Fibrotic phenotype of IgG4-related disease.

A prompt response to glucocorticoids is a clinical hallmark of IgG4-related disease. However, manifestations characterised by prominent tissue fibrosis on histological examination can be less responsive to glucocorticoid therapy than other types of IgG4-related disease. These manifestations include retroperitoneal fibrosis, fibrosing mediastinitis, Riedel thyroiditis, orbital pseudotumor, and hypertrophic pachymeningitis, among others. To explain this discrepancy, a preliminary distinction into proliferative and fibrotic phenotypes of IgG4-related disease has been proposed on the basis of clinical presentation, pathological features, and response to immunosuppressive therapy. Implications of this classification for patient management remain an important area of investigation. In this Series paper, we aim to dissect the pathophysiology of tissue fibrosis in IgG4-related disease and discuss how clinicians should approach the management of fibrotic manifestations of IgG4-related disease based on the most recent diagnostic and therapeutic developments.

Decreased absolute number of peripheral regulatory T cells in patients with idiopathic retroperitoneal fibrosis.

Objective: In order to determine whether the immune balance of T helper 17(Th17)/regulatory T(Treg) is related to the pathogenesis of idiopathic retroperitoneal fibrosis (IRPF), we analyzed the differences in peripheral blood lymphocytes, CD4+T cell subsets and cytokines between patients with IRPF and healthy people to clarify the CD4+T cell subsets, especially Treg cell subsets, and the role of cytokines in the pathogenesis of IRPF. Methods: This study included 22 patients with IRPF, 36 patients with IgG4-related diseases (IgG4-RD) without retroperitoneal fibrosis (RPF), and 28 healthy controls. The absolute numbers and percentage of peripheral blood lymphocyte subsets and CD4+T cell subsets in each group were detected by flow cytometry, and the serum cytokine level was detected by flow cytometric bead array (CBA). Results: Compared with the healthy group, the absolute value of B cells in peripheral blood of IRPF patients was significantly decreased, and T, natural killer (NK), CD4+ and CD8+ were not significantly abnormal. The absolute numbers of Th2 cells were lower than healthy group(p=0.043). In particular, the absolute numbers of Treg cells were significantly lower than healthy group(p<0.001), while the absolute numbers of Th17 cells increased(p=0.682). Th17/Treg was significantly higher than healthy group (p< 0.001). Cytokine analysis showed that the level of interleukin (IL)-4 in IRPF patients was higher than healthy group(p=0.011), IL-6, IL-10, IL-17, TNF-α and IFN-γ were significantly higher than healthy group (all p<0.001). Receiver operating characteristic (ROC) curves showed that IL-10 and TNF-α could distinguish bilateral ureteral dilatation in IRPF patients, with areas under the ROC curve (AUCs) of 0.813 (95% CI:0.607-1.000, p=0.026) and 0.950 (95% CI:0.856-1.000, p=0.001), respectively. IL-6 could distinguish bilateral ureteral obstruction, with an AUC of 0.861 (95% CI: 0.682-1.000, p=0.015). Conclusions: Our study showed that IRPF patients had reduced Treg cells and indeed had Th17/Treg imbalance, which may be related to the pathogenesis of the disease. The levels of IL-6, IL-10 and TNF-α appear to be associated with the progression of IRPF.

Surgical strategy of IgG4-related inflammatory abdominal aortic aneurysm with preoperative steroid therapy: A case report.

Immunoglobulin G4 (IgG4)-related disease, characterized by high serum IgG4 concentrations and IgG4-positive plasma cell infiltration, often presents as an inflammatory aneurysm. We herein report the case of a 78 year-old man, presenting with elevated inflammatory markers and IgG4 concentrations, who was diagnosed with IgG4-related inflammatory abdominal aortic aneurysm with dense perianeurysmal fibrosis. Before the surgical intervention, steroid therapy was administered to resolve his perianeurysmal inflammatory fibrosis. Half a year after the initiation of steroid therapy, there was an improvement in serum inflammatory markers and IgG4 concentrations, and the perianeurysmal fibrosis had regressed. Thus, we performed a surgical intervention including resection of the aneurysm and interposition with a prosthetic graft. Histopathological examination demonstrated few IgG4-positive plasma cells were distributed in the adventitia, which was suspected to be associated with the preoperative steroid therapy. This case study suggests preoperative steroid therapy is a useful therapeutic strategy for IgG4-related abdominal aortic aneurysm because it allows the use of open surgical procedures with reduced surgical risk.

