IgG4-related disease (IgG4-RD) is a multi-organ inflammatory immune-mediated illness caused by IgG4-secreting plasma cells infiltrating the tissue. This condition usually affects elderly men. A 90-year-old Chinese male was diagnosed with IgG4-RD based on the new 2019 ACR/EULAR classification criteria, as he had multiple organ involvement. After receiving treatment with glucocorticoids, leflunomide, and gamma-globulin, the patient\'s clinical symptoms significantly improved, confirming the accuracy of the diagnosis. The patient had an 18-year medical history during which the disease progressively worsened due to delayed diagnosis and treatment. Although the relevant symptoms were alleviated with appropriate medication, the overall treatment process encountered challenges. Due to the patient\'s relative lack of adrenocortical function, he experienced symptoms such as nausea, exhaustion, and loss of appetite during the hormone reduction process. Therefore, timely intervention is especially crucial to address the side effects of hormone therapy.

OBJECTIVE: Retroperitoneal fibrosis is a rare disease characterized by chronic inflammation and fibrosis in the retroperitoneal space that may wrap around the ureter and cause an obstruction. Here we present the cases of three patients diagnosed and treated between April and August 2022.
METHODS: Here we present three cases of retroperitoneal fibrosis. Imaging revealed hydronephrosis and/or ureteral dilation, whereas laboratory findings such as erythrocyte sedimentation rate, C-reactive protein, and immunoglobulin G4 were abnormal. Serum creatinine and blood urea nitrogen levels suggested renal injury. Additionally, two patients had unclear diagnoses from other hospitals. Later, all patients underwent ureteral stenting and laparoscopic ureterolysis at our hospital and simultaneous diagnosis by biopsy. The two patients with high immunoglobulin G4 levels exhibited extremely severe fibrosis. After discharge, each received maintenance prednisone to prevent recurrence as well as methotrexate, followed by follow-up every 3 months. Fortunately, serum creatinine, blood urea nitrogen, and intravenous urography findings remained normal with an average follow-up of 8.5 months.
CONCLUSIONS: Here we discovered interesting findings in the diagnosis and treatment of retroperitoneal fibrosis, including the stable effect of medical plus surgical treatment, an unclear ureteral obstruction etiology, and the relationship between immunoglobulin G4 level and fibrosis hardness. However, the mechanisms behind these new findings require further study.

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.

OBJECTIVE: To explore the diagnostic value of contrast-enhanced ultrasound (CEUS) in the disease activity of idiopathic retroperitoneal fibrosis (IRPF).
METHODS: This retrospective study included 148 CEUS examinations from 63 patients with IRPF treated in our hospital from April 2016 to September 2021. They were divided into two groups: IRPF active group (69 examinations) and inactive group (79 examinations). Uni- and multivariable analyses were used to identify independent risk factors for IRPF activity. Receiver operating characteristic (ROC) curves were drawn to establish different diagnostic models to evaluate the diagnostic value of IRPF activity. The z test was used to compare the differences of the area under the curves (AUCs). The value of CEUS in evaluating the variation of disease activity over time was also investigated between repeat patient studies.
RESULTS: Univariate and multivariate logistic regression analyses revealed the thickness [odds ratio (OR) = 14.125, 95% confidence interval (CI) = 3.017-66.123] was the most significant independent risk factor for IRPF activity (P < 0.01). The best diagnostic model was model 3, which was established by CEUS score combined with thickness. The AUC was 0.944 (95%CI = 0.912-0.977), and the sensitivity and specificity were 89.86% and 86.08%, respectively. The diagnostic performance was not significantly improved after combining clinical symptom (back pain) and laboratory indicators [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]. Compared with before treatment, the CEUS score and thickness were significantly decreased after treatment (x2 = 14.580, P < 0.001 and z = 4.708, P < 0.001, respectively).
CONCLUSIONS: CEUS has good diagnostic value for IRPF disease activity. Key points • Thickness and contrast-enhanced ultrasound score were significantly higher in the active group than those in inactive group (P < 0.001). • With thickness of 4 mm and contrast-enhanced ultrasound 2 score as optimal cut-off values, the sensitivity and specificity were 89.86%, 81.01% and 52.17%, 100.00%, respectively. • During follow-up, when the disease progressed, the change of CEUS score was earlier than the change of thickness.

To investigate the effectiveness and safety of TCZ (tocilizumab) monotherapy for chronic periaortitis (CP) patients at acute active stage.
Twelve patients with definite or possible diagnosis of CP were enrolled and received intravenous infusions of TCZ (8 mg/kg) every 4 weeks for at least 3 months. Clinical features, laboratory and imaging findings were recorded at baseline and during the follow-up. The primary endpoint was the rate of partial and complete remission after 3 months TCZ monotherapy and the secondary endpoint was the frequency of treatment related adverse events.
Three patients (27.3%) achieved partial remission and seven patients (63.6%) obtained complete remission after 3 months TCZ treatment. The total remission rate achieved 90.9%. All patients reported improvement in clinical symptoms. Inflammatory markers such as erythrocyte sedimentation rate and C reactive protein decreased to normal levels after TCZ treatment. Nine patients (81.8%) showed remarkable shrinkage of perivascular mass greater than or equal to 50% on CT.
Our study showed that TCZ monotherapy contributed to remarkable clinical and laboratory improvement in CP patients and could be an alternative treatment option for CP.

BACKGROUND: IgG4-related disease (IgG4-RD) is a chronic fibrotic disease mediated by immunity recognized by clinicians in recent years. When the kidney is involved, it is called IgG4-related kidney disease (IgG4-RKD). IgG4-related tubulointerstitial nephritis (IgG4-TIN) is a representative manifestation of IgG4-RKD. IgG4-TIN can cause obstructive nephropathy complicated by retroperitoneal fibrosis (RPF). Cases of IgG4-TIN complicated with RPF are rare. Glucocorticoids are the first-line therapeutic medication for IgG4-RD and can significantly improve renal function.
METHODS: Herein, we report the case of a 56-year-old man with IgG4-RKD complicated with RPF. The patient presented to the hospital with complaints of elevated serum creatinine (Cr), nausea, and vomiting. During hospitalization, Cr was 1448.6 µmol/L, and serum IgG4 was increased. A total abdominal computed tomography (CT) scan and enhanced CT scan obviously indicated RPF. Although this patient had a long course and renal insufficiency, we performed a kidney biopsy. Renal biopsy showed that the renal tubulointerstitium had focal plasma cell infiltration and increased lymphocyte infiltration accompanied by fibrosis. After combining the biopsy results with immunohistochemistry, it was found that the absolute number of positive IgG4+ cells per high power field exceeded 10, and the ratio of IgG4/IgG was over 40%. Finally, the patient was diagnosed with IgG4-TIN complicated with RPF and given glucocorticoids as long-term maintenance therapy, helping him keep out of dialysis. After a follow-up of 19 mo, the patient had recovered well. Previous literature on IgG4-RKD and RPF was retrieved from PubMed to characterize the clinical and pathological features and to identify the diagnosis and treatment of IgG4-RKD.
CONCLUSIONS: Our case report demonstrates the clinical characteristics of IgG4-RKD complicated with RPF. Serum IgG4 is a favorable indicator for screening. Performing renal biopsy actively plays a vital role in diagnosis and treatment, even if the patient has a long course and manifests with renal insufficiency. It is remarkable to treat IgG4-RKD with glucocorticoids. Hence, early diagnosis and targeted therapy are essential for reversing renal function and improving extrarenal manifestations in patients with IgG4-RKD.

Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum. Its current treatments involve long-term uptake of glucocorticoids (e.g., prednisone) for controlling inflammation; however, side effects are common. We strived for an improved therapy for fibrosis remission while reducing side effects.
We surveyed gene-disease-drug databases and discovered that mammalian target of rapamycin (mTOR) was a key signalling protein in RPF and the mTOR inhibitor compound sirolimus affected many RPF pathways. We designed a therapy combining a gradual reduction of prednisone with a long-term, stable dosage of sirolimus. We then implemented a single-arm clinical trial and assessed the effects in eight RPF patients at 0, 12 and 48 weeks of treatment by measuring fibrous tissue mass by CT, markers of inflammation and kidney functions by lab tests, immune cell profiles by flow cytometry and plasma inflammatory proteins by Olink proteomics.
With the combined therapy, fibrous tissue shrunk about by half, markers of acute inflammation reduced by 70% and most patients with abnormal kidney functions had them restored to normal range. Molecularly, fibrosis-related T cell subsets, including TH2, TH17 and circulating TFH cells, were reduced and tumour necrosis factor and related cytokines restored to healthy levels. No severe long-term side effects were observed.
Our combined therapy resulted in significant fibrosis remission and an overall regression of the immune system towards healthy states, while achieving good tolerance. We concluded that this new therapy had the potential to replace the steroid monotherapy for treating RPF.

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.
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).
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).
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.

Idiopathic retroperitoneal fibrosis (iRPF) is a chronic autoimmune disease characterized by fibroinflammatory tissue surrounding the abdominal aorta and iliac arteries and extending into the retroperitoneum to envelop neighboring structures. Hydronephrosis due to obstruction of ureters is the most common complication of iRPF. Glucocorticoid with or without immunosuppressants or tamoxifen, the mainstay of iRPF treatment, usually brings good response. Nevertheless, in some conditions, the obstruction of ureters remains unresolved with the treatment of all these medications. One of the reasons lies in the innate feature of the fibroinflammatory tissue. The proliferation of fibrosis tissue in addition to inflammation in the mass was associated with insufficient response to immunosuppressive therapies. Pirfenidone, an anti-fibrosis agent, has been successful in treating pulmonary fibrosis and renal fibrosis. Therefore, it is rationale to assume the effectiveness of pirfenidone in the treatment of iRPF. In the current article, we report a 61-year-old Chinese man with iRPF who responded well to pirfenidone.

BACKGROUND: Retroperitoneal fibrosis is a rare disease characterized by chronic nonspecific inflammation, which leads to clinical compression manifestations of retroperitoneal organs especially ureter. Approximately 70 percent of retroperitoneal fibrosis cases are idiopathic which has no clear etiology. This study reported a rare case of a 48-year-old woman presented with idiopathic retroperitoneal fibrosis and endometrial cancer.
METHODS: A 48-year-old woman presented with irregular vaginal bleeding without abdominal pain, bloating or discomfort. The patient was diagnosed iRPF after splenectomy 13 years ago. Then she took prednisone for 2 years and took tamoxifen for about 11 years. She stopped taking the medication from October 2019 to May 2020 and then started taking tamoxifen again until November 2020. Two weeks after she stopped taking tamoxifen, she presented with irregular vaginal bleeding. Gynecological ultrasound revealed a thick endometrium with uneven echo enhancement and blood flow signals. Then diagnostic curettage was performed with pathological examination showed endometroid carcinoma. Later, the patient was admitted to Peking University Third Hospital for surgery. Preoperative imaging examinations, including CT, MRI, and PET/CT, all showed pelvic enlarged lymph nodes and they were highly suspected to have lymph node metastasis. The patient underwent laparoscopic surgical staging and enlarged lymph nodes in the pelvic and aortic regions were removed. Finally, the pathology confirmed that endometrioid adenocarcinoma and fibrosis, but there was no tumor infiltration in these enlarged lymph nodes. The patient is now in good condition.
CONCLUSIONS: This case report stressed the difficulty to distinguish between lymph node metastasis and inflammatory hyperplasia by common imaging methods. Due to increased surgical difficulty among retroperitoneal patients, lymphadenectomy should be carefully evaluated to avoid additional surgical complications and over-treatment.