Publications by authors named "Alexandre Karras"

142 Publications

Evolution of kidney antibody secreting cells molecular signature in lupus patients with active nephritis upon immunosuppressive therapy.

Arthritis Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

Institut Necker Enfants Malades, INSERM U1151/CNRS UMS 8253, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Objectives: To characterize kidney and urine antibody secreting cells (ASC) from patients with active lupus nephritis (LN), before and after induction therapy.

Methods: We included patients with biopsy proven active LN and performed anti-CD138 staining of kidney biopsy samples to visualize ASC. We performed single-cell gene expression profiling on sorted ASC from fresh biopsy samples by multiplex RT-PCR. We used a gene set allowing the study of ASC maturation from plasmablast to long-lived plasma cells. We quantified urine ASC from untreated LN patients at diagnosis and after 6 months of prospective follow up during induction therapy.

Results: The number of kidney CD138+ ASC in 46 untreated LN patients correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASC from 3 untreated patients had a plasmablast molecular signature, contrasting with ASC from 4 patients refractory to immunosuppressant drugs that expressed long-lived plasma cells genes and clustered with long-lived bone marrow plasma cells from 2 healthy donors. Some urine ASC with plasmablast signature were detected in patients with untreated active LN. The presence of urine ASC at 6 months was associated with treatment failure.

Conclusion: These results suggest a potential interest of ASC-directed therapy in refractory LN.
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http://dx.doi.org/10.1002/art.41703DOI Listing
March 2021

Acute renal failure under encorafenib, binimetinib and cetuximab for BRAF V600E-mutated colorectal cancer.

Eur J Cancer 2021 Feb 19;147:60-62. Epub 2021 Feb 19.

Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, Université de Paris, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.01.024DOI Listing
February 2021

Granulomatosis with polyangiitis: Study of 795 patients from the French Vasculitis Study Group registry.

Semin Arthritis Rheum 2021 Feb 10;51(2):339-346. Epub 2021 Feb 10.

National Referral Center for Rare Systemic Autoimmune Diseases, Université Paris Descartes, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (APHP), 27, rue du faubourg Saint-Jacques, Paris, Cedex 14 75679, France. Electronic address:

Objective: To describe the characteristics and long-term outcomes of patients with granulomatosis with polyangiitis (GPA) from the French Vasculitis Study Group database.

Methods: Patients' clinical and laboratory characteristics, Birmingham Vasculitis Activity Score (BVAS)-assessed disease activity, malignancies, opportunistic infections, and vital status were collected at diagnosis and each visit. Estimated probabilities and predictors of overall (OS) and relapse-free survival (RFS) were analyzed by Cox regression.

Results: We enrolled 795 newly diagnosed patients, followed for a median of 3.5 years. Initial clinical manifestations involved ear, nose & throat (ENT; 80%), lungs (68%) and kidneys (56%). Among the 728 available ELISA results, 75.0% were PR3-ANCA-positive, 16.5% MPO-ANCA-positive and 62 (8.5%) ANCA-negative. Relapses occurred in 394 (50%) patients, involving ≥1 organ(s) affected at onset in 179 (46%), mainly ENT, lungs and kidneys, with mean BVAS 10.2 points below that at diagnosis (p<0.001). Five- and 10-year RFS rates were 37% and 17%, respectively. PR3-ANCA-positivity independently predicted relapse (p = 0.05) and prolonged survival (p = 0.038). OS-but not RFS-improved significantly over time (p<0.001); 10-year OS reached 88.2% (95% CI 83.9 to 92.7) for the 660 patients diagnosed after 2000. Infections were the main causes of death. Malignancy or opportunistic infection each occurred in ≤5% of the patients.

Conclusion: Survival has improved dramatically over the last decades but the high relapse rate remains a major concern for GPA patients, once again stressing the need for therapeutic strategy optimization to lower it. PR3-ANCA-positivity was associated with increased probability of relapse and survival.
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http://dx.doi.org/10.1016/j.semarthrit.2021.02.002DOI Listing
February 2021

IgA nephropathy in association with inflammatory bowel diseases: results from a national study and systematic literature review.

Nephrol Dial Transplant 2021 Jan 8. Epub 2021 Jan 8.

Département de Néphrologie et Transplantation, Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Hôpital Universitaire Henri Mondor, Assistance Publique-Hôpitaux de Paris AP-HP, Créteil, France.

Background: Little is known about clinical characteristics and kidney outcome in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD).

Methods: We conducted a retrospective multicenter study with centralized histological review, to analyze the presentation, therapeutic management and outcome of 24 patients suffering from IBD associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD.

