Infiltration Of IgG4-bearing Plasma Cells Research Articles

The levels of IL-1β and soluble IL-1 receptors in patients with IgG4-related periaortitis/periarteritis

PurposeIgG4-related disease (IgG4-RD) is a chronic fibrotic inflammatory and an immune-mediated disease characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system, and its pathogenesis and characteristics remain unclear.The inflammatory cytokine IL-1β is involved in a variety of cellular activities including inflammation, fibrosis, and angiogenesis. The present study compared the levels of the inflammatory cytokine IL-1β and two soluble IL-1 receptors, IL-1R1 and IL-1R2, between IgG4-RD patients with and without IgG4-related periaortitis/periarteritis. MethodsThe patients with IgG4-related periaortitis/periarteritis (n ​= ​38), those without (n ​= ​66) and healthy (n ​= ​33) were recruited to measure cytokines of IL-1β and soluble receptors (sIL-1R1 and sIL-1R2) in sera by ELISA assay. ResultsSerum IgG4 was significantly higher in patients with periaortitis/periarteritis compared to non-periaortitis/periarteritis (p ​= ​0.0074), while serum IL-1β was significantly lower in patients with periaortitis/periarteritis (p ​= ​0.00037).The three groups did not show significant difference in sIL1-R1, while sIL-1R2 in the periaortitis/periarteritis and healthy group was higher than in the group without periaortitis/periarteritis (p ​= ​0.00001). ConclusionsThe characteristic changes in IL-1β, sIL-1R1, and sIL-1R2 levels in IgG4-RD patients with and without IgG4-related periaortitis/periarteritis may indicate an active phase of the inflammatory process in these diseases.

IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility. A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects. The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P<0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR=2.41, 95% CI:1.42-4.10). Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations.

M195 IGG4-RELATED DISEASE WITH NASOPHARYNGEAL MASSES IN THE PEDIATRIC PATIENT

IgG4-related disease is a fibroinflammatory process characterized by elevated serum IgG4 levels, multiorgan involvement with infiltration of IgG4-bearing plasma cells and storiform fibrosis. The diagnosis is confirmed by the characteristic histopathological features of the affected organs but can be challenging as it can present with a wide range of clinical manifestations that mimics other inflammatory processes.

Cardiovascular and lung involvement in patients with autoimmune pancreatitis

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated disease characterised pathologically by the infiltration of IgG4-bearing plasma cells into the involved organs. Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis with a heavy lymphocytic infiltration and two distinct histopathological subtypes, namely: lymphoplasmacytic sclerosing pancreatitis (AIP type 1) and idiopathic duct-centric pancreatitis (AIP type 2). Lung involvement and aortic involvement have been reported in 12% and 9% of patients with systemic IgG4-RD, respectively. In series including patients with AIP, both lung and aortic involvement were described in 2% of the patients. Most of the epidemiological data come from Japan, and there is a lack of information from Europe, especially the Scandinavian countries. Patients and methods: We performed a single-centre retrospective study on a prospectively collected cohort of patients diagnosed with AIP at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden, from 2004 to 2019. Demographic and clinical data were collected from the medical charts. Results: One hundred and thirty-three patients with AIP were analysed. Six patients were excluded because they lacked some of the clinical data relevant to the study. Demographic and clinical features of 127 patients were presented. There were 98 patients with AIP type 1-35 (35.7%) female and 63 (64.3%) male, with a mean age of 55.4 ± 18.2. Among them, 15 (15.3%) patients had lung and/or cardiovascular involvement-11 (11.2%) patients had lung involvement, 10 (10.2%) patients had cardiovascular involvement (six patients had both). Most of them (67.0%) had never smoked. The mean follow-up time of the patients with AIP type 1 was 49 months. Conclusions: Lung and/or cardiovascular involvement were diagnosed in 15 (15.3%) patients in our historical cohort of patients with AIP type 1. Most of the lung involvement was presented in the form of nodular lesions in the lungs, non-specific infiltrates, “ground-glass” appearance with pleura thickening, and effusion. Aortic involvement was a major form of vascular involvement in patients with AIP, as in previous published studies on patients with IgG4-RD.

