Giovanni Maria Rossi

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome

OBJECTIVE Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap. METHODS We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria. RESULTS Eighteen patients were included (median age 55.5years, 13 men). AAV and IgG4-RD were diagnosed concomitantly in 13/18 (72%) patients; AAV preceded IgG4-RD in 3/18 (17%) while IgG4-RD preceded AAV in 2/18 (11%). AAV diagnoses included granulomatosis with polyangiitis in 14 (78%), microscopic polyangiitis in 3 (17%), and eosinophilic granulomatosis with polyangiitis in one case. IgG4-RD diagnosis included definite IgG4-RD in 5 (28%) cases, probable IgG4-RD in 5 (28%) and possible IgG4-RD in 8 (44%). IgG4-RD manifestations were chronic periaortitis in 9/18 (50%) patients, orbital mass and tubulointerstitial nephritis in 4 (22%) cases, prevertebral fibrosis in 3 (17%), pachymeningitis and autoimmune pancreatitis in 2 (11%) cases. Patients required median number of 2 (range 0-4) lines of immunosuppressants in combination with glucocorticoids. During the follow-up (median 49,8months, range 17,25-108months), AAV manifestations relapsed in 10/18 (56%) cases and IgG4-RD lesions in 5/18 (28%). When used, mainly for relapses, rituximab showed response in all cases. CONCLUSION AAV and IgG4-RD may overlap. Clinicians should consider that atypical manifestations during AAV could be related to IgG4-RD rather than to refractory granulomatous or vasculitic lesions.

A large-scale genetic analysis reveals an autoimmune origin of idiopathic retroperitoneal fibrosis

In this large-scale immunogenetic study performed using the Immunochip array, we demonstrate that idiopathic retroperitoneal fibrosis is associated with HLA alleles (HLA-DRB1*03) and HLA-DRβ amino acid variants (Arg74) traditionally linked to typical autoimmune diseases.

Hemoptysis in Behçet’s syndrome: from bedside to bench?

The “vascular cluster” of Behçet’s syndrome includes protean clinical entities, since veins and arteries of variable size and anatomical site may be involved. Vascular events tend to occur together and compose distinct clinical pictures [1]. Three out of four patients with Behçet’s syndrome experience a vascular event within 5 years from disease onset. Young age at onset (20–30 years) and male predominance also apply to the “vascular cluster” of the syndrome, with an important exception being represented by non-pulmonary arterial involvement, i.e., the involvement of the aorta or peripheral arteries, which tends to occur at a later age (> 40 years). Vascular events of any type relapse in a relevant portion of patients [1, 2]. The most frequent type of vascular involvement is lowerextremity superficial and deep vein thrombosis, which often clusters with other vascular manifestations as follows: dural sinus thrombosis and pulmonary artery involvement, inferior vena cava syndrome and Budd–Chiari syndrome, and superior vena cava syndrome and inferior vena cava syndrome [3]. Pulmonary artery involvement is also associated with lower-extremity deep vein thrombosis and intracardiac thrombosis [2]. Although these associations are important clues for the clinician, since, for example, a patient with inferior vena cava syndrome and headache should raise concern for the co-occurrence of dural sinus thrombosis, and thus Behçet’s syndrome, they remain challenging when they precede or do not associate with other diagnostic criteria [4]. This is the case of the Hughes–Stovin syndrome, i.e., the association of pulmonary artery aneurysm and lower-extremity deep vein thrombosis in the absence of other Behçet’s manifestations, thus not meeting the International Criteria for Behçet’s disease [4, 5]. Pulmonary artery involvement is rare, affecting roughly 5% of Behçet patients, and carries a high mortality (25% at 7 years). It mainly consists of pulmonary artery aneurysms, often accompanied by pulmonary artery thrombosis. It has been speculated that the structural similarity between veins and pulmonary arteries is the reason behind the association of venous thrombosis and pulmonary artery involvement. Indeed, several anatomical and functional features of large veins are shared by pulmonary arteries: the thin vascular wall, the lower pressure, and the greater compliance, if compared to systemic arteries of comparable size [1, 2, 6]. In general, pulmonary artery involvement is bilateral, with a predilection for the lower lobe branches. Pulmonary artery aneurysm and thrombosis are often associated with several findings: parenchymal consolidations, especially at the onset, and cavities at a later stage, supposedly due to parenchymal infarction; pericardial and pleural effusions [2]. The vasculitic process involving pulmonary arteries in Behçet is different from that observed in other vasculitides [7]. Isolated reports of pulmonary aneurysms in microscopic polyangiitis do exist, but the vessels involved, unlike in Behçet or Takayasu, are small and medium branches of pulmonary arteries, and microaneurysms rather than aneurysms were observed [8]. Takayasu arteritis patients with pulmonary artery involvement do not usually have hemoptysis and tend to have a slower disease onset, with the main symptoms being dyspnea and fatigue. Concomitant involvement of the branches of the thoracic aorta is usually the rule. In Behçet’s syndrome, pulmonary hypertension is milder than in Takayasu. Moreover, while in Behçet patients both thrombosis and aneurysms are observed, in Takayasu arteritis vessel wall thickening with or without occlusion is the classic finding [2, 9]. In the acute phase of Takayasu arteritis, the inflammatory lesions originate in intimal and adventitial vasa vasorum, and This comment refers to the article available at https ://doi. org/10.1007/s1173 9-018-1817-y.

FCGR2A single nucleotide polymorphism confers susceptibility to childhood-onset idiopathic nephrotic syndrome

Childhood-onset idiopathic nephrotic syndrome affects 1.15-3.4 children/100,000 children/year in Western Countries. Immune-mediated mechanisms, particularly T cell-mediated, are thought to play a key pathogenic role. The genetic basis of the disease is still poorly understood. We tested the association between single nucleotide polymorphisms (SNPs) of four genes encoding Fc gamma receptors (FCGR2A, FCGR2B, FCGR3A, FCGR3B) and idiopathic nephrotic syndrome in a case-control study of paediatric patients. Children with idiopathic nephrotic syndrome (aged 1-16 years) were included. FCGR2A rs1801274 and FCGR3A rs396991 SNPs were genotyped using real-time PCR with the TaqMan method, while FCGR2B rs1050501 and FCGR3B NA1/NA2 were genotyped using Sanger sequencing. Fishers exact test was used to explore genetic association. We enrolled 103 idiopathic nephrotic syndrome patients and 181 healthy controls. A significant association was found between idiopathic nephrotic syndrome and FCGR2A rs1801274 SNP (both with the T allele and the TT genotype, p value=0.0009, OR 1.81, 95% CI 1.27-2.59 and p value=0.0007, OR 2.39, 95% CI 1.44-3.99, respectively). No associations were found for the remaining SNPs. Fc gamma receptors might modulate response to rituximab; since 60 of the enrolled patients were treated with rituximab, we also tested the association between the studied SNPs and rituximab efficacy in this patient subgroup, but found only a weak association with FCGR2A CC genotype (p value=0.03). The FCGR2A rs1801274 SNP in the gene encoding the activating receptor CD32A confers susceptibility to idiopathic nephrotic syndrome.

Idiopathic Mediastinal Fibrosis

Fibrosing mediastinitis, also known as mediastinal fibrosis or sclerosing mediastinitis, is a clinical entity characterized by abnormal proliferation of fibrous tissue within the mediastinum. The compression of mediastinal vital structures by the fibroinflammatory tissue determines the clinical presentation [1]. Primitive and secondary forms have been described.