Aortitis and periaortitis: The puzzling spectrum of inflammatory aortic diseases

Aortitis and periaortitis are inflammatory diseases of the aorta and its main branches; they differ in the extension of inflammation, which is confined to the aortic wall in aortitis, and spreads to the periaortic space in periaortitis. Aortitis is classified as non-infectious or infectious. Non-infectious aortitis represents a common feature of large-vessel vasculitides but can also be isolated or associated with other rheumatologic conditions. Periaortitis can be idiopathic or secondary to a wide array of etiologies such as drugs, infections, malignancies, and other proliferative diseases. Notably, both aortitis and periaortitis may arise in the context of IgG4-related disease, a recently characterised fibro-inflammatory systemic disease. Prompt recognition, correct diagnosis and appropriate treatment are essential in order to avoid life-threatening complications.     

Hematuria duration does not predict kidney function at 1 year in ANCA-associated glomerulonephritis

Objectives

Hematuria is considered a marker of active renal disease in ANCA-associated glomerulonephritis (ANCA-GN) with induction immunosuppression often continued until hematuria has resolved. We aim to determine whether longer hematuria duration is associated with lower estimated glomerular filtration rate (eGFR) at 1 year.

Methods

We conducted a retrospective study of 55 patients with biopsy-proven ANCA-GN. Linear regression models were constructed to determine predictors of eGFR at 1 year. The primary exposure was hematuria (>5 rbc/hpf) duration, defined as <90 days vs. ≥90 days following renal biopsy. Covariates included age, gender, ANCA type, baseline eGFR, and baseline proteinuria.

Results

Mean age at diagnosis was 58 years (53% male, 80% Caucasian, 38% PR3-ANCA, and 45% MPO-ANCA). At baseline, all patients had hematuria, 95% had proteinuria, and mean serum creatinine was 3.1 [standard deviation (SD) = 2.3] mg/dL. Overall, 93% were treated with steroids in combination with either cyclophosphamide or rituximab. Mean hematuria duration was 92 (SD = 77) days with 34 (62%) patients having hematuria resolution within 90 days. Older age and lower baseline eGFR were associated with lower eGFR at 1 year (p = 0.03 and p < 0.001, respectively). Hematuria resolution (<90 days vs. ≥90 days) was not predictive of eGFR at 1 year (p = 0.93).

Conclusions

In ANCA-GN, hematuria duration does not predict eGFR at 1 year. Our findings provide support that among individuals who are otherwise considered to be in clinical remission, the persistence of hematuria should not delay transition from induction to maintenance immunosuppression.     

Rituximab treatment of ANCA-associated vasculitis

ABSTRACT

Introduction

Rituximab, an anti–B-cell biological therapy, has been investigated in several clinical trials on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs).     

CD14 expression is increased on monocytes in patients with anti‐neutrophil cytoplasm antibody (ANCA)‐associated vasculitis and correlates with the expression of ANCA autoantigens

Monocyte subsets with differing functional properties have been defined by their expression of CD14 and CD16. We investigated these subsets in anti‐neutrophil cytoplasm antibody (ANCA)‐associated vasculitis (AAV) and determined their surface expression of ANCA autoantigens. Flow cytometry was performed on blood from 14 patients with active AAV, 46 patients with AAV in remission and 21 controls. The proportion of classical (CD14^highCD16^neg/low), intermediate (CD14^highCD16^high) and non‐classical (CD14^lowCD16^high) monocytes and surface expression levels of CD14 and CD16 were determined, as well as surface expression of proteinase 3 (PR3) and myeloperoxidase (MPO) on monocyte subsets. There was no change in the proportion of monocytes in each subset in patients with AAV compared with healthy controls. The expression of CD14 on monocytes from patients with active AAV was increased, compared with patients in remission and healthy controls (P < 0·01). Patients with PR3‐ANCA disease in remission also had increased monocyte expression of CD14 compared with controls (P < 0·01); however, levels in patients with MPO‐ANCA disease in remission were lower than active MPO‐ANCA patients, and not significantly different from controls. There was a correlation between CD14 and both PR3 and MPO expression on classical monocytes in AAV patients (r = 0·79, P < 0·0001 and r = 0·42, P < 0·005, respectively). In conclusion, there was an increase in monocyte CD14 expression in active AAV and PR3‐ANCA disease in remission. The correlation of CD14 expression with ANCA autoantigen expression in AAV may reflect cell activation, and warrants further investigation into the potential for increased CD14 expression to trigger disease induction or relapse.     