Results: Crohn's disease and ulcerative colitis accounted for 75% and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9 years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. Urinary protein-to-creatinine ratio exceeded 100 mg/mmol in 70.8% of patients (mean: 254 mg/mmol). Estimated glomerular filtration rate (eGFR) exceeded 60 ml/min/1.73m2 in 13/24 patients and only one patient required dialysis. In the Oxford MEST-C classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1+T2 and 38% C1+C2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2 years, four patients (16.7%) had a poor kidney outcome: end-stage renal disease (n = 3) or a > 50% decrease in eGFR from initial values (n = 1). A similar evolution was observed in patients with primitive IgAN.

Conclusions: This first case series suggests that IBD-associated IgAN have frequent inflammatory lesions at onset and variable long-term outcome.
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http://dx.doi.org/10.1093/ndt/gfaa378DOI Listing
January 2021

French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and ANCA-associated vasculitides).

Orphanet J Rare Dis 2020 12 29;15(Suppl 2):351. Epub 2020 Dec 29.

Internal Medicine, CHU Cochin, AP-HP, Paris, France.

Systemic necrotizing vasculitis comprises a group of diseases resembling polyarteritis nodosa and anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA): granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis. The definitive diagnosis is made in cooperation with a reference center for autoimmune diseases and rare systemic diseases or a competency center. The management goals are: to obtain remission and, in the long term, healing; to reduce the risk of relapses; to limit and reduce the sequelae linked to the disease; to limit the side effects and the sequelae linked to the treatments; to improve or at least maintain the best possible quality of life; and to maintain socio-professional integration and/or allow a rapid return to school and/or professional activity. Information and therapeutic education of the patients and those around them are an integral part of the care. All health professionals and patients should be informed of the existence of patient associations. The treatment of vasculitis is based on variable combinations of glucocorticoids and immunosuppressants, chosen and adapted according to the disease concerned, the severity and/or extent of the disease, and the underlying factors (age, kidney function, etc.). Follow-up clinical and paraclinical examinations must be carried out regularly to clarify the progression of the disease, detect and manage treatment failures and possible relapses early on, and limit sequelae and complications (early then late) related to the disease or treatment. A distinction is made between the induction therapy, lasting approximately 3-6 months and aimed at putting the disease into remission, and the maintenance treatment, lasting 12-48 months, or even longer. The role of the increase or testing positive again for ANCA as a predictor of a relapse, which has long been controversial, now seems to have greater consensus: Anti-myeloperoxidase ANCAs are less often associated with a relapse of vasculitis than anti-PR3 ANCA.
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http://dx.doi.org/10.1186/s13023-020-01621-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771069PMC
December 2020

Nephronophthisis in Young Adults Phenocopying Thrombotic Microangiopathy and Severe Nephrosclerosis.

Clin J Am Soc Nephrol 2020 Dec 2. Epub 2020 Dec 2.

Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, 4 Rue de la Chine, Assistance Publique-Hôpitaux de Paris, Paris, France

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http://dx.doi.org/10.2215/CJN.11890720DOI Listing
December 2020

Circulating plasmablasts and high level of BAFF are hallmarks of minimal change nephrotic syndrome in adults.

Nephrol Dial Transplant 2020 Nov 26. Epub 2020 Nov 26.

Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Fédération Hospitalo-Universitaire « Innovative Therapy for Immune Disorders », Créteil, France.

Background: The recent success achieved with the use of B cell-depleting agents in some patients with minimal change nephrotic syndrome (MCNS) suggests an unexpected role for B lymphocytes in the pathogenesis of this immune-mediated glomerular disease. Nevertheless, no extensive B-cell phenotyping analysis has ever been performed in untreated adult patients soon after MCNS diagnosis.

Methods: We investigated the distribution of the different B-cell subpopulations in 22 untreated adult patients with biopsy-proven MCNS [MCNS relapse (MCNS-Rel)]. We compared these data with those for 24 healthy controls, 13 MCNS patients in remission (with no specific treatment) and 19 patients with idiopathic membranous nephropathy (IMN).

Results: Patients with MCNS-Rel or IMN had higher proteinuria and lower serum albumin and gammaglobulin levels (P < 0.0001 for all comparisons) than MCNS patients in remission. Plasmablasts were the only B-cell subsets present at significantly higher levels in MCNS-Rel patients than in the patients of the other three groups (P < 0.05 for all comparisons). The lower albumin levels and higher proteinuria levels were positively correlated with the percentage of circulating plasmablasts (Spearman test's ρ = -0.54, P = 0.01 and ρ = 0.65, P = 0.002, respectively). Similarly, the increase of immunoglobulin M (IgM) and the decrease of IgG levels were significantly associated with the percentage of plasmablasts in MCNS-Rel patients (Spearman's ρ = 0.36, P = 0.01 and Spearman's ρ = -0.60, P = 0.01, respectively). Increased production of interleukin (IL)-21, IL-6 and B-cell activating factor (BAFF) in the serum of MCNS-Rel patients was found significantly correlated with the percentage of plasmablasts (ρ = 0.72, P = 0.0002, ρ = 0.49, P = 0.04 and ρ = 0.62, P = 0.009, respectively).

