Clinical and pathological predictors of relapse in IgG4-related disease.

OBJECTIVES: In IgG4-related disease, the relationship between pathological findings and relapse has not been well established. This study aimed to identify the clinical and pathological predictors of disease relapse in IgG4-RD. METHODS: Patients with newly diagnosed IgG4-RD (n = 71) were enrolled between January 2011 and April 2020; all cases were pathologically confirmed. The clinical and pathological features were recorded in a database at baseline and each follow-up visit. Patients were followed up at least once a month via outpatient clinic examinations and telephone calls. Univariate and multivariate Cox regression analyses and receiver operating curve (ROC) analysis were used to identify the predictors of disease relapse and to assess their predictive value. RESULTS: Over a median follow-up of 26 (range, 6-123) months, 3/71 (4.2%) patients died. Of the remaining 68 patients, 47 (69.1%) patients had achieved clinical remission and 21 (30.9%) had suffered relapse at the last follow-up. The independent predictors of relapse were IgG4 ≥ 6.5 g/L (HR = 2.84, 95% CI: 1.11-7.23), IgG ≥ 20.8 g/L (HR = 4.11, 95% CI: 1.53-11.06), IgG4-RD responder index (RI) ≥ 9 (HR = 3.82, 95% CI: 1.28-11.37), and severe IgG4+ plasma cell infiltration (HR = 6.32, 95% CI: 1.79-22.41). A prognostic score developed using three of the identified predictors (IgG ≥ 20.8 g/L, IgG4-RD RI ≥ 9, and severe IgG4+ plasma cell infiltration) showed good value for predicting impending relapse (AUC, 0.806). CONCLUSIONS: In patients with IgG4-RD, IgG4 ≥ 6.5 g/L, IgG ≥ 20.8 g/L, IgG4-RD responder index (RI) ≥ 9, and severe IgG4+ plasma cell infiltration are predictors of relapse.

Improved clinical outcomes of tocilizumab versus cyclophosphamide for IgG4-related disease: insights from a prospective IgG4-related disease registry.

OBJECTIVE: To compare the clinical outcomes of patients with active immunoglobulin G (IgG) 4 related disease (IgG4-RD) receiving tocilizumab versus those receiving cyclophosphamide (CYC). METHODS: This IgG4-RD registry study was a prospective cohort study conducted among patients with active IgG4-RD hospitalized at Zhongshan Hospital, Fudan University. Patients who were treated with tocilizumab or CYC along with glucocorticoids (GCs) were enrolled. All participants were followed up at the hospital clinic at 3 and 6 months after discharge. Primary clinical outcomes were measured via the IgG4-RD responder index (RI), complete response (CR), and partial response (PR), as well as side effects. RESULTS: From January 2015 to June 2020, 29 patients enrolled. Fourteen and 15 patients were treated with tocilizumab and CYC, respectively. At the 6-month follow-up, disease activity parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IgG4, and IgG4-RD RI, decreased significantly in both groups. At 6 months, tocilizumab demonstrated its superiority, with 50% of patients achieving CR in the Tocilizumab group versus 20% in the CYC group. However, no statistical significance was identified (p = 0.128). The GC dosage at 6 months was significantly lower in the tocilizumab group than in the CYC group [10 (9.4-15) mg/d versus 15 (15-15) mg/d, p = 0.025]. In the CYC group, two patients experienced lumbar vertebral compression fractures related to GCs. Other patients in both groups showed mild adverse effects. CONCLUSIONS: Tocilizumab could be a better steroid-sparing agent, with a comparable curative effect and tolerance, than CYC, in the treatment of IgG4-RD.

Effect of hydroxychloroquine on angiographic progression in routine treatment of Takayasu arteritis.