Neutrophil extracellular traps can activate alternative complement pathways

The interaction between neutrophils and activation of alternative complement pathway plays a pivotal role in the pathogenesis of anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV). ANCAs activate primed neutrophils to release neutrophil extracellular traps (NETs), which have recently gathered increasing attention in the development of AAV. The relationship between NETs and alternative complement pathway has not been elucidated. The current study aimed to investigate the relationship between NETs and alternative complement pathway. Detection of components of alternative complement pathway on NETs in vitro was assessed by immunostain and confocal microscopy. Complement deposition on NETs were detected after incubation with magnesium salt ethyleneglycol tetraacetic acid (Mg‐EGTA)‐treated human serum. After incubation of serum with supernatants enriched in ANCA‐induced NETs, levels of complement components in supernatants were measured by enzyme‐linked immunosorbent assay (ELISA). Complement factor B (Bb) and properdin deposited on NETs in vitro. The deposition of C3b and C5b‐9 on NETs incubated with heat‐inactivated normal human serum (Hi‐NHS) or EGTA‐treated Hi‐NHS (Mg‐EGTA‐Hi‐NHS) were significantly less than that on NETs incubated with NHS or EGTA‐treated NHS (Mg‐EGTA‐NHS). NETs induced by ANCA could activate the alternative complement cascade in the serum. In the presence of EGTA, C3a, C5a and SC5b‐9 concentration decreased from 800·42 ± 244·81 ng/ml, 7·68 ± 1·50 ng/ml, 382·15 ± 159·75 ng/ml in the supernatants enriched in ANCA induced NETs to 479·07 ± 156·2 ng/ml, 4·86 ± 1·26 ng/ml, 212·65 ± 44·40 ng/ml in the supernatants of DNase I‐degraded NETs (P < 0·001, P = 0·008, P < 0·001, respectively). NETs could activate the alternative complement pathway, and might thus participate in the pathogenesis of AAV .     

TLR4基因1837A／G多态性与广西汉族人群原发抗中性粒细胞胞浆抗体相关性小血管炎的相关性

目的：探讨TLR4基因启动子区－1837A／G基因多态性与广西汉族人群原发抗中性粒细胞胞浆抗体相关性小血管炎（ AAV）易感性之间的关系。方法采用PCR限制性片段长度多态性分析法检测110例AAV患者及101例年龄、性别相匹配的健康成人的TLR4基因1837A／G,行病例－对照研究、临床和病理资料分析。结果（1）110例AAV患者TLR4－1837 A／G多态性AA、AG、GG基因型频率分别为53.64％、40.00％、6.36％, A和G等位基因频率分别为73.64％、26.36％;101例健康人AA、AG、GG基因型频率分别为50.50％、39.60％、9.90％,A和G等位基因频率分别为70.30％、29.70％;两者基因型及等位基因频率比较差异无统计学意义（ P＞0.05）。（2）AA型及GG基因型血尿发生率、C反应蛋白、血沉水平均高于AG基因型,差异有统计学意义（P＜0.05）。（3）3种基因型血红蛋白水平差异有统计学意义（P＜0.05）, AG型的血红蛋白水平明显高于AA型及GG型。结论广西汉族人群中, TLR4－1837A／G基因型多态性可能与AAV 患者血尿发生率、血红蛋白、C反应蛋白、血沉水平相关,但可能与AAV患者的遗传易感性不相关联。     

Predictors of renal histopathology in antineutrophil cytoplasmic antibody associated glomerulonephritis

