Objectives The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. Methods In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Results Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. Conclusions MTX may be effective and safe for remission-maintenance in AAV. Trial registration clinicaltrials.gov NCT00751517

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.

The evolving paradigm of cancer risk related to cyclophosphamide therapy in granulomatosis with polyangiitis Can judicious use of cyclophosphamide reduce the risk of cancer?This editorial refers to Prolonged risk of specific malignancies following cyclophosphamide therapy among patients with granulomatosis with polyangiitis, by

OBJECTIVE:Chronic periaortitis (CP) is a rare disease characterized by fibro-inflammatory tissue surrounding the abdominal aorta and the iliac arteries. Anecdotal reports have shown that CP may also involve other vascular districts, particularly the thoracic aorta. The aim of this study was to investigate the thoracic aorta and epiaortic artery involvement in CP.METHODS:Patients were eligible if they had undergone imaging studies assessing inflammatory involvement of the thoracic aorta and its major branches (e.g. contrast CT, MRI or PET-CT). We explored the patterns of thoracic vessel involvement and compared the clinical characteristics of patients with and without thoracic disease. Where available, we also reviewed the thoracic vascular/perivascular tissue biopsies.RESULTS:Of 153 CP patients seen between 1999 and 2012, 77 were eligible. Of these, 28 (36%) had thoracic involvement: 15 (54%) had thoracic periaortitis, with 7 also showing epiaortic artery involvement; 6 (21%) had periaortitis surrounding a thoracic aortic aneurysm, 2 of them with epiaortic artery involvement; 7 (25%) had a thoracic aortic aneurysm without periaortitis. Patients with thoracic disease were more frequently female (P = 0.01), were older (P = 0.001) and had a higher frequency of pain and constitutional symptoms (P = 0.02). Thoracic (peri)vascular biopsies revealed adventitial and peri-adventitial fibro-inflammatory patterns similar to those observed in abdominal CP.CONCLUSION:In about one-third of patients, CP also involves the thoracic aorta and the epiaortic arteries, which supports the hypothesis of a systemic inflammatory disease of the large arteries.

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.

In recent years, black fungi have been increasingly reported as causing opportunistic infections after solid organ transplantation. Here, we report a case of insidious, relentless, and multifocal Exophiala xenobiotica infection in a kidney transplant recipient that eventually required multiple surgical excisions along with oral and intravenous antifungal combination therapy using liposomal amphotericin B and posaconazole. We compare the present case with all previously reported cases of Exophiala infection after kidney transplantation.

Retroperitoneal fibrosis (RPF) is an uncommon disease characterized by a fibrous reaction that takes place in the peri-aortic retroperitoneum and often entraps the ureters causing obstructive uropathy. RPF is idiopathic in the majority of cases, but can also be secondary to malignancies, infections, drugs, radiotherapy, and rare histiocytic disorders such as Erdheim-Chester disease. Idiopathic RPF is an immune-mediated disease, which can either be isolated, associated with other autoimmune diseases, or arise in the context of a multifocal fibro-inflammatory disorder recently renamed as IgG4-related disease. The differential diagnosis between idiopathic, IgG4-related and secondary RPF is crucial, essentially because the therapeutic approaches - especially of idiopathic vs. secondary RPF - can be dramatically different. This review focuses on the clinical, laboratory and imaging features of the different RPF forms, and also provides an overview of the available treatment options. (C) 2014 Published by Elsevier Masson SAS on behalf of the Societe nationale francaise de medecine interne (SNFMI).