The Cellular and Molecular Bases of Allergy, Inflammation and Tissue Fibrosis in Patients with IgG4-related Disease.

IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato–hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part.

Cardiovascular and Lung Involvement in Patients with Autoimmune Pancreatitis

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated disease characterised pathologically by the infiltration of IgG4-bearing plasma cells into the involved organs. Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis with a heavy lymphocytic infiltration and two distinct histopathological subtypes, namely: lymphoplasmacytic sclerosing pancreatitis (AIP type 1) and idiopathic duct-centric pancreatitis (AIP type 2). Lung involvement and aortic involvement have been reported in 12% and 9% of patients with systemic IgG4-RD, respectively. In series including patients with AIP, both lung and aortic involvement were described in 2% of the patients. Most of the epidemiological data come from Japan, and there is a lack of information from Europe, especially the Scandinavian countries. Patients and methods: We performed a single-centre retrospective study on a prospectively collected cohort of patients diagnosed with AIP at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden, from 2004 to 2019. Demographic and clinical data were collected from the medical charts. Results: One hundred and thirty-three patients with AIP were analysed. Six patients were excluded because they lacked some of the clinical data relevant to the study. Demographic and clinical features of 127 patients were presented. There were 98 patients with AIP type 1-35 (35.7%) female and 63 (64.3%) male, with a mean age of 55.4 ± 18.2. Among them, 15 (15.3%) patients had lung and/or cardiovascular involvement-11 (11.2%) patients had lung involvement, 10 (10.2%) patients had cardiovascular involvement (six patients had both). Most of them (67.0%) had never smoked. The mean follow-up time of the patients with AIP type 1 was 49 months. Conclusions: Lung and/or cardiovascular involvement were diagnosed in 15 (15.3%) patients in our historical cohort of patients with AIP type 1. Most of the lung involvement was presented in the form of nodular lesions in the lungs, non-specific infiltrates, “ground-glass” appearance with pleura thickening, and effusion. Aortic involvement was a major form of vascular involvement in patients with AIP, as in previous published studies on patients with IgG4-RD.

P43 Immunoglobulin G4-related disease in a 10 year-old girl with multisystem involvement

Abstract Background IgG4-related disease (IgG4RD) is an immune-mediated fibroinflammatory condition characterized by the infiltration of IgG4-carrying plasma cells and storiform fibrosis in most of the tissues. The condition is reported to cause multisystem involvement, however salivary gland is the most commonly affected organ with IgG4-related sialadenitis. Raised IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands have been confirmed. Methods We conducted a retrospective case review of a 10 year-old girl who was diagnosed with IgG4-RD at Great Ormond Street Hospital for Children in 2017. Patient’s clinical, laboratory and imaging data was extracted from our database and literature search was done to find out different manifestations of the IgG4-RD in Children. Results 10 year-old-girl with lacrimal and salivary gland swelling, sicca symptoms and fatigue. Ultrasound scan neck revealed multiple small lymph nodes and enlargement of both submandibular glands (Picture1) Salivary glands also appeared bulky and heterogenous with multiple small hypoechoic focci. Appearances likely to represent sialoadenitis and there was no evidence of malignancy or lymphoma. USS abdomen normal. Full blood count, routine biochemistry and urine microscopy normal. Autoantibodies came back negative (ANA: Negative, ANCA: Negative, Anti-Ro and Anti-La: Negative, RF:Negative, Thyroid autoantibodies:Negative) IgG level elevated (in repeated samples). IgA, IgM and IgE levels normal. IgG subgroups revealed significantly elevated IgG4 levels (21.49 Normal range: 0-1.1) IgG1, IgG2 and Ig G3 levels elevated as well. Lymphocyte subsets were normal. The biopsy of salivary gland: Chronic inflammation with IgG4 staining, suggestive of IgG4 related disorder. Lung function test showed decreased DLCO at 76 %, FEV1 at 82% and FVC at 89% suggestive of interstitial lung involvement. CT Thorax: Multiple abnormalities including moderate lymphadenopathy, renal parenchymal lesions and interstitial lung abnormality. MRI Abdomen: T2 hypointense renal foci, suggestive of infiltration as part of the IgG4 related disease. Diagnosed with IgG4 related disease. Treatment started with intravenous methylprednisolone followed by Anti-CD20 (Rituximab) therapy and a weaning plan for steroids. Mycophenolate mofetil commenced for the maintenance therapy. Patient has shown good response with clinical and lung function improvement. Conclusion IgG4-RD is a rare condition which can cause multisystem involvement with the infiltration of IgG4-bearing plasma cells in the tissues. We wanted to emphasize that this condition could also be seen in the paediatric population. We also wanted to highlight that after further investigations multisystem involvement can be discovered. Steroids are mainstay of the treatment with Anti-CD20 medication (Rituximab) and steroid sparing agents such as mycophenolate mofetil could be the choice for maintenance therapy. However, further studies need to be done in paediatric age group. Conflicts of Interest The authors declare no conflicts of interest.

