-specialists in the diagnosis, the sum of the clinical picture, imaging, laboratory, pathological anatomy, and immunohistochemistry will always be evaluated together for a definitive diagnosis.

Hypereosinophilia with IgG4 Associated Cholangiopathy

IgG4-related sclerosing cholangitis (IgG4-SC) belongs to the spectrum of IgG4-related disease which encompasses many medical conditions. We report a case of a 59-year-old man who presented with clinical and radiologic features of primary sclerosing cholangitis but where hypereosinophilia along with an extremely high blood level of IgG4, liver infiltration with IgG4-positive plasma cell and a spectacular response to corticoids treatment, confirmed the diagnosis of IgG4-SC.

Eosinophilic angiocentric fibrosis and immunoglobulin 4-related disease revisited.

Eosinophilic angiocentric fibrosis (EAF) has been postulated to lie on the spectrum of IgG4-related disease (IgG4-RD) in a study reported in 2011. However, the aetiology of EAF remains controversial, despite increasing literature reporting IgG4-RD targeted investigations in those studies. This review aims to formally evaluate the relationship between EAF and IgG4-RD using the latest 2019 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification scheme for IgG4-RD. A literature search was performed on the PubMed database for all studies describing patients diagnosed with EAF. Additionally, two EAF cases were retrospectively identified from our institution and presented. The demographics, clinical presentation, histological and serological data of each patient were analysed. A total of 20 cases were evaluated, including 18 patients from 14 articles in the English literature and two cases from our institution. Six of 20 (30%) patients with EAF met the criteria for IgG4-RD with the 2019 ACR/EULAR classification scheme. This represents the first attempt at formally evaluating the relationship between EAF and IgG4-RD using a validated set of classification criteria. Using the currently available data, a small proportion of patients with EAF met the criteria for IgG4-RD. However, various limitations of this study suggest that further efforts at disease characterization of EAF may be required.

IgG4-related pseudotumours: a series of 12 cases and a review of the literature

IgG4-related pseudotumours (IgG4-RPT) represent a distinctive manifestation in the broad spectrum of IgG4-related diseases (IgG4-RD). Due to their wide morphology and rarity, IgG4-RPTs represent a diagnostic challenge in the differential between reactive lesions and a fibrous soft tissue tumours. Thus, our aim was to characterise our cases and review the literature, focusing on the macroscopic and microscopic features of the lesions. In this paper, we summarise the possible presentations and histomorphological features of IgG4-RPT based on data collected from the literature and from cases at our institute and provide an overview of the pathogenesis and histological characteristics based on the knowledge accumulated in recent years. We collected surgical cases with a diagnosis of IgG4-RPT over the period 2013-2020 at two centres and analysed their macroscopic, histological, and immunohistochemical profiles. Furthermore, we performed a literature research in the MEDLINE and EBSCO databases regarding case reports and studies with the explicit diagnosis of IgG4-RPT. Our cases consist of nine men and three women, with an average age of 60±14 years, representing about 0.05% of the lesions evaluated at the two departments. The involved sites include the kidney, lung, gallbladder, pterygopalatine fossa, spleen, tongue, mediastinum, and submandibular gland. Grossly, nine lesions showed sharp margins. On histological examination, all the lesions showed an abundant inflammatory infiltrate with lymphocytes and IgG4-positive plasma cells as well as characteristic fibroblastic storiform proliferation. The literature search revealed 266 cases and similar histomorphological features in 23 locations. In 30 of these cases (11%), IgG4-RPTs were multifocal. IgG4-RPT are exceedingly rare lesions, which makes them challenging to diagnose. They can affect different sites, and the histomorphological presentation may differ.

Sinonasal IgG4-related disease: a rare and emerging entity broadening the differential diagnosis in the sinonasal universe.

IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated disorder characterized by fibroinflammatory mass-forming lesions, mimicking malignancy or infection. While well-documented in salivary glands, orbit and thyroid in the head and neck, sinonasal IgG4-RD is rare. Cases of sinonasal IgG4-RD were retrieved, and clinicopathological features reviewed. Seven cases of sinonasal IgG4-RD were identified over a 2-year period, including three males and four females, with an age range of 13-48years(median: 32years). Patients presented with cheek swelling, pain and visual disturbances. Serum IgG4 levels were mildly elevated. Storiform fibrosis, obliterative phlebitis and plasma cell infiltration were seen in varying proportions. Destruction of bone and subepithelialmucoserous glands was present. ALK-1 negativity distinguished from inflammatory myofibroblastic tumor. Sinonasal IgG4-RD expands the growing spectrum of IgG4-RD. A high degree of suspicion is required to include IgG4-RD in differential diagnosis of sinonasal masses, and perform detailed histological and immunohistochemical workup for accurate diagnosis.