BACKGROUND:Idiopathic retroperitoneal fibrosis (IRF) is a rare disease often associated with autoimmune disorders. Whether IRF is associated with Hashimoto's thyroiditis (HT) is poorly understood and only addressed by case-reports. We evaluated the prevalence of HT in a large IRF cohort and in matched controls. METHODS:We studied 73 consecutive patients with new-onset IRF and 71 controls. The association between HT and IRF was cross-sectionally evaluated in a referral center. Longitudinally, thyroid function tests were also performed. Serum concentrations of FT4, TSH, and anti-thyroperoxidase antibodies (AbTPO) were evaluated together with thyroid ultrasound (US). Lymphocytic infiltrates were characterized in thyroid nodule fine needle aspirates (FNAB). In patients undergoing thyroidectomy, thyroid histology was also reviewed. RESULTS:A higher prevalence of AbTPO positivity (P<0.03) and US findings suggestive of autoimmune thyroiditis (US-AIT) (P<0.0001) were found in IRF patients compared to controls. In the logistic regression analysis, the risk of AbTPO-diagnosed HT and that of US-AIT was significantly higher in IRF patients than in controls (ORs, 3.56, 95% CI 1.48-8.59, P=0.004 and 4.74, 95% C.I., 2.34-9.61, P<0.0001 in AbTPO-diagnosed HT and US-AIT, respectively). Thyroid histology in IRF patients showed either classical or the fibrous variant of HT. At the end of the follow-up (median, 45 and 36 months in patients and controls, respectively), 25% of IRF patients and 3% of controls were receiving l-thyroxine. CONCLUSIONS:IRF patients have a higher risk of HT compared to controls. Thyroid function should be monitored in patients with IRF.

Introduction: Idiopathic retroperitoneal fibrosis (RPF) is a rare condition hallmarked by a periaortic fibro-inflammatory tissue that often causes ureteral obstruction. Its clinical manifestations include abdominal or back pain, systemic symptoms such as fatigue, weight loss and fever and, less frequently, constipation, testicular pain, claudicatio and edema of the lower limbs. The primary goal of treatment is the relief of ureteral obstruction and the regression of the fibro-inflammatory process. The treatment is still empiric because, to date, there is only one randomized controlled trial. Patients often need long-term therapy because this disease may have a chronic-relapsing course. Areas covered: This review summarized current strategies for the treatment of idiopathic RPF. An overview of the different therapeutic protocols is provided and the most relevant published references have been considered. Expert opinion: Idiopathic RPF is potentially curable with the available treatments. It usually responds to glucocorticoids but patients with suboptimal responses to these drugs or multiple relapses should be treated with alternative approaches, including tamoxifen or immunosuppressive drugs.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disorder, belonging to the small vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, defined as an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium-sized vessels, associated with asthma and eosinophilia. EGPA pathogenesis is not well known: HLA-DRB1*04 and *07, HLA-DRB4 and IL10.2 haplotype of the IL-10 promoter gene are the most studied genetic determinants. Among the acquired pathogenetic factors, the exposure to different allergens, infections, vaccinations, drugs, and silica exposure have been involved. Eosinophils are the most characteristic cells in EGPA and different studies have demonstrated their role as effector and immunoregulatory cells. EGPA is considered as a disease with a prevalent activation of the Th-2 cellular-mediated inflammatory response and also humoral immunity plays an important role. A link between B and T inflammatory responses may explain different disease features. EGPA typically develops into three sequential phases: the allergic phase, distinguished by the occurrence of asthma, allergic rhinitis, and sinusitis, the eosinophilic phase, in which the main pathological finding is the eosinophilic organ infiltrations (e.g., lungs, heart, and gastrointestinal system), and the vasculitic phase, characterized by purpura, peripheral neuropathy, and constitutional symptoms. ANCA (especially pANCA anti-myeloperoxidase) are present in 40-60% of the patients. An elevation of IgG4 is frequently found. Corticosteroids and cyclophosphamide are classically used for remission induction, while azathioprine and methotrexate are the therapeutic options for remission maintenance. B-cell depletion with rituximab has shown promising results for remission induction.

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2) + interferon-alpha (IFN-alpha) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2 + IFN-alpha or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12-151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54-1.31; P = 0.44] and of 1.07(95% CI, 0.64-1.79; P = 0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of >= 2 of these factors, immunotherapy had a positive effect on RFS (HR = 0.44; 95% CI, 0.24-0.82; P <= 0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR = 2.27; 95% CI, 1.03-5.03 P = 0.037). Toxicity of, immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2 + IFN-alpha showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-α (IFN-α) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-α or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12-151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54-1.31; P=0.44] and of 1.07 (95% CI, 0.64-1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥ 2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24-0.82; P ≤ 0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03-5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-α showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