Thyroid Rosai-Dorfman disease with infiltration of IgG4-bearing plasma cells associated with multiple small pulmonary cysts

BackgroundRosai-Dorfman disease (RDD) is a rare histiocytosis which involves principally lymph nodes. Thyroid involvement in RDD is a very rare situation, and lung involvement is even rarer.Case presentationWe report the case of a 46-year-old woman presenting a painless mass in the right side of the neck and subacute dyspnoea. Computerised tomography (CT) scans of the neck and thorax showed a large thyroid mass causing tracheal stenosis and multiple cystic lesions in both lungs. Subtotal thyroidectomy with a tracheal segment resection and histological analysis confirmed the diagnosis of nodal and extranodal (thyroid, tracheal and probably lung) Rosai-Dorfman disease (RDD) with the presence of increased numbers of IgG4-bearing plasma cells. Clinical, functional and radiological follow up 4 years after surgery without medical treatment did not show any disease progression.ConclusionsThis case report indicates a benign course of nodal RDD with thyroid and tracheal infiltration following surgical resection, association of typical histological signs of RDD (emperipolesis) with IgG4-related disease features, and that lung cysts might be a manifestation of RDD.

Immunoglobulin G4-related Disease: An Overview.

Immunoglobulin G4-related disease (IgG4-RD) is a recently established systemic disease that is characteristically associated with elevated serum immunoglobulin G4 (IgG4) levels and believed to be caused by autoimmune mechanisms. The clinical features of IgG4-RD include (i) systemic distribution, (ii) imaging findings of swelling, nodules, and/or wall thickening, (iii) high serum IgG4 levels, (iv) abundant IgG4-bearing plasma cell infiltration and fibrosis in affected organs, (v) a favorable response to corticosteroid therapy, and (vi) coexistence with other IgG4-RD manifestations simultaneously or in a metachronous fashion. The concept of IgG4-RD was established based on the culmination of specific discoveries. Specifically, a close association between autoimmune pancreatitis (AIP) and high serum IgG4 levels, massive IgG4-bearing plasma cell infiltration in pancreatic tissues affected by AIP, and systemic other organ involvements in AIP with similar IgG4-bearing plasma cell features opened the gateway from AIP to IgG4-RD. The systemic distribution of IgG4-RD seems to be capable of affecting every organ, causing well-established members including AIP, lacrimal and salivary gland lesions such as Mikulicz’s disease, respiratory diseases, sclerosing cholangitis, kidney diseases, and retroperitoneal fibrosis. IgG4-RD has been diagnosed worldwide, and international collaboration efforts on the disease have led to consensus publications on its nomenclature, pathology findings, and management approach. The algorithms developed for the comprehensive diagnostic criteria for IgG4-RD have remarkably increased detection sensitivity. Oral glucocorticoids are the first-line agents for remission induction, and certain patients with high disease activity may benefit from maintenance therapy afterwards. Originally, IgG4-RD had been considered reversible and to have a good prognosis; however, long-term afflictions sometimes result in transition to advanced-stage conditions with dysfunction and/or complicating malignancy. The immunological abnormalities in IgG4-RD have been reported in both innate and adaptive immune systems; however, it remains unclear whether IgG4 has a pathogenic role or a protective one in disease onset and progression.

