Alessandra Palmisano

Prednisone versus tamoxifen in patients with idiopathic retroperitoneal fibrosis: an open-label randomised controlled trial

BACKGROUND Glucocorticoids are the mainstay of treatment of idiopathic retroperitoneal fibrosis, but they often have substantial toxic effects. Several reports have suggested tamoxifen as an alternative to glucocorticoids. We compared the efficacy of prednisone with that of tamoxifen in maintainance of remission in patients with idiopathic retroperitoneal fibrosis. METHODS In this open-label, randomised controlled trial, we enrolled patients aged 18-85 years with newly diagnosed idiopathic retroperitoneal fibrosis at the Parma Hospital, Parma, Italy, between Oct 1, 2000, and June 30, 2006. After induction therapy with 1 mg/kg daily of prednisone for 1 month, the patients who achieved remission were randomly assigned to receive tapering prednisone (initial dose 0·5 mg/kg daily) for 8 months or tamoxifen (fixed dose 0·5 mg/kg daily) for 8 months. The sequence of randomisation (1:1), blocked in groups of two and four (with block size randomly selected), was generated by the trial statistician with a computer programme. After the end of treatment, the patients were followed up for an additional 18 months. Neither patients nor those giving interventions or analysing the data were masked to group assignment. The two radiologists who assessed CT and MRI scans were masked. The primary endpoint was the relapse rate by the end of treatment (month 8), which was analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00440349. FINDINGS After induction therapy, 36 of the 40 enrolled patients achieved remission and were randomly assigned to treatment (18 per group). One patient (6%) in the prednisone group and seven patients (39%) in the tamoxifen group relapsed by the end of treatment (difference -33% [95% CI -58 to -8, p=0·0408]. The difference in relapse rate between the groups was sustained after the additional 18-month follow-up: the 26-month estimated cumulative relapse probability was 17% with prednisone and 50% with tamoxifen (difference -33% [-62 to -3, p=0·0372]). Cushingoid changes and grade 2 hypercholesterolaemia were more common in the prednisone group than in the tamoxifen group (p=0·0116 and p=0·0408, respectively). INTERPRETATION Prednisone is more effective in prevention of relapses than is tamoxifen in patients with idiopathic retroperitoneal fibrosis. Therefore, prednisone should be considered as first-line treatment for patients with newly diagnosed idiopathic retroperitoneal fibrosis. FUNDING Parma University Hospital.

Chronic periaortitis: a fibro-inflammatory disorder

Chronic periaortitis includes a spectrum of rare conditions characterized by fibro-inflammatory tissue surrounding the abdominal aorta. Although it has been considered a localized inflammatory disease secondary to atherosclerosis, several clinico-laboratory findings suggest a systemic autoimmune origin; additionally, it may involve the thoracic aorta and the origin of its major branches, with a pattern similar to that of the large-vessel vasculitides. Its pathogenesis is still unclear. Computed tomography and magnetic resonance imaging are the modalities of choice for the diagnosis, whereas fluorodeoxyglucose/positron emission tomography emerges as a sensitive imaging modality to assess the inflammatory activity of the periaortic tissue. The treatment of chronic periaortitis is largely empirical, since no randomized trials have been carried out. Corticosteroids, immunosuppressants and endoscopic or surgical procedures must be appropriately combined for the correct management of chronic periaortitis patients.

A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis

OBJECTIVE Assessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis. METHODS A total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearmans correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physicians global assessment (PGA), the physicians treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity. RESULTS WG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI [ρ = 0.82 (95% CI 0.77, 0.85)], PGA [ρ = 0.85 (95% CI 0.81, 0.88)] and the physicians treatment decision [ρ = 0.54 (95% CI 0.44, 0.62)]. There was little or no correlation between BVAS v. 3 and the CRP level [ρ = 0.18 (95% CI 0.05, 0.30)] or with the VDI [ρ = -0.10 (95% CI 0.22, 0.03)]. The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score. CONCLUSION The BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis.

Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index

Objectives To compare the Vasculitis Damage Index (VDI) with the Combined Damage Assessment Index (CDA) as measures of damage from vasculitis. Methods A total of 283 patients with vasculitis from 11 European centres were evaluated in a cross-sectional study using the VDI and CDA. Results Wegeners granulomatosis (58.4%) and microscopic polyangiitis (11.0%) were the most common diagnoses. Agreement between VDI and CDA scores (Spearmans correlation) was 0.90 (95% CI 0.87 to 0.92). There was good correlation between individual comparably evaluated organ systems (Spearmans correlation 0.70–0.94). Interobserver reliability (assessed by intraclass correlation coefficient (ICC)) was 0.94 (95% CI 0.89 to 0.98) for VDI and 0.78 (95% CI 0.63 to 0.93) for CDA. Intraobserver reliability was 0.92 (95% CI 0.83 to 1.00) for VDI and 0.87 (95% CI 0.75 to 1.00) for CDA. A total of 13 items were not used in the VDI compared to 23 in the CDA. Observers agreed that the CDA covered the full spectrum of damage attributable to vasculitis but was more time consuming and thus possibly less feasible for clinical and research purposes. Conclusions The VDI and CDA capture reliable data on damage among patients with vasculitis. The CDA captures more detail but is more complex and less practical than the VDI. Further evolution of damage assessment in vasculitis is likely to include key elements from both instruments.

Polyreactive Antibodies Developing Amidst Humoral Rejection of Human Kidney Grafts Bind Apoptotic Cells and Activate Complement

Antibody mediated rejection (AMR) is associated with a variety of graft‐reactive antibodies following kidney transplant. To characterize these antibodies, we immortalized 107 B cell clones from a patient with AMR. In a previous study, we showed that six clones were reacting to multiple self‐antigens as well as to HLA and MICA for two of them, thus displaying a pattern of polyreactivity. We show here that all six polyreactive clones also reacted to apoptotic but not viable cells. More generally we observed a nearly perfect overlap between polyreactivity and reactivity to apoptotic cells. Functionally, polyreactive antibodies can activate complement, resulting in the deposition of C3d and C4d at the surface of target cells. Testing the serum of 88 kidney transplant recipients revealed a significantly higher IgG reactivity to apoptotic cells in AMR patients than in patients with stable graft function. Moreover, total IgG purified from AMR patients had increased complement activating properties compared to IgG from non‐AMR patients. Overall, our studies show the development of polyreactive antibodies cross‐reactive to apoptotic cells during AMR. Further studies are now warranted to determine their contribution to the detection of C4d in graft biopsies as well as their role in the pathophysiology of AMR.

Methotrexate plus prednisone in patients with relapsing idiopathic retroperitoneal fibrosis

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease, characterised by a fibroinflammatory tissue surrounding the aortoiliac axis and frequently entrapping the ureters.1 ,2 Glucocorticoids effectively induce remission, but 24% to 72% of patients relapse, half of them repeatedly.3 ,4 Immunosuppressants and glucocorticoids are usually required in relapsing IRF but no studies are available. In this prospective, open-label trial we enrolled 16 relapsing patients with IRF (July 2004 to April 2011) aged 18–85 years and with an estimated glomerular filtration rate (eGFR)>50 ml/min5 after ureteral decompression (if required), and treated them with methotrexate and prednisone for 12 months. Relapse was defined in case of mass enlargement, hydronephrosis, or disease-related symptoms associated with high inflammatory markers.3 Prednisone was given at 0.5–1 mg/kg/day depending on flare severity, tapered to 12.5–10 mg/day by month 3, 7.5–5 mg/day by month 6 and maintained at 5–2.5 mg/day until month 12. Methotrexate was given at 15–20 mg/week until month 12. After month 12, the clinician was free to continue or withdraw the treatment. The primary endpoint was remission (at month 12) defined as a stable, reduced mass and absence of hydronephrosis, disease-related symptoms and normal inflammatory markers.3 Secondary endpoints were changes in erythrocyte sedimentation …

Peripheral inflammatory arthritis in patients with chronic periaortitis: report of five cases and review of the literature

OBJECTIVES Chronic periaortitis (CP) is a rare disease with a potentially immune-mediated pathogenesis. The study aims to report the frequency and the clinical characteristics of peripheral inflammatory arthritis in a cohort of CP patients, and to review the literature regarding the association between arthritis and CP. METHODS Forty-nine consecutive CP patients were seen at our department between 2000 and 2006; all of them underwent imaging (abdominal computed tomography and magnetic resonance imaging) and laboratory examinations, also including erythrocyte sedimentation rate, C-reactive protein and a panel of autoantibodies. The clinical history of the patients who developed peripheral inflammatory arthritis is reported in detail. A PubMed/Medline search without any date limits was performed for English-language articles reporting the association between CP and arthritis. RESULTS Five of the 49 enrolled patients developed an inflammatory form of peripheral arthritis: three were diagnosed as having RA, one palindromic rheumatism and one acute reactive arthritis. In all but one case, arthritis became clinically overt months to years after the onset of CP, and its outcome was good, since almost all patients were asymptomatic at the end of follow-up. No patient suffered from ankylosing spondylitis. In the literature review, 20 cases of CP-associated arthritis were found, mainly in the form of case reports: 14 of them were spondyloarthropathies, whereas the remaining ones were RA, juvenile RA or undifferentiated arthritis. CONCLUSIONS Peripheral inflammatory arthritis, particularly RA or RA-like forms, may develop in CP patients. This overlap strengthens the hypothesis of an autoimmune origin of CP.

Asbestos and Smoking as Risk Factors for Idiopathic Retroperitoneal Fibrosis: A Case–Control Study

BACKGROUND Idiopathic retroperitoneal fibrosis (RPF) is a rare disease. Asbestos exposure has been proposed as a risk factor for idiopathic RPF. OBJECTIVE To investigate the role of asbestos and other occupational agents (such as silica, metals, and organic solvents), as well as environmental agents (such as smoking), and their interactions as potential risk factors for idiopathic RPF. DESIGN Case-control study. SETTING National referral hospital for idiopathic RPF. PATIENTS 90 patients with idiopathic RPF and 270 control participants matched for age, sex, and region of residency. MEASUREMENTS Occupational history was obtained using structured questionnaires administered by blinded specialists in occupational medicine. Exposure to nonoccupational agents and presence of diseases that were potentially predisposing to idiopathic RPF were assessed through patient interviews and examination of medical records. RESULTS A history of asbestos exposure was associated with idiopathic RPF (odds ratio [OR], 4.22 [95% CI, 2.14 to 8.33]). Both current smoking (OR, 3.21 [CI, 1.46 to 7.07]) and former smoking (OR, 2.93 [CI, 1.39 to 6.14]) were more prevalent among patients than among those who never smoked. A multiplicative effect was found between tobacco smoke and both occupational asbestos exposure (OR, 12.04 [CI, 4.32 to 38.28]) and extraoccupational asbestos exposure (OR, 8.42 [CI, 2.77 to 30.58]). LIMITATION Retrospective, questionnaire-based assessment of occupational exposure. CONCLUSION Exposure to asbestos and tobacco smoke resulted in strong risk factors for idiopathic RPF. Coexposure to asbestos and smoke had a multiplicative effect on risk compared with single exposure. PRIMARY FUNDING SOURCE None.

CC chemokine receptor 5 polymorphism in chronic periaortitis

OBJECTIVE Chronic periaortitis (CP) is a rare disease characterized by a fibro-inflammatory tissue surrounding the abdominal aorta, and includes non-aneurysmal [idiopathic retroperitoneal fibrosis (IRF)] and aneurysmal forms [inflammatory abdominal aortic aneurysm (IAAA)]. We investigated whether CC chemokine receptor 5 (CCR5)Δ32 polymorphism confers susceptibility to CP. METHODS One hundred CP patients and 180 healthy controls were genotyped for CCR5Δ32 polymorphism by molecular methods. The patients were subgrouped according to the type of CP (IRF or IAAA) and the presence of established atherosclerotic disease (ischaemic heart disease, cerebrovascular disease and peripheral arterial disease). RESULTS The distribution of the CCR5Δ32 genotype differed between CP patients and controls (P = 0.01). The CCR5Δ32 allele was more frequent in CP patients than in controls [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. The distribution of the CCR5Δ32 genotype did not differ significantly between IRF patients and controls, whereas the CCR5Δ32 allele was more frequent in IAAA patients than in controls [P = 0.0001, OR 10.0 (95% CI 3.7, 27.3)]. Furthermore, the CCR5Δ32 allele occurred more frequently in IAAA than in IRF patients [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)]. The CCR5Δ32 allele frequency was higher in IAAA patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)], but not in IAAA patients with atherosclerotic disease and IRF patients with or without atherosclerotic disease. CONCLUSIONS The CCR5Δ32 polymorphism might be associated with an increased risk of developing the aneurysmal form of CP, IAAA, particularly in patients without established atherosclerotic disease. Chemokines may have a role in the pathophysiology of CP.

Vascular endothelium as a target of immune response in renal transplant rejection.

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.