Combination of autoimmune pancreatitis and peripheral neuropathy on an IgG4-related disease patient with 4 years following-up

Type1 autoimmune pancreatitis (AIP) is the first recognized and the most common manifestation of IgG4-related disease. However, AIP patient presented with neuropathy in the extremities have not been reported previously. We reported a rare combination of autoimmune pancreatitis and peripheral neuropathy on an IgG4-related disease patient based on histological features to expand the clinical spectrum of IgG4-related disease.

La fibrose rétropéritonéale idiopathique

Retroperitoneal fibrosis (RPF) is a rare disease characterized by the presence of fibro-inflammatory tissue around the aorta entrapping the adjacent structures. RPF can be idiopathic or secondary to many disorders. The physiopathology is unknown but can be part of the spectrum of IgG4 related diseases. Imaging studies and inflammatory markers are essential for initial evaluation and follow-up. Biopsy is usually not recommended. The first line of treatment is corticosteroids associated or not with immunosuppressive drugs. In case of ureteral obstruction with renal failure, ureteral stent placement or nephrostomies are recommended. Initial response to treatment is usually good but relapses are frequent.

IgG4-related aortitis/periaortitis and periarteritis: a distinct spectrum of IgG4-related disease

BackgroundLarge vessels could be involved in immunoglobulin (Ig)-G4-related disease (IgG4-RD). This study aimed to clarify the clinical features and evaluate the treatment efficacy for IgG4-RD with aortitis/periaortitis and periarteritis (PAO/PA).MethodsThis study prospectively enrolled 587 patients with IgG4-RD with a follow-up time of more than 6 months. The distribution of IgG4-related PAO/PA was classified into four types: type 1, thoracic aorta; type 2a, abdominal aorta; type 2b, abdominal aorta and iliac artery; type 2c, iliac artery; type 3, thoracic and abdominal aorta; and type 4, other arteries. Patient’s demographic data, clinical characteristics, laboratory parameters, and treatment efficacy were analyzed.ResultsOf 587 IgG4-RD patients, 89 (15.2%) had PAO/PA. The average age was 58.3 ± 11.1 years, with male predominance (85.4%). Vessels affected were as follows: abdominal aorta (83.1%), iliac artery (70.8%), thoracic aorta (13.5%), and other vessels (13.5%). The most prevalent distribution type of IgG4-related PAO/PA was type 2b, with 74 (83.1%) patients, followed by type 2a, type 2c, type 3, and type 1. Fifty-five (61.8%) PAO/PA patients had hydronephrosis, with renal insufficiency occurring in 43 (48.3%), and 31 (34.8%) PAO/PA patients had D-J stent drainage due to severe ureteral obstruction. After treatment with a glucocorticoid and immunosuppressants, 82% patients achieved remission with shrinking of the perivascular mass by more than 30%.ConclusionsIgG4-RD with PAO/PA was distinct from non-PAO/PA in demographic features, organ involvement distribution, inflammatory markers, and serum IgG4 and IgE. The most common affected vessel was the abdominal aorta, and most patients responded well with treatment.

A reappraisal of sclerosing nodular and/or polypoid lesions of the gastrointestinal tract rich in IgG4-positive plasma cells.

To describe additional cases of nodular and polypoid sclerosing lesions of the gastrointestinal tract (GIT) that are associated with numerous IgG4-positive plasma cells, review the pertinent literature to ascertain the relationship with systemic IgG4-related disease, and provide a reporting framework for such lesions. Five new cases of sclerosing polyps or nodules were collected over a 10-year period, occurring in four females and one male ranging in age from 32years to 56years (mean, 41.6years). Patients were asymptomatic or had epigastric pain, and one had rectal bleeding. None had autoimmune or other obvious IgG4-related disease, and serum IgG4 levels were normal. All were solitary nodules in the stomach (two cases), ileum, caecum, and rectum. Four lesions were submucosal and one was subserosal; all were well circumscribed, composed of hyalinised, keloidal fibrous tissue with lymphoplasmacytic inflammation. Obliterative phlebitis was not seen. Lineage-specific immunomarkers were negative. In excess of 10 IgG4-positive plasma cells per high-power field were seen, and the IgG4/IgG ratios were >0.4. Very few IgG4-related lesions in the tubular GIT are associated with disease at other sites and/or elevated serum IgG4 levels. The majority may represent a lesion in the spectrum of IgG4-related disease. The use of the term 'IgG4-positive nodule or polyp with probable histological features of IgG4-related disease' is advocated for nodular and/or polypoid lesions in the GIT with ≥10 IgG4-positive plasma cells in a high-power field and an IgG/IgG4 ratio of >0.4.