Conclusions: An increase in the proportion of circulating plasmablasts seems to be a hallmark of untreated MCNS in adult patients. Further studies are required to more precisely determine the phenotype and functions of these cells.
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http://dx.doi.org/10.1093/ndt/gfaa279DOI Listing
November 2020

New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients.

Clin Rheumatol 2020 Oct 24. Epub 2020 Oct 24.

Department of Internal Medicine and Clinical Immunology, CHRU Tours, Tours, France.

Objective: IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the baseline characteristics and/or outcome of vasculitis. We aimed to describe the presentation of IgAV in patients with cancer (IgAV ca+) compared to patients without cancer.

Methods: We conducted a nationwide retrospective study of adult patients in France who presented with both IgAV and cancer. Baseline characteristics were described and compared with those of the 260 patients included in a nationwide French IgAV study.

Results: Thirty patients were included. The mean age was 69 ± 12 years; 80% were men. Compared to patients without underlying cancer, IgAV ca+ patients were older (69 ± 12 vs. 50 ± 18 years; p < 0.0001) and they presented more frequently with necrotic purpura (53 vs. 26%; p < 0.002) and intra-alveolar hemorrhage (10 vs. 0.5%; p < 0.0001). IgAV ca+ patients frequently had elevated serum IgA levels (79 vs. 53%; p < 0.034); most (n = 22, 73%) had adenocarcinoma or urothelial carcinoma involving the large intestines (n = 6), bladder (n = 5), and lung (n = 5). Most IgAV ca+ patients had progressive cancer (n = 21); a minority had metastatic disease (n = 2) at IgAV diagnosis. After a median follow-up of 3 months, 8 deaths were observed but none was related to IgAV.

Conclusion: Compared to their noncancer counterpart, patients with IgAV related to cancer were older and more frequently presented with necrotizing purpura, intra-alveolar hemorrhage, and elevated serum IgA levels. Adult patients with IgAV and these latter characteristics should be carefully screened for cancer. Key Points • Clinical and biological characteristics of patients presenting with IgAV are distinct depending on the underlying cause of vasculitis related to cancer. • Patients with IgAV related to cancer are older, and compared to their counterparts without IgAV, they present more frequently with necrotic purpura, alveolar hemorrhage, and elevated serum IgA levels. • All adult patients with IgAV should be screened for cancer, and there should be a focus on elderly male patients presenting with necrotic purpura and/or alveolar hemorrhage.
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http://dx.doi.org/10.1007/s10067-020-05455-zDOI Listing
October 2020

Sustained Remission of Granulomatosis With Polyangiitis After Discontinuation of Glucocorticoids and Immunosuppressant Therapy: Data From the French Vasculitis Study Group Registry.

Arthritis Rheumatol 2020 Oct 7. Epub 2020 Oct 7.

National Referral Center for Rare Systemic Autoimmune Diseases, Université de Paris, Hôpital Cochin, AP-HP, Paris, France.

Objective: Data on sustained remission of granulomatosis with polyangiitis (GPA) after discontinuation of therapy (referred to as GPA with sustained remission off-therapy [SROT]) are scarce. In the present study, SROT among GPA patients from the French Vasculitis Study Group Registry was evaluated to identify factors associated with its occurrence and durability.

Methods: For inclusion of patients in the study, the diagnosis of GPA had to meet the GPA classification criteria defined by the American College of Rheumatology and/or the revised Chapel Hill Consensus Conference nomenclature for vasculitis. SROT was defined as achievement of remission (a Birmingham Vasculitis Activity Score of 0) that was sustained for ≥6 consecutive months after having discontinued glucocorticoid (GC) and immunosuppressant treatments. The characteristics of the patients at baseline and treatments received were compared at 3, 5, and 10 years postdiagnosis according to whether or not SROT had been reached and maintained.

Results: Among 795 patients with GPA, 92 GPA patients with SROT at 3 years postdiagnosis were compared to 342 control subjects who had experienced disease relapse and/or were still receiving GCs or immunosuppressants. No baseline differences were found, but patients with SROT at 3 years postdiagnosis had more frequently received intravenous cyclophosphamide as induction therapy compared to control subjects (P = 0.01), with a higher median number of infusions (P = 0.05). At 5 years postdiagnosis, no baseline differences were observed between groups, but patients with SROT at 5 years postdiagnosis had received more cyclophosphamide infusions compared to control subjects (P = 0.03). More patients with SROT had received rituximab as maintenance therapy than control subjects at 3 years and 5 years postdiagnosis (P = 0.09 and P < 0.001, respectively). Of the 74 patients enrolled in the GPA Registry with 10-year follow-up data after having received conventional maintenance therapy, 15 (20%) had reached SROT at 3 years, and 5 (7%) maintained SROT at 10 years postdiagnosis.