Clinical features of IgG4-related retroperitoneal fibrosis among 407 patients with IgG4-related disease: a retrospective study.

OBJECTIVES: IgG4-related disease (IgG4-RD) is recently recognized as a fibro-inflammatory condition featured by tumefactive lesions in multiple organs, and the retroperitoneum is one of the common involved sites. We undertook this study to compare detailed demographic, clinical and laboratory characteristics of IgG4-RD patients with retroperitoneum lesion (IgG4-RD RPF+) and retroperitoneum free IgG4-RD (IgG4-RD RPF-) in a large cohort. METHODS: We carried out a retrospective review of the medical records of 407 cases of IgG4-RD diagnosed at Peking University People's Hospital between March 2009 and May 2019. RESULTS: Among 407 patients, 58 had retroperitoneum affected. As compared with IgG4-RD RPF- patients, IgG4-RD RPF+ patients showed older age at disease onset and diagnosis. IgG4-RD RPF+ group involved more male patients. In terms of organ involvement, IgG4-RD RPF+ group was more frequently presented with kidney involvement, while salivary gland, lacrimal gland and pancreas were more prominent in the IgG4-RD RPF- group. In addition, the CRP, ESR level and creatinine level were significantly higher in IgG4-RD RPF+ patients, and hypocomplementemia were more common in this group. CONCLUSION: We have revealed demographic, clinical and laboratory differences between IgG4-RD RPF+ and RPF- patients, which indicated potential differences in pathogenesis and important implications for the diagnosis and management of these two phenotypes.

Standardized approach to idiopathic retroperitoneal fibrosis: a comprehensive review of the literature.

BACKGROUND: Idiopathic retroperitoneal fibrosis (iRPF) is a rare fibro-inflammatory disease, characterized by inflammation of the abdominal aorta and its surrounding structures. The exact pathophysiology remains unclear. Diagnosis is often troublesome due to the non-specific and highly variable clinical presentation. Standardized treatment protocols are lacking. OBJECTIVE: This article presents a review on iRPF, addressing clinical and diagnostic modalities as well as its pathophysiology and the possible inclusion within the IgG4-related disease (IgG4-RD) spectrum. Finally, a diagnostic-therapeutic algorithm for a standardized approach to iRPF is proposed. METHODS: The PubMed Internet database was searched. Articles were selected based on the relevance of abstract, article type and impact of the journal. RESULTS: iRPF and IgG4-RD share a common autoimmune aetiology. Diagnostics are multimodal and based on imaging. Ruling out malignancy should be of primary concern. Complications are mostly of renal or vascular origin due to compression of retroperitoneal structures. Corticosteroids remain the first-line treatment regimen and are mostly successful, but evidence supporting alternative immunosuppressive and anti-inflammatory treatments is growing. Long-term therapy, as well as follow-up, is paramount in this chronic and often relapsing disease.

A Case of Immunoglobulin (Ig) G4-related Sclerosing Periaortitis Mimicking Mediastinal Malignant Tumor.

Sclerosing mediastinitis was first described by Oulmont in 1855. The aggressive fibro-inflammatory process that occurs in the mediastinum is the end result of a number of inflammatory processes. It is thought that hypersensitivity reactions to various antigens, autoimmune reactions, and idiopathic fibro-inflammatory responses play a role in the etiology of the disease. It has been shown in recent years that immonoglobulin (Ig) G4-related autoimmune diseases may lead to sclerosing mediastinitis. In this study, a rare case of Ig G4-related sclerosing periaortitis is presented in a 50-year male patient. The disease responded well to steroid treatment, but soon recurred following stoppage of the treatment. The treatment with deflazacort was started again; and he responded well. The lesion disappeared within six months of retreatment.

Concomitant presentation of IgG4-negative idiopathic retroperitoneal fibrosis and Addison's disease.

We describe a patient who was admitted to our medical centre with acute renal failure, hyponatraemia and hyperkalaemia. CT of the abdomen and pelvis showed a retroperitoneal mass with bilateral ureteral obstruction. Biopsy revealed fibrosis with inflammatory infiltrate, but rare IgG4-positive plasma cells. After placement of bilateral pigtail nephrostomy catheters, renal failure improved but metabolic derangements remained. Morning serum cortisol level was equivocal, but with blunted response on cosyntropin stimulation testing indicating adrenal insufficiency. Serology for 21-hydroxylase antibodies was strongly positive, supporting the diagnosis of Addison's disease. In addition to nephrostomy catheters for obstructive uropathy, idiopathic retroperitoneal fibrosis was treated with mycophenolate mofetil. Physiological doses of hydrocortisone and fludrocortisone for Addison's disease were also initiated. The patient continues to be monitored for regression of the mass. Based on review of the literature, this is the first reported case of IgG4-negative idiopathic retroperitoneal fibrosis presenting with autoimmune primary adrenal insufficiency.

Characteristics and prognosis of IgG4-related periaortitis/periarteritis: A systematic literature review.

OBJECTIVE: Immunoglobulin G4 (IgG4)-related disease is a systemic chronic fibroinflammatory disease that can affect almost every organ of the body. IgG4-related periaortitis/periarteritis is a newly recognized subset of IgG4-related disease, and its characteristics and prognosis remain unclear. We investigated the clinical characteristics and prognosis of IgG4-related periaortitis/periarteritis. METHODS: We performed a systematic literature review of IgG4-related periaortitis/periarteritis. Additionally, we have summarized the characteristics and prognosis of IgG4-related coronary arteritis. RESULTS: We investigated 248 patients with IgG4-related periaortitis/periarteritis. All studies reported the condition in elderly patients, and male predominance was observed. The infra-renal abdominal aorta and iliac arteries were the most commonly affected sites. Most reports showed the serum C-reactive protein elevation in this disease entity, in contrast to non-vascular IgG4-related disease. Based on radiological findings observed in 27 patients with IgG4-related coronary arteritis, vasculitic lesions were classified into 3 types: stenotic (67% of patients), aneurysmal (42%), and diffuse wall thickening type (92%). Serum IgG4 level, but not C-reactive protein level, was associated with the number of affected organs in IgG4-related coronary arteritis. Corticosteroid treatment with or without cardiac surgery or percutaneous coronary intervention was effective in most patients with IgG4-related coronary arteritis; however, 33% of patients showed an unfavorable clinical course including disease progression, relapse, or death. Pre-treatment stenosis and/or aneurysms were associated with progression of stenosis or aneurysm after corticosteroid treatment. CONCLUSION: Most clinical characteristics were similar between the IgG4-related periaortitis/periarteritis and the non-vascular IgG4-related disease groups; however, serum C-reactive protein level elevation was observed only in the former. Although corticosteroid treatment was effective, this disease can be life-threatening secondary to myocardial infarction, aortic dissection, and aneurysmal rupture. Pre-treatment evaluation of stenosis or aneurysms is important for predicting progression of stenosis or aneurysm after corticosteroid treatment.

IgG4-related Retroperitoneal Fibrosis: An Emerging Masquerader With a Sinister Presentation.

OBJECTIVE: Retroperitoneal fibrosis (RPF) is a rare proliferative fibro-inflammatory disease involving the soft tissues of the retroperitoneum. IgG4 related retroperitoneal fibrosis is an emerging entity which needs to be distinguished from idiopathic RPF. We describe a clinical case of IgG4 related RPF highlighting the importance of clinching this diagnosis. METHODS: A 70 year old female was referred to the outpatient department of our institute with complaints of fatigue, bilateral flank pain and loss of appetite for the past 1 month. The CT and PET scan demonstrated a uniformly enhancing bulky retroperitoneal mass causing bilateral hydroureteronephrosis. The biopsy from the mass lesion revealed IgG4 related disease. The patient was started on corticosteroids after percutaneous nephrostomy placement. RESULTS: Three months post induction of therapy, repeat PET-CT shows resolution of the mass with no FDG avid lesion. Serum IgG4 levels were reduced to normal (27 mg/dL) suggestive of response to treatment. The percutaneous nephrostomies were removed and the patient is doing well on maintenance dose of corticosteroids for her disease. CONCLUSION: The availability of serum IgG4 levels for monitoring treatment response and follow-up can curtail the repeated radiological imaging and associated contrast exposure as compared to idiopathic RPF. Secondly, the diagnosis of IgG4-related RPF shall alert the clinician to look out for extra-retroperitoneal diseases on follow up of this multi-organ disease.

Fibrocytes in Chronic Periaortitis: A Novel Mechanism Linking Inflammation and Fibrosis.

OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by periaortic and periiliac fibroinflammatory tissue. The pathogenic mechanisms leading to tissue accumulation and activation of fibroblasts are unclear. This study was undertaken to explore the role of fibrocytes, circulating precursors of tissue fibroblasts, in patients with CP. METHODS: We studied 44 patients with newly diagnosed CP and 30 healthy controls. Circulating fibrocytes were identified as Col1+CD45+ cells using flow cytometry. Retroperitoneal tissue biopsy samples from 9 CP patients were stained with anti-type I procollagen, anti-CXCR4, and anti-CD45 antibodies and analyzed by confocal microscopy to detect tissue-infiltrating fibrocytes. Circulating levels and tissue expression of CXCL12, a CXCR4 ligand that promotes fibrocyte homing, were investigated using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We also characterized T helper polarization in biopsy samples from CP patients and measured serum levels of a panel of cytokines that are hallmarks of T helper responses and capable of influencing fibrocyte differentiation. RESULTS: The frequency of circulating Col1+CD45+ fibrocytes was higher in patients than in controls (P = 0.0371). CD45+proCol1+ and CXCR4+proCol1+ cells were detected in all examined biopsy samples from CP patients. Serum levels of CXCL12 were also higher in CP patients than controls (P = 0.0056), and tissue-infiltrating inflammatory cells intensely expressed CXCL12. Increased serum levels of Th2 cytokines (e.g., interleukin-13 [IL-13] and IL-10) were found in patients, and immunohistochemistry revealed a dominant infiltration of GATA-3+ cells, also indicating Th2 polarization; Th2-skewed responses are known to promote fibrocyte differentiation. CONCLUSION: Our findings indicate that fibrocytes are enriched in the peripheral blood of CP patients and infiltrate target lesions. The accumulation of fibrocytes in the pathologic tissue might be driven by CXCL12, and Th2-skewed immune responses are likely to facilitate their differentiation.

Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts.

OBJECTIVE: IgG4-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. METHODS: We 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. RESULTS: In 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, p<0.001). CONCLUSION: We 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.

Comparison of two subsets of Chinese patients with retroperitoneal fibrosis in terms of IgG4 immunohistochemical staining.

OBJECTIVE: To identify clinical and pathological differences between IgG4-related retroperitoneal fibrosis (IgG4-RPF) and idiopathic RPF (iRPF) in a Chinese population. METHOD: Clinical and pathological data of 50 RPF patients from 2006 to 2016 were retrospectively analysed. The presence of at least one characteristic histopathological feature, >30 IgG4+ plasma cells per high power field, and an IgG4+/IgG+ plasma cells ratio cutoff of >40% were used to define IgG4-RPF. RESULTS: Patients with IgG4-RPF were significantly more likely to have pain (94.1 vs 68.8%, P = 0.048), elevated serum IgE concentration (166.1 vs 40.2 IU/ml, P = 0.029) and tissue eosinophilia (47.1 vs 12.5%, P = 0.018), compared with patients with iRPF. In the IgG4-RPF subgroup, patients with tissue eosinophilia demonstrated higher levels of CRP (4.3 vs 1.9 mg/dl, P = 0.027) and ESR (62.1 vs 22.8 mm/h, P = 0.001). Among the 50 patients with RPF, the average number of tissue IgG4+ plasma cells was positively correlated with the number of tissue eosinophils (r = 0.37, P = 0.009). Moreover, serum IgG4 concentration and serum IgE concentration showed positive correlation (r = 0.834, P = 0.000). CONCLUSION: The distinct serological and histopathological features of Chinese patients with IgG4-RPF were elevated serum IgE concentration and tissue eosinophilia, which potentially can aid and support the diagnosis. As serum IgG4 concentration may be normal in patients with IgG4-RPF, serum IgE may represent a useful serological marker in distinguishing IgG4-RPF from iRPF.

Retroperitoneal fibrosis. Steroid treatment response seems to depend on its association to IgG4 related disease.

Retroperitoneal fibrosis (RF) is part of a rare fibrosclerotic disorder. Oral steroids are the initial treatment. Steroid combination with other immunosupressants is used in refractory cases. Steroids refractoriness has been observed in chronic cases. Some cases of RF represent a manifestation of the IgG4 related disease (IgG4-RD) that is associated to a dramatic response to steroid therapy. It is uncertain if RF́s treatment response differs according to its association with IgG4-RD. We hypothesize that RF́s treatment response to steroids depends on the association with IgG4-RD, thus, we collected and compared clinical data from 10 RF cases; 6 male, mean age 50.6 (±16.15 SD) years. Mean FU was 28 (±25.7 SD) months. According to IgG4 levels, patients were categorized as idiopathic RF (IRF n = 5) or RF-IgG4-RD (n = 5). Therapy response was categorized as complete, partial, stable disease, recurrence or non-response. Nine cases received initial therapy with prednisone; complete response was achieved in 4 RF-IgG4 RD. The remaining 5 cases (1 RF-IgG4RD and 4 IRF) underwent a 2nd line therapy; 4 prednisone + tamoxifen and 1 prednisone + azathioprine. Prednisone + tamoxifen combination achieved complete response in 1 case (RF-IgG4RD), partial response in 1 IRF; in 1 IRF case, disease remained stable and 1 did not respond. The prednisone + azathioprine treatment achieved complete response. At follow-up all patients remained stable and no recurrence was registered. These observations suggest and support the hypothesis that response to steroid monotherapy depends on the association of RF with IgG4, suggesting that IRF cases might benefit from initial combination therapies instead of steroid monotherapy.

