Davide Gianfreda

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.

Does pregnancy have any impact on long term damage accrual and on the outcome of lupus nephritis

No data are available about the impact of pregnancy on the long-term outcome of lupus nephritis. Thirty-two women with lupus nephritis with a 10-year follow-up after their first pregnancy (women who gave birth) and 64 matched controls with the same follow-up and who never had pregnancies (controls) were compared for the occurrence of SLE flares, chronic kidney disease (CKD), and SLICC/ACR Damage Index (SDI) in the post pregnancy period. The same evaluations were done before and after pregnancy in women who gave birth. The predictors of CKD and damage accrual in the whole population were studied. All patients were Caucasians and had biopsy proven LN. At conception and after 10 years, in both groups, less than 10% of patients had active renal disease (pxa0=xa0ns). Controls had more frequent arterial hypertension (pxa0=xa00.025). Between the two groups there was no difference in SLE flares and in CKD free survival curves (pxa0=xa00.6 and pxa0=xa00.37) during the 10-year follow-up. In both groups, the temporal trend, based on annual evaluation, of glomerular filtration rate and serum creatinine shows a significant decrease and increase respectively. However, the women who gave birth persistently maintained better values of renal function than controls during the whole follow-up (Pxa0=xa00.00001). There was no difference in the CKD-free survival curves. SDI did not increase significantly in women who gave birth in comparison to controls. All the above mentioned clinical parameters were comparable before and after pregnancy in the women who gave birth. Among the basal clinical characteristics, high serum creatinine and occurrence of SLE flares predicted CKD, whereas low levels of C3, pre-existing damage score, and occurrence of SLE flares predicted SDI increase. Pregnancy was not a predictor of CKD or SDI increase. Carrying a pregnancy during inactive lupus nephritis does not seem to increase the rate of SLE flares, worsen renal prognosis or increase SDI significantly in the very long-term.

ANCA-associated vasculitis in childhood: recent advances

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.

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.

Changing patterns in clinical–histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis

Objectives To evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time. Patients and methods We studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970–1985, P2 1986–2001 and P3 2002–2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test. Results A progressive increase in patient age at the time of LN diagnosis (p<0.0001) and a longer time between systemic lupus erythematosus onset and LN occurrence (p<0.0001) was observed from 1970 to 2016. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased (p<0.0001) and that of isolated urinary abnormalities increased (p<0.0001). No changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016 (p=0.023). Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). At multivariate analysis, male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD. Conclusions Clinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival.

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.

Drug-induced lupus: Traditional and new concepts

Drug-induced lupus (DIL) includes a spectrum of drug-induced reactions often characterised by a clinical phenotype similar to that of idiopathic systemic lupus eruthematosus (SLE) but usually lacking major SLE complications. Different drugs may be associated with distinct clinical and serological profiles, and early recognition is crucial. Drugs traditionally associated with DIL include procainamide, hydralazine, quinidine and others, but strong associations with newer agents, such as TNF α (TNFα) inhibitors, are increasingly recognised. The pathogenic mechanisms explaining how drugs that have heterogeneous chemical structure and function lead to autoimmunity are only partially understood. However, it is likely that traditional DIL-associated agents can boost innate immune responses, particularly neutrophil responses, with neutrophil extracellular trap (NET) formation and exposure of autoantigens. Research in the field of DIL is evolving and may provide interesting models for the study of autoimmunity.

Alport syndrome and pregnancy: a case series and literature review

PurposeTo assess pregnancy outcome in women with Alport syndrome and the impact of pregnancy on the disease progression.MethodsWe describe one of the largest series of pregnancies in Alport syndrome. Seven pregnancies of six women were monitored by a multidisciplinary team of nephrologists and gynecologists. After delivery, patients were followed for at least 3xa0years. We compare our results with those in the literature.ResultsPregnancy course was uneventful in the patient with isolated microscopic hematuria. In the other cases, all presenting mild proteinuria at conception, some complications occurred. Proteinuria worsened during the last trimester, reaching nephrotic ranges in five out of six pregnancies and was associated with fluid overload leading to hospitalizations and early delivery. The majority of the newborns had a low birth weight. The two patients with arterial hypertension at conception and twin pregnancy developed pre-eclampsia and renal function deterioration persisted after delivery. The one with pre-pregnancy renal dysfunction reached end-stage renal disease. In the other patients, in which renal function and blood pressure were and remained normal, proteinuria improved after delivery and no signs of disease progression were recorded at last observation.ConclusionsOur observations suggest that Alport syndrome should be considered a potential risk factor for pregnancy in proteinuric patients due to the development of pre-eclampsia, renal function deterioration, and/or full-blown nephrotic syndrome that results in anasarca, slowing of fetal growth and pre-term delivery. Thus, all women with Alport syndrome should receive pre-conceptional counseling and be kept in close follow-up during pregnancy.