This review of clinical and experimental studies aims at analyzing the interplay between graft endothelium and host immune system in renal transplantation, and how it affects the survival of the graft. Graft endothelium is indeed the first barrier between self and non-self that is encountered by host lymphocytes upon reperfusion of vascularized solid transplants. Endothelial cells (EC) express all the major sets of antigens (Ag) that elicit host immune response, and therefore represent a preferential target in organ rejection. Some of the Ag expressed by EC are target of the antibody-mediated response, such as the AB0 blood group system, the human leukocyte antigens (HLA), and MHC class I related chain A antigens (MICA) systems, and the endothelial cell-restricted Ag; for each of these systems, the mechanisms of interaction and damage of both preformed and de novo donor-specific antibodies are reviewed along with their impact on renal graft survival. Moreover, the rejection process can force injured EC to expose cryptic self-Ag, toward which an autoimmune response mounts, overlapping to the allo-immune response in the damaging of the graft. Not only are EC a passive target of the host immune response but also an active player in lymphocyte activation; therefore, their interaction with allogenic T-cells is analyzed on the basis of experimental in vitro and in vivo studies, according to the patterns of expression of the HLA class I and II and the co-stimulatory molecules specific for cytotoxic and helper T-cells. Finally, as the response that follows transplantation has proven to be not necessarily destructive, the factors that foster graft endothelium functioning in spite of rejection, and how they could be therapeutically harnessed to promote long-term graft acceptance, are described: accommodation that is resistance of EC to donor-specific antibodies, and endothelial cell ability to induce Foxp3+ regulatory T-cells, that are crucial mediators of tolerance.

Background Chronic Periaortitis (CP) is a rare fibro-inflammatory disorder of unknown etiology, lying at the crossroads between large vessel vasculitides (LVV) and fibrosing diseases [1]. LVV-like pathogenic features are probably responsible for medial and adventitial inflammation of the aortic wall [2], whereas Th2-driven eosinophilic and B-cell responses are thought to account for the development of fibrosis of the adjacent peritoneum [1]. PTX3 is a soluble innate pattern recognition receptor of the pentraxin family, generated and released on demand at sites of inflammation. PTX3 is involved in ancestral defensive responses, processing of cell debris and autoantigens and regulation of tissue remodeling and cell recruitment [3]. Objectives The identification of a potential role of PTX3 in regulating the outcome of vessel inflammation and of its selective expression at sites of vessel injury in small and large vessel vasculitides prompted us to investigate its involvement in patients with CP. Methods PTX3 expression was assessed by immunohistochemistry on tissue samples of periaortic tissue from five patients with CP. PTX3 systemic concentration was assessed in plasma samples of 14 CP patients and 20 healthy controls. Results PTX3 was consistently expressed at high levels by leukocytes infiltrating the periaortic tissue of patients with CP. In contrast, a relatively restricted association with the extracellular matrix has been observed, which is an hallmark of several inflammatory conditions associated with vessel and tissue remodeling. Moreover, systemic levels of the protein do not apparently reflect the substantial expression of the protein in the retroperitoneal tissue. Conclusions PTX3 is expressed at sites of inflammation and tissue remodeling in patients with CP. Larger studies are required to confirm histological data and assess possible pathogenic roles of PTX3 in modulating cell recruitment and tissue remodeling. Serological data should also be replicated in larger cohorts of patients and appropriate controls. References Pipitone N, et al., Best Pract Res Clin Rheumatol, 2012 Ramshaw AL, et al., J Clin Pathol, 1994 Manfredi AA, et al., Curr Opin Immunol, 2008 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3387

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score <4 [median KDPI: 87; interquartile range (IQR): 78–94] and 62 with a score = 4 [median KDPI: 87; IQR: 76–93]; 102 dual transplants [median KDPI: 93; IQR: 86–96]) and 248 single standard transplant controls (median KDPI: 36; IQR: 18–51). PTDB-based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80–90 and of 37% for kidneys with a KDPI of 91–100. Although 1-year estimated GFRs were significantly lower in recipients of marginal kidneys (−9.3, −17.9 and −18.8 mL/min, for dual transplants, single kidneys with PTDB score <4 and =4, respectively; p < 0.001), graft survival (median follow-up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 [95% confidence interval: 0.80–1.79; p = 0.38]). In conclusion, PTDB-based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.