OBJECTIVES: Hydroxychloroquine (HCQ), an anti-malarial drug, is widely used in the treatment of rheumatic diseases. However, the benefits of HCQ in the treatment of Takayasu arteritis (TA) remain unclear, especially in terms of alleviation of vascular progression. METHODS: This longitudinal observational retrospective study was based on the East China TA cohort. Patients received routine treatment with prednisone and immunosuppressants. Fifty TA patients who underwent magnetic resonance angiography two times within a 1.5-year follow-up period of monitoring vascular changes were divided into HCQ and non-HCQ groups according to whether HCQ was prescribed. Changes in angiographic features were compared. Multivariate Cox regression analysis was employed to further validate the results. RESULTS: Of 50 TA patients, 21 were prescribed HCQ. The two groups shared a similar disease course, vascular types, prednisone with immunosuppressants intervention strategy, globin level, and disease remission rate at 6 months. The HCQ group showed greater reduction in the inflammatory indices erythrocyte sedimentation rate and C-reactive protein (CRP) level (p < .05), and a significantly lower incidence of angiographic progression than the non-HCQ group (19.0% vs. 51.7%, p = .035). After adjustment for age and usage of tocilizumab, angiographic progression was found to be independently associated with CRP (hazard ratio [95% confidence interval], HR [95% CI]: 1.102 [1.000-1.024], p = .046), and the usage of HCQ (HR [95% CI]: 0.266 [0.075-0.940], p = .040). CONCLUSION: HCQ enhanced the anti-inflammatory effect of routine treatment strategies with prednisone and immunosuppressants, and alleviated angiographic progression in TA.

Prognostic factors in IgG4-related disease: a long-term monocentric Chinese cohort study.

OBJECTIVES: Patients with IgG4-related disease (IgG4-RD) suffer high relapse rates during long-term treatment, but factors that predict relapse outcomes are not well established. In the present study, we aimed to identify predictive factors for treatment resistance and disease relapse in a Chinese IgG4-RD cohort. METHODS: This study enrolled 102 patients newly diagnosed with IgG4-RD. Disease prognosis was determined by evaluating disease activity and dosage of glucocorticoids. Predictive factors for refractory and relapsed disease were identified by univariate analysis and Cox regression. RESULTS: Among the 102 patients, 78 cases received medical treatment with regular follow-up (21 [6-111] months). During the follow-up period, 55 (70.5%) patients sustained clinical remission, and 23 (29.5%) patients suffered refractory or relapsed disease. The relapse rate of the patients with IgG4-RD was significantly higher among patients who stopped taking medicine than among those who continued treatment with glucocorticoids (GC) + immunosuppressor (IM). Serum TNF-α ≥ 13 pg/mL, sIL-2R ≥ 1010 U/mL, total cholesterol < 3.55 mmol/L, low-density lipoprotein < 2.0 mmol/L, IgG ≥ 20.2 g/L, and drug withdrawal were predictive factors for refractory and relapsed IgG4-RD. Multivariate Cox regression revealed that both sIL-2R and TNF-α were independent risk factors for refractory and relapsed disease. The combination of GC and IM treatment was an independent protective factor against refractory and relapsed IgG4-RD. CONCLUSIONS: High serum levels of sIL-2R and TNF-α may be informative risk factors for refractory and relapsed IgG4-RD. Our data suggest that a combination treatment of GC along with IM may be protective against refractory and relapsed IgG4-RD. Key Points • High sIL-2R and TNF-α levels are informative risk factors for refractory and relapsed IgG4-related disease. • Combination treatment of GC with IM protects against refractory and relapsed IgG4-related disease.

Clinical and genetic risk factors for glucocorticoid-associated osteonecrosis of the femoral head: a prospective cohort study / 中华骨科杂志

Objective:To perform a prospective cohort study to identify individual susceptibility of glucocorticoid (GC) -associated osteonecrosis of the femoral head (GA-ONFH) and their clinical and genetic risk factors. Methods:The present prospective cohort study enrolled patients who received their first GC therapy between July 2015 and January 2018 at Zhongshan Hospital. All patients did not receive any GC treatment before enrollment. Further, they planned to start GC treatment with the dose (equivalent prednisone) of ≥30 mg/d, lasted ≥3 weeks, or pulse dose ≥200 mg/d, lasted ≥3 d. Blood samples were collected before GC treatment to evaluate bone metabolism and its released factors. Hip MRI was performed at the 1st, 3rd, 6th, 12th and 24th month to diagnose GA-ONFH. All patients were followed-up for ≥2 years. The endpoint was regarded as diagnosis of GA-ONFH or completion of 2 years follow-up. Lasso regression was performed to determine which clinical features were associated with GA-ONFH. A nested case-control sub-cohort (A, n=12) was established prospectively based on the main cohort by 1∶1 matching. Whole exome sequencing was performed to screen differential and functional candidate single nucleotide polymorphisms and insertion-deletions (SNP/InDels). Another sub-cohort (B, n=50) was constructed retrospectively in patients with GA-ONFH and non-ONFH patients received standard high dose GC treatment for more than two years. The candidate SNP/InDels were verified by Sanger sequencing based on the patients from sub-cohort B. Results:A total of 96 patients were enrolled of which 88 of them (32 males and 56 females, mean age 42.30 years) completed follow-up. Eight cases (9.1%) were diagnosed with GA-ONFH. The median time from the start of GC therapy to the diagnosis of ONFH was 53.00(34.00,13.50) days. The baseline characteristics, such as age, sex and body mass index, indicated no significant difference between the ONFH group and the non-ONFH group. The cumulative GC dose of the ONFH patients in the first month was higher than that of non-ONFH [32.74(29.55, 47.05) mg/kg vs. 24.00(21.10, 29.45) mg/kg, Z=-2.410, P=0.016]. However, there was no significant difference of patients who underwent pulse therapy (37.5% vs. 10.0%, adjusted χ 2=2.829, P=0.093). The ratio of serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) in patients with ONFH was higher than that in non-ONFH group before GC use [0.95(0.80, 1.50) vs. 0.70(0.60, 0.80), Z=-2.875, P=0.000]. Due to the multicollinearity, Lasso regression model was performed to reduce overfitting. All variables were included in the model. The results suggested that higher ApoB/ApoA1 ratio, lower serum β-c-terminal telopeptide (β-CTX) and higher cumulative GC dose in the first month were the top three risk factors of GA-ONFH. This model had an accuracy of 0.982 in internal validation. Seven differential candidate SNP/InDels were found by whole exome sequencing of sub-cohort A. We further verified these SNP/InDels in sub-cohort B. The patients with COLEC12 mutation (rs2305027, G1816A) were at risk of GA-ONFH ( OR=6.00, 95% CI: 1.17, 30.73). Conclusion:Higher first-month GC dose, lower serum β-CTX level before treatment, higher ApoB/ApoA1 ratio and COLEC12 mutation (rs2305027, G1816A) could increase the risk of GA-ONFH.

Clinicial features of Takayasu arteritis: a cohort study / 中华风湿病学杂志

Objective:To analyze the characteristics of patients with Takayasu arteritis (TA) in the east China Takayasu arteritis (ECTA) cohort and their subgroups, and evaluate the disease characteristics.Methods:Patients diagnosed with TA in ECTA cohort from January 2009 to October 2019 were enrolled and their data were analyzed. The characteristics were analyzed and compared within subgroups using t-test or Wilcoxon rank sum test or Chi-square test. Results:A total of 454 patients were included, with the male to female ratio of 1∶4.75(79/375), and the main complaint were dizziness/headache, fatigue, and chest tightness/pain. The type Ⅴ and Ⅰ were the most common angiographic pattern, among which the subclavian artery and carotid artery were most vulnerable, manifested as vascular stenosis. Hypertension, tuberculosis and hepatitis B were common complications. In subgroup comparison, symptoms and inflammation index were much more evident in the active group, female group, <40 years old, and newly diagnosed group. C-reactive protein (CRP)[10(2, 33) mg/L vs 3(1, 14) mg/L, Z=-4.49, P<0.01), erythrocyte sedimentation rate (ESR) [(45±33) mm/1 h vs (25±23) mm/1 h, t=-5.82, P<0.01), in the active group were significantly higher than those in the inactive group, while the ESR in female patients was only higher than that in males, but without statistical significant difference. SAA in the young age group, ESR in the newly diagnosed group was significantly higher than that in the other subgroups [19(6, 95) mg/L vs 10(4, 39) mg/L, Z=2.06, P<0.05] [(44±34) mm/1 h vs (32±28) mm/1 h, t=3.77, P<0.01]. Conclusion:The TA patients are mainly young women, and are in active disease when first being diagnosed. The type Ⅴ and Ⅰ are the most common artery involve-ment pattern. Hypertension and tuberculosis are the most frequent complications.

In vitro IL-6/IL-6R Trans-Signaling in Fibroblasts Releases Cytokines That May Be Linked to the Pathogenesis of IgG4-Related Disease.

Background: The remarkable mechanisms of storiform fibrosis and the formation of high levels of IgG4 with a pathogenic germinal center (GC) in the inflammatory tissue of IgG4-RD remains unknown and may be responsible for the unsatisfactory therapeutic effect on IgG4-related diseases when using conventional therapy. Objectives: To investigate the mechanisms of interleukin 6 (IL-6) inducing fibroblasts to produce cytokines for pathogenic GC formation in the development of IgG4-related disease (IgG4-RD). Methods: The clinical data and laboratory examinations of 56 patients with IgG4-RD were collected. IL-6 and IL-6R expression in the serum and tissues of patients with IgG4-RD and healthy controls were detected by ELISA, immunohistochemistry, and immunofluorescence. Human aorta adventitial fibroblasts (AAFs) were cultured and stimulated with IL-6/IL-6 receptor (IL-6R). The effect of IL-6/IL-6R on AAFs was determined by Luminex assays. Results: The serum IL-6 and IL-6R levels were elevated in active IgG4-RD patients and IL-6 was positively correlated with the disease activity (e.g., erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and IgG4-RD responder index). IL-6 and IL-6R expression in the tissue lesions of IgG4-related retroperitoneal fibrosis and IgG4-related sialadenitis patients were also significantly higher than that in the normal tissues. In addition, there is a relative abundance of myofibroblasts as well as IgG4+ plasma cells in the tissues of IgG4-related retroperitoneal fibrosis. α-SMA and B cell differentiation cytokines (i.e., B cell activating factor), and α-SMA and T follicular helper (Tfh) cell differentiation cytokines (e.g., IL-7, IL-12, and IL-23) were co-expressed in the local lesions. In vitro, IL-6/IL-6R significantly promoted the production of B cell activating factor, IL-7, IL-12, and IL-23 in AAFs in a dose-dependent manner. This effect was partially blocked by JAK1, JAK2, STAT3, and Akt inhibitors, respectively. Conclusions:In vitro IL-6/IL-6R trans-signaling in fibroblasts releases Tfh and B cell differentiation factors partially via the JAK2/STAT3, JAK1/STAT3, and JAK2/Akt pathways, which may be linked to the pathogenesis of IgG4-RD. This indicated that IL-6 and fibroblasts may be responsible for GC formation and fibrosis in the development of IgG4-RD. Blocking IL-6 with JAK1/2 inhibitors or inhibiting fibroblast proliferation might be beneficial for IgG4-RD treatment.

Efficacy and safety of leflunomide versus cyclophosphamide for initial-onset Takayasu arteritis: a prospective cohort study.

BACKGROUND: Leflunomide (LEF) has been considered as an alternative treatment for Takayasu arteritis (TA); however, data on its efficacy are still scanty. OBJECTIVE: To investigate the efficacy and safety of LEF versus cyclophosphamide (CYC) for initial-onset TA. METHODS: Initial-onset TA patients with active disease were enrolled in this research. Patients enrolled from 1 January 2009 to 31 December 2015 were treated with glucocorticoids and CYC, while patients enrolled from 1 January 2016 to 31 October 2018 received glucocorticoids and LEF. Treatment response including complete remission (CR), partial remission (PR), and effectiveness rate (ER) and side effects were evaluated at 6 and 12 months. RESULTS AND CONCLUSION: In total, 92 patients were enrolled. A total of 47 patients were treated with LEF, while 45 patients were treated with CYC. The CR and ER rates were 75.55%, and 88.89% at 6 months, and 85.37% and 95.12% at 12 months in the LEF group. The CR and ER rates were 39.02% and 70.73% at 6 months, and 56.41% and 82.05% at 12 months in the CYC group. The CR rate was significantly higher in the LEF group than in the CYC group both at 6 months (75.61% versus 38.24%, p < 0.01) and 12 months (77.42% versus 53.33%, p < 0.05) after adjustment for propensity scores. The incidence of side effects in the LEF group was much lower than that in the CYC group (21.28% versus 44.44%). In conclusion, LEF provided a better treatment response, along with lower reproductive toxicity, compared with CYC in initial-onset TA.

Anti-neutrophil cytoplasmic antibody-associated vasculitis overlap immunoglobulin G4-related diseases: a 4 case series and review of literature / 中华风湿病学杂志

Objective:To summarize the characteristics and treatment outcomes of immunoglobulin G4-related disease (IgG4-RD) overlapped with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV).Methods:The clinical data of four patients with AAV overlaped with IgG4-RD from Zhongshan Hospital of Fudan University from August 2018 to July 2019 were collected and the related literature were reviewed.Results:Four patients were included, in which two were diagnosed with IgG-RD and granulomatosis with polyangiitis (GPA), one was probable IgG4-RD and microscopic polyangiitis (MPA), and one was probable IgG4-RD and GPA. All patients were female, with an average age of (42±12) (26-56) years, and disease duration was (7±4) (4-13) months. The manifestations were ocular inflammatory pseudotumor, sinusitis, otitis media, mastoiditis, parotitis, meningitis, lung and kidney involvement. After treatment with glucocorticoid and immunosuppressants (including cyclophosphamide, methotrexate, azathioprine, leflunomide), 2 patients failed to achieve remission, and 2 patients relapsed 8-15 months after treatment. One patient was treated withglucocorticoid pulse therapy combined with rituximab and one was treated with glucocorticoid combined with methotrexate and rituximab, and the patient was relieved.Conclusion:AAV and IgG4-RD may be a new overlap syndrome. Hypertrophic meningitis, orbital mass, chronic periaortic inflammation and interstitial glomerulonephritis are reported in the literature. The pathological changes of orbit, nasopharynx, parotid gland and lung are common. Glucocorticoids and immunosuppressive agents have poor treatment response, which indicates that AAV is refractory when combined with elevated IgG4. The induced remission rate is low, and easy to relapse. Glucocorticoid pulse therapy and rituximab treatment are effective.

18F-Fluorodeoxyglucose positron emision tomography in the assessment of disease activity of Takayasu arteritis: a meta-analysis / 中华风湿病学杂志

Objective To evaluate the performance of Positron emision tomography (PET) in the assessment of disease activity of Takayasu arteritis (TA). Methods Information retrieval was based on database such as PubMed/Medline and CNKI, etc. The research before Dec 2016 involving Takayasu arteritis and PET were included.The quality of the research was evaluated by diagnostic accuracy studies-2Q(UADAS-2) and the data was analyzed by Meta-disc. Results Among the 70 research, nine studies were included in this study with a total of 126 patients and 254 controls. All patients were diagnosed according to the classification criteria of American College of Rheumatology. The disease activity was mostly assessed by the scoring system of National Institutes of Health and by clinical assessment in one study. The result of PET was evaluated by visual grade and semi-quantitative analysis. The pooled DOR of the 9 studies was 17.54, the pooled sensitivity and specificity was 84% and 73%,respectively.However,the heterogeneity of specificity was 81.4%. Two studies had included one patients repeatedly and suspected active patients were included in the in-active group in one study,which might impact the statistical result of the meta-analysis.After excluded these studies, the pooled DOR was 30.32. The pooled sensitivity and specificity was 86% and 85%, respectively, with better consistency. Conclusion PET shows stable sensitivity and variant specificity in the diagnosis and assess of disease activity of TA, which is a useful method in the clinically evaluation of disease activity of TA.

Clinical analysis of 49 cases with IgG4-related disease / 中华风湿病学杂志

Objective To investigate the clinical manifestations,radiographic presentations,histopathological features,treatment and clinical follow-up of IgG4 related disease (IgG4-RD).Methods Forty-nine cases in our hospital were enrolled from 2009 to 2012 and were followed up.Results Of the 49 patients with IgG4-RD,the male to female ratio was 2.1∶1,the mean age was (53±15) years,and the serum IgG4 ranged between 0.39 to 20.8 g/L.The most commonly affected organ was pancreas.Two or more organs were involved in 15 patients.Histopathological findings included tissue infiltration by lymphocytes,IgG+ plasma cells and IgG4+ plasma cells and diffuse fibrosis among 45 patients.The IgG4+ plasma cells were over 10/high power fields (HPF).Responses to glucocorticoid in combination with immunosuppressants were good except 3 patients suffered relapses.Conclusion IgG4-RD is an autoimmune disease affecting multiple organs,and the increased IgG4 positive plasma cells is characteristic.This disease can be effectively alleviated with prompt use of glucocorticoid.