The broad and challenging landscape of extranodal lymphoproliferations.

Two sessions in the workshop of the 19th meeting of the European Association for Haematopathology termed "challenging extranodal lymphoproliferations" and "extranodal non-site-specific lymphoproliferations", dealt with a series of heterogenous cases. These included lymphoproliferations of all cell lineages, from reactive lesions mimicking lymphomas through indolent lymphoid neoplasia and tumours with unclear biological behaviour to aggressive and transformed lymphomas. The themes addressed included cases with borderline features between hyperplastic and neoplastic lesions, the diagnostic spectrum of IgG4-related disease, T cell lymphoproliferations arising in extranodal sites with presumed indolent behaviour, diverse clinical presentations of intravascular large B cell lymphoma, diagnostic problems encountered with tumours displaying plasmablastic morphology, pitfalls concerning rare entities like adult T cell lymphoma/leukaemia (ATLL) and extranodal natural killer/T cell (NK/T) lymphomas, and unusual clinical presentations of various lymphomas. Altogether, within the frame of these two sessions, 75 cases remarkably differing in their clinical background, genetic features and overall need for a meticulous diagnostic approach were presented and discussed. In this paper, the salient points raised during the discussion of the cases, current diagnostic concepts and recommendations relevant to the diagnosis of these lymphoproliferations are described.

An old disease, a new diagnosis; A 49 year-old man with nephrotic syndrome

Background: IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that typically manifests as fibro-inflammatory masses that can affect nearly any organ system. Case Report: We present here a case of a 49-year old man with forgotten old disease (Mikulicz disease) with membranous nephropathy (MN). Conclusions: This entity is currently included within the spectrum of IgG4-related disease. The development of renal disease shortly after the suspension of rituximab suggests another probable pathway involved. To our knowledge the transforming growth factor may be responsible for existing pattern of fibrosis in this disease. The lack of response or at least partial response to rituximab can be explained by greater involvement of regulatory T lymphocyte in the pathophysiology of this entity.

DIAGNOSIS OF ENDOCRINE DISEASE: IgG4-related thyroid autoimmune disease.

IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel's thyroiditis, Hashimoto's thyroiditis and its fibrotic variant, Graves' disease and Graves' orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.

Clinical and Prognostic Significance of Serum IgG4 in Chronic Periaortitis. An Analysis of 113 Patients.

Objective: Chronic periaortitis (CP) is a rare fibro-inflammatory disorder that incorporates idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms, and perianeurysmal retroperitoneal fibrosis. CP is included in the spectrum of IgG4-related disease. Since CP patients rarely undergo diagnostic biopsies, serum IgG4 levels are often used to classify CP as IgG4-related. However, the clinical and prognostic significance of serum IgG4 in CP is unknown.Methods: We measured serum IgG4 in active CP patients and compared the clinical characteristics, response to therapy and outcome of patients with high and normal levels. We also tested the diagnostic significance of IgG4 by comparing its levels in CP patients, healthy and disease controls (malignancies, Erdheim-Chester disease, large-, and small-vessel vasculitis).Results: We studied 113 consecutive patients with active CP. Twenty-four (21.2%) had high serum IgG4 (>135 mg/dL). The demographic, laboratory, and clinical characteristics of patients with high and normal IgG4 were similar, and so were the rates of ureteral obstruction and the disease characteristics on CT, MRI, and 18F-FDG-PET. Patients with high IgG4 only had a higher frequency of extra-retroperitoneal fibro-inflammatory lesions (p = 0.005). There were no significant differences in response to therapy and relapses between the two groups. Serum IgG4 levels did not discriminate CP from controls.Conclusions: Serum IgG4 levels are high in a minority of CP patients and do not identify specific clinical or prognostic subgroups; only a higher frequency of extra-retroperitoneal lesions is found in high-IgG4 patients. Serum IgG4 levels do not help in the differential diagnosis between CP and its mimics.

Anterior hypopituitarism secondary to biopsy-proven IgG4-related hypophysitis in a young man.