Multivisceral IgG4-related disease presenting as recurrent massive gastrointestinal bleeding: a case report and literature review

BackgroundIgG4-related disease (IgG4-RD) is a newly recognized autoimmune systemic disorder characterized by elevated levels of serum IgG4 and abundant infiltration of IgG4-positive plasmacytes in the affected organs. The liver, biliary system and pancreas are the most commonly affected organs. However, involvement of the digestive tract is very rare. To date, only a few cases of isolated gastric IgG4-RD have been reported.Case presentationWe present a case of IgG4-RD of the liver, gallbladder, pancreas and duodenum, which was clinically misinterpreted and thereafter over-treated. A 52-year-old male presented with obstructive jaundice for 3 years, melena for 5 months and hematemesis for 10 days. Three years prior, the patient had undergone biopsies of pancreatic lesions, liver lesions, cholecystectomy and choledochojejunostomy. Histopathology showed chronic inflammatory changes. Endoscopy at admission revealed a duodenal ulcer with active bleeding. Despite medical management, the patient presented with repeated gastrointestinal bleeding. Upon evaluation, serum IgG4 levels were found to be elevated. Histopathology of the duodenal ulcer biopsy and repeated examination of the gallbladder and pancreatic and liver biopsies confirmed IgG4 positive plasma cell infiltration. A definitive diagnosis of IgG4-RD was made and steroid administration was initiated. At last follow up, 11 months to-the-day after initiating steroid treatment, the patient was asymptomatic.ConclusionsNotably, IgG4-RD of multiple digestive organs is still very rare. As a systemic disease, it is characterized by the infiltration of IgG4-bearing plasma cells and raised IgG4 levels. Histopathology findings remain the diagnostic gold standard for this disorder.

Clinical features of IgG4-related periaortitis/periarteritis based on the analysis of 179 patients with IgG4-related disease: a case\u2013control study

BackgroundImmunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic condition characterized by high serum immunoglobulin G4 (IgG4) concentration and IgG4-bearing plasma cell infiltration in affected organs. Although it has become evident that IgG4-RD also involves the systemic aortic/arterial system, the precise details of this condition remain unclear. The present study sought to clarify the clinical features of IgG4-related periaortitis/periarteritis.MethodsAmong 223 patients with IgG4-RD, 179 (131 male, median onset age 67 years) were recruited for this study. Periaortitis/periarteritis was defined as vessel wall thickness with circumferential enhancement on contrast-enhanced computed tomography.ResultsPeriaortitis/periarteritis was identified in 65 (36.3%; 53 male) of 179 IgG-RD patients. The distribution of IgG4-related periaortitis/periarteritis could be broadly classified into five types, with the most prevalent Type 2 (44.6%) being localized at the infra-renal artery portion of the abdominal aorta and continuing to the iliac arteries. The infra-renal artery region of the abdominal aorta was most frequently involved (>80%) among IgG4-related periaortitis/periarteritis cases. Comparisons of clinical parameters between IgG4-RD patients with and without periaortitis/periarteritis revealed significantly higher propensities for older IgG4-RD onset age and highly active disease state featuring elevated serum IgG, IgG4, circulating immune complex, and soluble interleukin-2 receptor. All patients showed improvement of wall thickening after steroid therapy, although nine patients (20.9%) exhibited worsening of luminal dilatation. The main risk factor for this manifestation was prior luminal dilatation according to multivariate analysis.ConclusionIgG4-related periaortitis/periarteritis predominantly occurred at the infra-renal artery portion of the abdominal aorta, affected older IgG4-RD onset patients, and was prevalent in highly active disease states. As reported previously, the main risk factor for worsening luminal dilation after corticosteroid therapy was the existence of luminal dilation beforehand.