ObjectivesPrompt, aggressive therapy is vital for anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. In this regard, we aimed to identify predictors of distinct renal histopathological classes at the time of clinical diagnosis.Patients & methodsAn inception cohort of patients with biopsy proven ANCA-associated glomerulonephritis was studied retrospectively. Demographics, clinical, laboratory, serological and radiological parameters were analyzed. Patients were classified on the basis of renal histopathology. A risk score was developed for each histopathological class using univariate and stepwise logistic regression analyses.ResultsVariables independently associated with focal class included disease duration up to diagnosis <8 weeks, absence of erythrocyte casts by urine microscopy and eGFR >49 ml/min/1.73 m²; with crescentic class >40 erythrocytes/hpf, identification of erythrocyte casts in urine, upper respiratory tract involvement and eGFR <49 ml/min/1.73 m²; with mixed class age >54 years, male gender, and absence of upper respiratory tract involvement. In the presence of these risk factors a predictive risk score for each histopathological classes was calculated: odds ratio, 95% confidence intervals (CI), for focal class (≥2 risk factors, 20.8 (95% CI: 5.1–84.2), p < 0.0001, and 441.0 (95% CI: 16.8–11,590), p = 0.0003 for crescentic class (≥3 risk factors) while the small number of patients in the mixed and sclerotic class precluded any estimates.ConclusionWe propose a predictive algorithm of specific histolopathological classes of ANCA-associated glomerulonephritis, which might provide a crude estimation of the disease activity in the glomeruli at presentation. This tool might assist the clinician in making decisions regarding the level of intensity of inductive immunosuppressive therapy at clinical diagnosis.     

Multiple cerebral infarcts with a few vasculitic lesions in the chronic stage of cerebral amyloid angiopathy‐related inflammation

We report a 75‐year‐old man with a 3.5‐year history of cerebral amyloid angiopathy (CAA)‐related inflammation. His initial symptom was headache and sensory aphasia appeared 1 month later. Brain MRI revealed features compatible with meningoencephalitis involving the right frontal, parietal and temporooccipital lobes. A brain biopsy sample from the right parietal lobe showed thickening of the leptomeninges, and granulomatous vasculitis with multinucleated giant cells and vascular Aβ deposits. No vascular lesions were evident by cerebral angiography. Serological examination revealed an elevated level of proteinase 3 anti‐neutrophil cytoplasmic autoantibodies (PR3‐ANCA). The patient was treated with corticosteroids, but this was only partially and temporarily effective. Autopsy revealed marked leptomeningeal thickening with inflammatory cell infiltrates and hemosiderin deposits, many superficial predominantly small infarcts at various stages in the cerebral cortex and only a few cerebral active vasculitic lesions. Immunohistochemically, CAA showing widespread Aβ‐positive blood vessels with double‐barrel formations was demonstrated. In conclusion, we consider that, although the association of PR3‐ANCA with the pathogenesis of Aβ‐associated vasculitis remained unclear, the present case represents a rare example of CAA‐related inflammation at the chronic stage.     

Predicting Mortality in Microscopic Polyangiitis with Renal Involvement: A Survival Analysis Based on 64 Patients

Background: To determine predictors of survival in patients with microscopic polyangiitis (MPA). Methods: A cohort of 64 patients who met the Chapel Hill criteria for MPA with renal involvement participated in the study. All subjects received cytotoxic drugs. All of the diagnoses were biopsy proven. Results: We retrospectively studied 64 patients (median age, 59 years; male/female ratio, 1.6:1). The mean follow-up was 38 months; 34 (53.13%) patients died or acquired end-stage renal disease. According to univariate analysis, a preliminary prognostic value was attributed to serum creatinine (Scr) > 459 μmol/L (p < 0.001); erythrocyte sedimentation rate (ESR) > 99 mm/h (p < 0.001); serum albumin < 30 g/L (p < 0.001); and hemoglobin < 84 g/L (p < 0.001). Logistic regression analysis showed that Scr level (β = 1.02, p = 0.0002) and ESR (β = 1.02, p = 0.0002) at baseline were associated with poor prognosis, and Cox regression analysis further confirmed this result [Scr: β = 1.004, 95% confidence interval (CI): 1.002–1.006, p < 0.001; ESR: β = 1.018, 95% CI: 1.000–1.037, p = 0.046]. The receiver operating characteristic curve showed that Scr and ESR were predictors of MPA patient prognosis, their areas under the curves were 0.95 and 0.80, their sensitivities were 94.1% and 92.3%, and their specificities were 94% and 70%, respectively. Conclusion: Despite the small number of patients in this study, the prevalence of renal vasculitis was high in patients with MPA. The level of Scr and ESR may be a useful clinical biomarker for monitoring prognosis.