SummaryIgG4-related disease (IgG4-RD) is an immune-mediated fibro-inflammatory condition which can affect various organs including the pituitary gland. The true annual incidence of this condition remains widely unknown. In addition, it is unclear whether IgG4 antibodies are causative or the end result of a trigger. With no specific biomarkers available, the diagnosis of IgG4-related hypophysitis remains a challenge. Additionally, there is a wide differential diagnosis. We report a case of biopsy-proven IgG4-related hypophysitis in a young man with type 2 diabetes mellitus.Learning points:IgG4-related hypophysitis is part of a spectrum of IgG4-related diseases.Clinical manifestations result from anterior pituitary hormone deficiencies with or without diabetes insipidus, which can be temporary or permanent.A combination of clinical, radiological, serological and histological evidence with careful interpretation is required to make the diagnosis.Tissue biopsy remains the gold standard investigation.Disease monitoring and long-term management of this condition is a challenge as relapses occur frequently.

Chronic Periaortitis: an Update.

We aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP). CP is a rare disorder hallmarked by a periaortic fibro-inflammatory tissue. It can present as an isolated disease, but it can also be associated with other autoimmune and fibro-inflammatory lesions (e.g., fibrosing mediastinitis, sclerosing pancreato-cholangitis) that are part of the spectrum of IgG4-related disease. In a subgroup of patients, it also involves the thoracic aorta (so-called "diffuse periaortitis"), which supports the notion of an inflammatory disorder of large arteries. The pathogenesis of CP is multifactorial: recent studies have elucidated the predisposing role of immunogenetic variants and exposures to environmental agents such as smoking and asbestos. CP is a rare immune-mediated disease that affects the abdominal aorta and the iliac arteries and, in some cases, the thoracic aorta. It may overlap with manifestations of IgG4-related disease, and its treatment comprises glucocorticoids, conventional and biological immunosuppressive agents.

The spectrum of IgG4-related diseases

The spectrum of IgG4-related diseases

IgG4-related disease; a unifying entity

IgG4-related disease (IgG4-RD) is characterized by dense lymphoplasmacytic infiltration of different organs and elevated serum IgG4 level. The disease involves different organs including pancreas, kidney, aorta, lung, thyroid, salivary and lacrimal glands. IgG4-RD mimics malignancies, infectious and inflammatory disorders. Many disorders previously regarded as isolated, single-organ diseases such as autoimmune pancreatitis type 1, Mikulicz disease, and Riedel thyroiditis are connected within the spectrum of IgG4-RD. Chronic interstitial nephritis (CIN) is the main type of renal involvement. Membranous nephropathy is another renal picture of IgG4-RD. Multiple, hypo-dense, cortical, round and wedge-shape lesions are the main renal ultrasound features. IgG4-RD during its inflammatory phase successfully responds to glucocorticoid therapy. Here we presented a case of IgG4-RD and then reviewed the existing literature.

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome.

Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap. We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria. Eighteen patients were included (median age 55.5years, 13 men). AAV and IgG4-RD were diagnosed concomitantly in 13/18 (72%) patients; AAV preceded IgG4-RD in 3/18 (17%) while IgG4-RD preceded AAV in 2/18 (11%). AAV diagnoses included granulomatosis with polyangiitis in 14 (78%), microscopic polyangiitis in 3 (17%), and eosinophilic granulomatosis with polyangiitis in one case. IgG4-RD diagnosis included definite IgG4-RD in 5 (28%) cases, probable IgG4-RD in 5 (28%) and possible IgG4-RD in 8 (44%). IgG4-RD manifestations were chronic periaortitis in 9/18 (50%) patients, orbital mass and tubulointerstitial nephritis in 4 (22%) cases, prevertebral fibrosis in 3 (17%), pachymeningitis and autoimmune pancreatitis in 2 (11%) cases. Patients required median number of 2 (range 0-4) lines of immunosuppressants in combination with glucocorticoids. During the follow-up (median 49,8months, range 17,25-108months), AAV manifestations relapsed in 10/18 (56%) cases and IgG4-RD lesions in 5/18 (28%). When used, mainly for relapses, rituximab showed response in all cases. AAV and IgG4-RD may overlap. Clinicians should consider that atypical manifestations during AAV could be related to IgG4-RD rather than to refractory granulomatous or vasculitic lesions.

Surgical management of isolated mesenteric autoimmune disease: addressing the spectrum of IgG4-related disease and sclerosing mesenteritis

IgG4-related disease (IgG4-RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG4 and tissue IgG4 levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid...