High level of serum complement 3 is a risk factor for vascular stenosis progression in TA patients receiving tocilizumab: a prospective observational study.

BACKGROUND: The IL-6R antibody tocilizumab has been proven effective in treating Takayasu arteritis (TA). However, some patients show silent vascular stenosis progression (VSP) despite treatment with tocilizumab. The aim of the study was to explore the related risk factors of VSP in patients treated with tocilizumab. METHODS: Patients receiving tocilizumab were enrolled from the prospective living ongoing East China Takayasu Arteritis cohort. Their medical information was uniformly recorded with a homogenized evaluation method. Magnetic resonant angiography or computed tomographic angiography was employed to monitor VSP during the follow-up period, and Cox regression analysis was performed to explore the related risk factors. RESULTS: Thirty-eight patients were enrolled, among whom 18 (47.4%) experienced VSP, and seven and three patients experienced new and worsened vascular ischemic symptoms and events (VISE) during follow-up, respectively. The median period for VSP occurrence was 6.9 months during follow-up. Patients with VSP showed higher levels of baseline complement 3 (C3) than those in the patients without VSP. Multivariate Cox regression analysis revealed baseline C3 level (hazard ratio [HR] = 7.05, 95% confidence interval: 1.50-33.07, p = 0.013) was independently associated with VSP, with a cut-off value of 1.22 g/L. CONCLUSIONS: 47.4% of TA patients treated with tocilizumab would suffer VSP. A high C3 level is a risk factor for VSP in TA patients receiving tocilizumab, which may facilitate the option of tocilizumab in the future.

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.

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.