IgG4-related skin disease may have distinct systemic manifestations: a systematic review.

IgG4-related disease (IgG4-RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi-organ infiltration of IgG4-bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4-related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck - lymphatics, orbit, salivary, and lacrimal glands - but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4-RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4-related skin disease, but obliterative venulitis is less common than in the prototypical IgG4-related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4-positive plasma cells per high-power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4-related skin disease defines a unique systemic disease complex along the spectrum of IgG4-RD.

Current Concepts and Diagnosis of IgG4-Related Pancreatitis (Type 1 AIP).

Although now considered to be a member of the systemic entity of immunoglobulin G4- (IgG4-) related disease, IgG4-related pancreatitis is generally referred to as type 1 autoimmune pancreatitis (AIP). Type 1 AIP was established based on a pathological background of lymphoplasmacytic sclerosing pancreatitis, high serum IgG4 concentration, and abundant IgG4-bearing plasma cell infiltration. The characteristic clinical features of type 1 AIP, such as elderly male preponderance, obstructive jaundice, and mass-forming lesions in the pancreas, often mimic those of pancreatic cancer. However, because AIP responds favorably to corticosteroid treatment, careful differentiation from pancreatic cancer is required. An AIP diagnosis is currently based on the 2011 International Consensus Diagnostic Criteria for AIP, which are based on high sensitivity, selectivity, and accuracy. Over the long term, AIP can progress to a chronic condition, with pancreatic stone formation and atrophy resembling that of chronic pancreatitis. Although AIP has been linked to the complication of malignancies, it remains controversial whether an association exists between the disease and tumor formation.

New strategies for the treatment of IgG4-related disease.

IgG4-related disease is a chronic and fibroinflammatory disorder, which is characterized with elevated levels of serum IgG4, and prominent infiltration of IgG4-bearing plasma cells in the involved organs. It often affects with lacrimal glands, salivary glands, pancreas, kidneys, lungs, and retroperitoneal cavity. Now, the first line of the induction therapy for IgG4-related disease is glucocorticoid, but almost patients need the maintenance treatment and experience the relapse. It is recently reported that biologic agents, including rituximab and abatacept, are effective for the relapse of IgG4-related disease. It is clear that the tapering effect of glucocorticoid is better than conventional oral immunosuppressants. We can use it in safely if we choose the appropriate cases. The investigator-initiated trial of rituximab for IgG4-related disease is scheduled in Japan. This article reviews the new strategies for the treatment of IgG4-related disease with our data of SMART registry, and discuss the problems of each biologic agents for IgG4-related disease.

The Immunobiology of Immunoglobulin G4 and Complement Activation Pathways in IgG4-Related Disease.

High serum immunoglobulin (Ig) G4 concentration and abundant IgG4-bearing plasma cell infiltration are characteristic features in autoimmune pancreatitis (AIP). AIP is also complicated with a variety of other organ involvements that commonly share marked IgG4-bearing plasma cell infiltration, suggesting the existence of a systemic disease associated with IgG4 currently recognized as IgG4-related disease (IgG4-RD). However, it is controversial whether IgG4 plays a role in the pathogenesis of AIP or IgG4-RD through such characteristic attributes as Fab-arm exchange and rheumatoid factor (RF)-like activity. Hypocomplementemia has been observed in AIP and several other IgG4-RDs. Muraki et al. reported that complements C3 and C4 were decreased in 36% of patients with AIP, which implicated the complement activation system in disease pathogenesis. AIP patients with a high level of immune complexes showed serum elevation of IgG4-type immune complexes in an active disease stage, elevated serum IgG1 concentration, and decreased C3 and C4 values. This inferred that while IgG4 may have had little contribution to complement activation, IgG1 played a prominent role via the classical pathway. On the other hand, Sugimoto et al. observed that polyethylene glycol-precipitated immune complexes from patients with IgG4-RD and hypocomplementemia had the ability to activate the complement system through both the classical and the mannose-binding lectin pathways and that IgG4 might participate in the complement activation system. Thus, debate continues on which complement activation systems are working in AIP and IgG4-RD and whether they are associated with the pathogenesis of these conditions.

