Maria Nicastro

Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, to whose pathogenesis neoplastic and immune-mediated mechanisms contribute. Mammalian target of rapamycin (mTOR)-inhibitors have antiproliferative and immunosuppressive properties. We tested in this study, the efficacy and safety of the mTOR-inhibitor sirolimus (SRL) plus prednisone (PDN) in patients with ECD. PDN was given initially at 0.75 mg/kg per day, tapered to 5 to 2.5 mg per day by month 6. Target SRL blood levels were 8 to 12 ng/mL. Treatment was continued for at least 24 months in patients who showed disease stabilization or improvement. Ten patients were enrolled; 8 achieved stable disease or objective responses, whereas 2 had disease progression. Responses were mainly observed at the following sites: retroperitoneum in 5/8 patients (62.5%), cardiovascular in 3/4 (75%), bone in 3/9 (33.3%), and central nervous system (CNS) in 1/3 (33.3%). The median follow-up was 29 months (interquartile range, 16.5-74.5); 2 patients died of progressive CNS disease and small-cell lung cancer, respectively. Treatment-related toxicity was mild. Using immunohistochemistry and immunofluorescence on ECD biopsies, we detected expression in foamy histiocytes of the phosphorylated forms of mTOR and of its downstream kinase p70S6K, which indicated mTOR pathway activation. In conclusion, SRL and PDN often induce objective responses or disease stabilization and may represent a valid treatment of ECD. The trial is registered at the Australia-New Zealand Clinical Trial Registry as #ACTRN12613001321730.

Association of Serum C3 Concentration and Histologic Signs of Thrombotic Microangiopathy with Outcomes among Patients with ANCA-Associated Renal Vasculitis

BACKGROUND AND OBJECTIVES Complement alternative pathway (cAP) activation has recently been recognized as a key pathogenic event in ANCA-associated vasculitis (AAV). cAP dysregulation is also a major determinant of thrombotic microangiopathies (TMA), which can in turn complicate AAV. We explored the prognostic significance of cAP activation and of histologic evidence of TMA in a cohort of patients with renal AAV. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We studied 46 patients with AAV diagnosed between January 1990 and December 2011 at the Nephrology Unit of Parma University Hospital; 30 of them had undergone renal biopsy. We analyzed serum levels of C3 (sC3) and C4 (sC4) and, for 19 patients who had frozen plasma, plasma Bb and C5b-9 levels. We also reviewed all kidney biopsy specimens, specifically searching for histologic signs of TMA, and performed immunofluorescence or immunohistochemistry for C3d, C4d, Bb and C5b-9. RESULTS sC3 was below the lower limit of normal in 35% of the patients, whereas C4 was low in only 2%. Patients with low sC3 tended to be older (P=0.04) and to have lower eGFR at diagnosis (P=0.06). The median follow-up was 78 months (interquartile range, 18-135 months); 18 patients reached ESRD (10 of 14 and 8 of 26 in the low and normal sC3 groups, respectively). Death-censored renal survival was lower in the low sC3 group than in the normal sC3 group (log-rank test, P=0.01). Eight of the 30 patients who had undergone biopsy (27%) had histologic signs of TMA; these signs were more frequent in patients with low sC3 (5 of 10 versus 3 of 20; P=0.04). Notably, patients with histologic signs of TMA had a dramatically worse death-censored renal survival than patients without TMA (log-rank test, P=0.01), with ESRD occurring in 8 of 8 patients with TMA versus 8 of 22 patients without TMA. CONCLUSIONS Low sC3 levels and histologic signs of TMA are associated with a poor renal prognosis in patients with AAV.

Interleukin-6 as an inflammatory mediator and target of therapy in chronic periaortitis.

OBJECTIVE Chronic periaortitis (CP) usually responds to glucocorticoids, but some patients have glucocorticoid-refractory disease or contraindications to glucocorticoid therapy. This study was undertaken to evaluate treatment with the anti-interleukin-6 receptor (anti-IL-6R) antibody tocilizumab in 2 patients with CP, one with refractory disease and the other with contraindications to glucocorticoids, and to assess IL-6 levels in an additional cohort of patients with CP. METHODS Both patients were given intravenous tocilizumab (8 mg/kg) once every 4 weeks for 6 months. Serum IL-6 was measured in 22 patients with active CP and 16 healthy controls. Tissue IL-6 expression was assessed by confocal microscopy in biopsy specimens obtained from 6 patients with CP. RESULTS In the first patient, whose disease was refractory to various immunosuppressive treatments, tocilizumab added to ongoing therapy with prednisone and methotrexate allowed prednisone withdrawal and induced resolution of symptoms, acute-phase reactant normalization, and reduction in (18) F-fluorodeoxyglucose ((18) F-FDG) uptake on positron emission tomography. The patient experienced a relapse 7 months later and was successfully retreated with tocilizumab. In the second patient, who was unable to tolerate glucocorticoids because of psychiatric side effects, tocilizumab monotherapy induced sustained clinical and laboratory remission, (18) F-FDG uptake disappearance, and CP shrinkage. Serum IL-6 levels were significantly higher in patients with active CP than in controls (P < 0.0001), and IL-6 was abundantly expressed in biopsy specimens from CP patients, particularly by T cells, B cells, histiocytes, fibroblasts, and vascular smooth muscle cells. CONCLUSION Tocilizumab may be a therapeutic option for CP. The systemic and tissue up-regulation of IL-6 in CP, together with the clinical benefit of IL-6R blockade observed in our 2 patients, suggest that IL-6 may contribute to CP pathogenesis.