Chronic Periaortitis: an Update.

PURPOSE OF REVIEW: We aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP). RECENT FINDINGS: 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.

A Case of Aortic Stenosis with Serum IgG4 Elevation, and IgG4-Positive Plasmacytic Infiltration in the Aortic Valve, Epicardium, and Aortic Adventitia.

A 74-year-old man was admitted for preoperative screening of aortic stenosis. Five months before this admission, he was found to have elevated serum immunoglobulin G4 (IgG4; 2,010 mg/dL). Computed tomography (CT) showed a soft tissue mass surrounding the abdominal aorta, suggestive of IgG4-related periaortitis. CT coronary angiography showed perivascular thickening of the right coronary artery, and subsequent coronary angiography showed a multi-vessel disease. The patient underwent aortic valve replacement and coronary bypass surgery. Immunohistochemical analysis showed IgG4-positive plasmacytic infiltration in specimens from the aortic valve, epicardium, and aortic adventitia, suggestive of the possible role of IgG4-related immune inflammation for the pathogenesis.

IgG4-related retroperitoneal fibrosis overlapping with primary biliary cirrhosis and primary Sjögren's syndrome: A case report.

RATIONALE: IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder which is characterized by elevated levels of serum IgG4 and infiltration of IgG4-bearing plasma cells in the involved organs. Primary biliary cirrhosis (PBC) and Primary Sjögren's syndrome (pSS) are both distinct from IgG4-related disease. We herein describe a Chinese patient with IgG4-related RPF overlapping with PBC and pSS. PATIENT CONCERNS: We report a case of 69-year-old male with recurrent lower abdominal pain for 10 months. Laboratory data showed elevated erythrocyte sedimentation rate and hepatobiliary enzymes, renal dysfunction, high titers of antinuclear antibody, anti-SS-A antibody and anti-mitochondrial type 2, high immunoglobulin (Ig) G levels and elevated serum IgG4 (9 g/L). Contrast-enhanced computed tomography and magnetic resonance imaging were suggestive of retroperitoneal fibrosis and unilateral ureteral occlusion. Immunohistochemical staining for IgG4 did not demonstrate infiltration of IgG4-positive plasma cells in the retroperitoneal mass, but revealed significant infiltration of lymphocytoplasma cells as well as fibrosis and fibrin accumulation. DIAGNOSES: The patient was diagnosed with IgG4-related retroperitoneal fibrosis based on the International Consensus Diagnostic Criteria. He was also diagnosed with primary biliary cirrhosis and primary Sjögren's syndrome. INTERVENTIONS: 250 mg ursodeoxycholic acid was administered twice daily, and prednisolone was initiated at a dose of 40 mg/day and then tapered to 25 mg after 45 days. OUTCOMES: The size of the retroperitoneal soft tissue mass gradually reduced and the abnormal laboratory parameters were restored to normal. LESSONS: This rare clinical condition has seldom been reported in the literature, which suggests that common immunogenetic factors may be involved in the development of IgG-related RPF, PBC and pSS.

Medical mirroring: granulomatosis with polyangiitis (formerly Wegener's) mimicking immunoglobulin-G4 related disease.

Granulomatosis with polyangiitis (GPA; formerly Wegener's) can present with clinical and histopathological features similar to those of immunoglobulin-G4 related disease (IgG4-RD), a recently described fibro-inflammatory condition. The ability of these two distinct entities to mimic each other closely creates significant pitfalls in diagnosis. We present a unique case in which GPA presented as a peri-aortic fibrotic mass in the retroperitoneum. The patient's other clinical features also overlapped with classic IgG4-RD disease manifestations, but the histopathology in two organs and the serological data confirmed the diagnosis of GPA. Rigorous histopathological review remains the gold standard for the diagnosis of GPA and the distinction of this entity from IgG4-RD and other mimickers.