IgG4-related disease with coronary arteritis

We have read with great interest the recently published article entitled “IgG4-related systemic disease with coronary arteritis and aortitis, causing recurring critical coronary ischemia” written by Tran MN and his colleagues [ [1] Tran M.N. Langguth D. Hart G. et al. IgG4-related systemic disease with coronary arteritis and aortitis, causing recurring critical coronary ischemia. Int. J. Cardiol. 2015; 201: 33-34 Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar ]. This paper described a 72 year old male with complex presentation of IgG4-related disease (IgG4-RD) with aortitis and coronary arteritis. IgG4-RD is a systemic immune-mediated disease characterized pathologically by the infiltration of IgG4-bearing plasma cells into involved organs and raised IgG4 levels [ [2] Stone J.H. Zen Y. Deshpande V. IgG4-RD. N. Engl. J. Med. 2012; 366: 539-551 Crossref PubMed Scopus (1873) Google Scholar ]. The cardinal clinical feature of IgG4-RD is single or multiple organ swelling and the organs more frequently involved are the pancreas, salivary/lacrimal glands, biliary tree, kidneys, thyroid gland, lungs, and aorta [ [3] Brito-Zerón P. Ramos-Casals M. Bosch X. et al. The clinical spectrum of IgG4-related disease. Autoimmun. Rev. 2014; 13: 1203-1210 Crossref PubMed Scopus (198) Google Scholar ].

Mechanisms of Lower Bile Duct Stricture in Autoimmune Pancreatitis

We attempted to clarify the mechanism underlying lower bile duct stricture in autoimmune pancreatitis. Imaging and histologic finding of the bile duct were assessed for 73 patients with autoimmune pancreatitis to clarify whether IgG4-related biliary inflammation or pancreatic head swelling is associated with lower bile duct stricture. Lower bile duct stricture was found in 59 (81%) patients. Pancreatic head swelling was significantly more frequent among patients with lower bile duct stricture than those patients without lower bile duct stricture (53 [90%] vs 4 [29%]; P < 0.01). Intraductal ultrasonography findings revealed lower bile duct wall thickening in 21 (95%) of the 22 patients with lower bile duct stricture, and the lower bile duct wall of the patients with pancreatic head swelling was significantly thicker than those patients without pancreatic head swelling (P = 0.028). Among the 38 patients with lower bile duct biopsies, 14 (37%) exhibited abundant IgG4-bearing plasma cell infiltration. Among the patients with lower bile duct stricture, an IgG4-related inflammation seemed to exert a dominant effect under limited conditions, including concomitant middle bile duct stricture and neither pancreatic swelling nor pancreatic duct stricture in the head region. Both pancreatic head swelling and IgG4-related biliary inflammation affect lower bile duct stricture, which may be included in IgG4-related sclerosing cholangitis. Pancreatic head swelling affects IgG4-related biliary wall thickening.

Skin sclerosis with elevation of serum interleukin-6 that is possibly associated with immunoglobulin 4-related disease.