Brief Report: Interleukin-6 as an Inflammatory Mediator and Target of Therapy in Chronic Periaortitis

OBJECTIVE Chronic periaortitis (CP) usually responds to glucocorticoids, but some patients have glucocorticoid-refractory disease or contraindications to glucocorticoid therapy. This study was undertaken to evaluate treatment with the anti-interleukin-6 receptor (anti-IL-6R) antibody tocilizumab in 2 patients with CP, one with refractory disease and the other with contraindications to glucocorticoids, and to assess IL-6 levels in an additional cohort of patients with CP. METHODS Both patients were given intravenous tocilizumab (8 mg/kg) once every 4 weeks for 6 months. Serum IL-6 was measured in 22 patients with active CP and 16 healthy controls. Tissue IL-6 expression was assessed by confocal microscopy in biopsy specimens obtained from 6 patients with CP. RESULTS In the first patient, whose disease was refractory to various immunosuppressive treatments, tocilizumab added to ongoing therapy with prednisone and methotrexate allowed prednisone withdrawal and induced resolution of symptoms, acute-phase reactant normalization, and reduction in (18) F-fluorodeoxyglucose ((18) F-FDG) uptake on positron emission tomography. The patient experienced a relapse 7 months later and was successfully retreated with tocilizumab. In the second patient, who was unable to tolerate glucocorticoids because of psychiatric side effects, tocilizumab monotherapy induced sustained clinical and laboratory remission, (18) F-FDG uptake disappearance, and CP shrinkage. Serum IL-6 levels were significantly higher in patients with active CP than in controls (P < 0.0001), and IL-6 was abundantly expressed in biopsy specimens from CP patients, particularly by T cells, B cells, histiocytes, fibroblasts, and vascular smooth muscle cells. CONCLUSION Tocilizumab may be a therapeutic option for CP. The systemic and tissue up-regulation of IL-6 in CP, together with the clinical benefit of IL-6R blockade observed in our 2 patients, suggest that IL-6 may contribute to CP pathogenesis.

Erdheim-Chester Disease as a Mimic of IgG4-Related Disease: A Case Report and a Review of a Single-Center Cohort.

AbstractImmunoglobulin-G4 (IgG4)-related disease (IgG4RD) is a fibro-inflammatory disorder characterized by tissue-infiltrating IgG4+ plasma cells, and, often, high serum IgG4. Several autoimmune, infectious, or proliferative conditions mimic IgG4RD. Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by foamy histiocytic infiltration, fibrosis, and chronic inflammation. ECD and IgG4RD manifestations may overlap.A patient presented with huge fibrous retroperitoneal masses causing compression on neighboring structures; the case posed the challenge of the differential diagnosis between IgG4RD and ECD mainly because of a prominent serum and tissue IgG4 response.Retroperitoneal biopsy led to the diagnosis of ECD; the V600E BRAF mutation was found. Treatment with the BRAF inhibitor vemurafenib was started.Treatment failed to induce mass regression and the patient died after 3 months of therapy. Prompted by this case, we examined serum and tissue IgG4 in a series of 15 ECD patients evaluated at our center, and found that approximately one-fourth of the cases have increased IgG4 in the serum and often in the tissue.The differential diagnosis between IgG4RD and ECD can be challenging, as some ECD patients have prominent IgG4 responses. This suggests the possibility of common pathogenic mechanisms between ECD and IgG4RD.

Brief Report : Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schönlein)

Adult‐onset IgA vasculitis (Henoch‐Schönlein) (IgAV) is a rare systemic vasculitis characterized by IgA1‐dominant deposits. The treatment of adult‐onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell–depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody–associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult‐onset IgAV.