Dear Editor: An 82-year-old Japanese man was found to have retroperitoneal fibrosis in 2006 and treated with 60 mg/day prednisolone, which tapered and finally discontinued in January 2010. Arthritis of both knees developed in 2011, and total knee arthroplasty was performed in January 2013. Histopathological examination of the joint synovium showed numerous infiltrations of plasma cells and fibrosis around the infiltrate (Fig. 1A). The ratio of immunoglobulin G4+ (IgG4+)/IgG+ plasma cells per high-power field was >60% (Fig. 1B). Serum IgG4 was elevated (125 mg/dl; reference, 4~108 mg/dl). IgG4-related disease (IgG4-RD) with involvement of the retroperitoneum and joint synovium was established. Computed tomography showed the remaining lesion of retroperitoneal fibrosis but did not show additional lesions of IgG4-RD. One month after the operation, he noticed an indurated skin lesion in his lower leg. Physical examination revealed diffuse, indurated skin sclerosis in his left lower leg (Fig. 1C). Histological examination revealed severe fibrosis in entire dermis and infiltrations of plasma cells around blood vessels (Fig. 1D). IgG4+ cells were rarely observed. Skin sclerosis appeared sequentially after the operation on the joint synovium and the establishment of the diagnosis of IgG4-RD, suggesting that skin sclerosis may be considered as the possible symptom of IgG4-RD. Topical and oral prednisolone (15 mg/day) was given. The skin sclerosis became soft gradually, and serum IgG4 levels returned to the reference range. We also found that the serum interleukin (IL)-6 level was elevated (13 pg/ml; reference, <0.5) before treatment and returned to the reference range in parallel with clinical improvement. Fig. 1 (A) Histopathological examination of the joint synovium. Infiltration of plasma cells and fibrosis (H&E, ×400). (B) Infiltration of IgG4+ plasma cells (×400). (C) Physical examination of the lower leg. Diffuse, indurated skin sclerosis ... IgG4-RD is a newly recognized disorder characterized by the infiltration of abundant IgG4+ plasma cells in lesions accompanied by fibrotic or sclerotic changes1,2. Skin involvement was rarely reported1. Ikeda et al.1 described the skin lesions as erythematous nodules, papules, and areas of induration. They also reported that the common feature of the skin lesions was the localization near the main area of IgG4-RD involvement, and that the appearance of skin lesions after the onset of IgG4-RD range from 2 months to 3 years1. Of note, our case is consistent with these features. Recently, there has been a report on 3 patients who had skin lesions with abundant infiltration of IgG4-bearing plasma cells and an elevated serum IL-62. An increase in IL-6 concentration has also been reported in other plasma cell-related diseases, including multicentric Castleman's disease and cutaneous plasmacytosis3. IL-6 induces B-cell proliferation and terminal differentiation, immunoglobulin secretion, and an acute inflammatory-phase response, suggesting that IL-6 might be important in the pathogenesis of IgG4-RD. Concerning IL-6 and fibrosis, it has been reported that serum IL-6 correlated with the extent of skin fibrosis in systemic sclerosis4. In addition, IL-6 enhanced collagen type I production from human fibroblasts in an in vitro assay5, suggesting that IL-6 is a potent stimulator of collagen production in fibroblasts, leading to skin sclerosis. Thus, the elevation of serum IL-6 level might be associated with the pathogenesis of skin sclerosis in our case. However, further examinations on the relation between IL-6 in IgG4-RD and fibrosis are warranted.

Mechanisms and assessment of IgG4-related disease: lessons for the rheumatologist

Recognition of IgG4-related disease as an independent chronic inflammatory disorder is a relatively new concept; previously, the condition was thought to represent a subtype of Sjögren's syndrome. IgG4-related disease is characterized by elevated serum levels of IgG4 and inflammation of various organs, with abundant infiltration of IgG4-bearing plasma cells, storiform fibrosis and obliterative phlebitis representing the major histopathological features of the swollen organs. The aetiology and pathogenesis of this disorder remain unclear, but inflammation and subsequent fibrosis occur due to excess production of type 2 T-helper-cell and regulatory T-cell cytokines. The disease can comprise various organ manifestations, such as dacryoadenitis and sialadenitis (also called Mikulicz disease), type 1 autoimmune pancreatitis, kidney dysfunction and lung disease. Early intervention using glucocorticoids can improve IgG4-related organ dysfunction; however, patients often relapse when doses of these agents are tapered. The disease has also been associated with an increased incidence of certain malignancies. Increased awareness of IgG4-related disease might lead to consultation with rheumatologists owing to its clinical, and potentially pathogenetic, similarities with certain rheumatic disorders. With this in mind, we describe the pathogenic mechanisms of IgG4-related disease, and outline considerations for diagnosis and treatment of the condition.

Clinical features of a new disease concept, IgG4-related thyroiditis

Objectives: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis.Method: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz’s disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland.Results: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and β2-microglobulin (β2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles.Conclusions: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.