Immunoglobulin G4-related disease: some missing pieces in a still unsolved complex puzzle.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immunemediated fibro-inflammatory disorder whose main structural feature is the development of sclerotic masses particularly rich in lymphocytes and IgG4 plasma cells. Thesemasses – varying in size –may affect synchronously or metachronously the soft tissues and/or different organs such as pancreas, lacrimal glands, salivary glands, gallbladder, and many other target locations including the cardiovascular system [1]. Most patients suffering from IgG4-RD have increased serum IgG4 concentrations; however, data from the English-language literature report that about 30% to 50% of them show normal levels of these immunoglobulins [2,3]. The notion of IgG4-RD is relatively recent. In fact, Hamano et al. [4] in 2001 first reported that serum IgG4 concentrations were drastically increased in patients with type 1 autoimmune pancreatitis (AIP) compared to those suffering from pancreatic adenocarcinoma and, the following year, that IgG4 plasma cells constituted a significant fraction of the inflammatory infiltrate in type 1 AIP [4,5]. Since then, the term IgG4-RD has become increasingly popular in the world of science, while many other systemic locations with similar histopathologic findings have been reported and labeled with this appealing designation which, furthermore, is presumed to provide clues on the disease pathogenesis. In 2011, a joint proposal to unify under the term “IgG4-RD” various previously described entities sharing similar histopathologic characteristics (e.g., Mikulicz disease, AIP, Riedels thyroiditis, orbital pseudotumor, Kuttner tumor) was made [6]. Due to the relatively young history of IgG4-RD and the fact that its recognition is based on a rigorous histopathological interpretation (supported by clinicopatholologic correlation), precise information on the epidemiology of this potentially systemic disorder is still incomplete and, more than likely, underestimated [1]. The overall prevalence rate of type 1 AIP in Japan has recently been updated as 4.6 cases per 100,000 population (male-to-female ratio 3.2; average age 66.3 years) with an annual incidence rate of 1.4 per 100,000 inhabitants [7]; however, the real epidemiology of IgG4-RD in terms of different systemic occurrences (and various combinations thereof) is still unknown. In this scenario, IgG4-RD can affect the cardiovascular system with fibroinflammatory locations predominantly occurring in the aorta (thoracic or abdominal) and its branches, coronary arteries, pericardium, or the aortic valve [2,8–13]. Idiopathic retroperitoneal fibrosis (IRF) is a fibro-inflammatory disorder included in the spectrum of “chronic periaortitis.” In its typical form, it develops around the infrarenal tract of a nondilated aorta and the downstream iliac arteries; during its centrifugal growth, IRF frequently entraps adjacent organs such as the ureters and the inferior vena cava [14]. Over the last few years, some authors have argued in favor of a theory that, according to current diagnostic criteria, some IRF cases could even fall within the spectrum of IgG4-RD [1,15].

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.

The Pathology of Systemic Fibroinflammatory Disorders

The broad denomination of “systemic fibroinflammatory disorders” includes a series of exceedingly different lesions whose common morphologic characteristic is a local deposition of varying amounts of fibrous tissue and inflammatory infiltrates. From a histopathological standpoint, the main consequence of such a feature is the fact that the morphofunctional architecture of a given parenchyma (or complex structure) is partially or totally replaced by nonfunctioning tissues. This fact is especially critical in multifocal systemic disorders and, what’s more, in cases characterized by particular aggressiveness, as in neoplastic fibroinflammatory diseases. A further point to be highlighted is the relative slow turnover of the above-mentioned newly formed tissues, first and foremost fibrosis. This fact makes most of clinical treatments scarcely effective in helping to induce restitutio ad integrum of the affected anatomical locations.

Brief Report: Interleukin-6 as an Inflammatory Mediator and Target of Therapy in Chronic Periaortitis: IL-6 in Chronic Periaortitis

OBJECTIVE Chronic periaortitis (CP) usually responds to glucocorticoids, but some patients have glucocorticoid-refractory disease or contraindications to glucocorticoid therapy. This study was undertaken to evaluate treatment with the anti-interleukin-6 receptor (anti-IL-6R) antibody tocilizumab in 2 patients with CP, one with refractory disease and the other with contraindications to glucocorticoids, and to assess IL-6 levels in an additional cohort of patients with CP. METHODS Both patients were given intravenous tocilizumab (8 mg/kg) once every 4 weeks for 6 months. Serum IL-6 was measured in 22 patients with active CP and 16 healthy controls. Tissue IL-6 expression was assessed by confocal microscopy in biopsy specimens obtained from 6 patients with CP. RESULTS In the first patient, whose disease was refractory to various immunosuppressive treatments, tocilizumab added to ongoing therapy with prednisone and methotrexate allowed prednisone withdrawal and induced resolution of symptoms, acute-phase reactant normalization, and reduction in (18) F-fluorodeoxyglucose ((18) F-FDG) uptake on positron emission tomography. The patient experienced a relapse 7 months later and was successfully retreated with tocilizumab. In the second patient, who was unable to tolerate glucocorticoids because of psychiatric side effects, tocilizumab monotherapy induced sustained clinical and laboratory remission, (18) F-FDG uptake disappearance, and CP shrinkage. Serum IL-6 levels were significantly higher in patients with active CP than in controls (P < 0.0001), and IL-6 was abundantly expressed in biopsy specimens from CP patients, particularly by T cells, B cells, histiocytes, fibroblasts, and vascular smooth muscle cells. CONCLUSION Tocilizumab may be a therapeutic option for CP. The systemic and tissue up-regulation of IL-6 in CP, together with the clinical benefit of IL-6R blockade observed in our 2 patients, suggest that IL-6 may contribute to CP pathogenesis.