Conclusion: After conventional therapies, 7% of GPA patients had reached SROT at 10 years postdiagnosis. No baseline vasculitis characteristics distinguished patients who achieved/maintained SROT from those who experienced disease relapse and/or those who continued to receive GCs or immunosuppressant therapy, but patients with SROT had received more intensive induction therapy and rituximab as maintenance therapy more frequently.
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http://dx.doi.org/10.1002/art.41551DOI Listing
October 2020

Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown?

Autoimmun Rev 2020 Nov 15;19(11):102671. Epub 2020 Sep 15.

Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address:

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.
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http://dx.doi.org/10.1016/j.autrev.2020.102671DOI Listing
November 2020

Ifosfamide nephrotoxicity in adult patients.

Clin Kidney J 2020 Aug 31;13(4):660-665. Epub 2019 Dec 31.

Department of Nephrology, Dialysis, Transplantation, Georges Pompidou European Hospital, Paris, France.

Background: Ifosfamide, a widely prescribed antineoplasic agent, is frequently associated with kidney dysfunction. Its nephrotoxicity is well documented in children, but data are lacking in adult patients.

Methods: The aim of this retrospective study was to describe the clinical, biological and histological characteristics of ifosfamide nephrotoxicity.

Results: We report 34 patients (median age: 41 years) admitted in six French nephrology departments for kidney failure and/or tubular dysfunction. Fifteen patients (44.1%) received cisplatin as part of their chemotherapy. In 6 patients (17.7%), ifosfamide nephrotoxicity was revealed by a proximal tubular dysfunction (PTD), in 5 patients (14.4%) by an acute kidney injury (AKI), in 6 patients (17.7%) by a chronic kidney disease (CKD) and in 17 patients (49.7%) by an association of PTD and AKI. Fourteen renal biopsies (41.2%) were performed and revealed acute tubular necrosis (85.7%), vacuolation (78.6%) and nuclear atypias (71.4%) of renal epithelial cells, interstitial inflammation (71.4%) and fibrosis (57.1%). Electron microscopy showed mitochondrial enlargement and dysmorphic changes suggestive of mitochondrial toxicity. Ten patients (29.4%) progressed to Stage 5 CKD, six (17.6%) required haemodialysis and six patients died during a median follow-up period of 31 months. Risk factors for Stage 5 CKD were age and cisplatin co-administration.
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http://dx.doi.org/10.1093/ckj/sfz183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467602PMC
August 2020

Kidney transplantation improves the clinical outcomes of Acute Intermittent Porphyria.

Mol Genet Metab 2020 Sep - Oct;131(1-2):259-266. Epub 2020 Sep 2.

Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris University, France; Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris University, Paris, France. Electronic address:

Background: Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known.

Methods: We examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry.

Results: AIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 μmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients.

Conclusion: Kidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity.
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http://dx.doi.org/10.1016/j.ymgme.2020.08.004DOI Listing
September 2020

Epstein-Barr virus-associated smooth muscle tumor in a kidney transplant recipient: A case-report and review of the literature.

Transpl Infect Dis 2021 Feb 16;23(1):e13456. Epub 2020 Sep 16.

Service de Néphrologie, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Introduction: Epstein-Barr virus (EBV) is a herpesvirus linked to pre-malignant lymphoproliferative diseases and up to nine distinct human tumors. The most frequent EBV-associated malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (SMT) which remain a very rare oncological entity. This study reports one case report of SMT and aims to offer the largest review of literature on post-transplantation-SMT (PT-SMT) in kidney transplant recipients, with a focus on therapeutic management and evolution of graft function.

Methods: Case reports and case series of PT-SMT in kidney transplant recipients were collected from 1996 to 2019.

Results: A total of 59 PT-SMT were evaluated. The median time at diagnosis was 74.6 months after kidney transplantation. The most frequent localizations were liver and lung. EBV seroconversion was notified in all six patients with previously negative status. Preferred therapeutic option was surgery (65.9%), associated with a reduction in immunosuppression (77.2%), which includes switch to mTOR inhibitors (29.5%), and discontinuation of MMF (32%). In our review, 13% of patients experienced rejection, 8.7% lost their graft and went back on hemodialysis; 8.8% of patients died of PT-SMT.

Conclusion: PT-SMT is a rare but serious condition in kidney transplant recipients. EBV seroconversion following transplantation appears as a risk factor in developing PT-SMT in solid-organ recipients. In the absence of guidelines, therapeutic management for PT-SMT is challenging and exposes the patient to high risk of graft loss.
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http://dx.doi.org/10.1111/tid.13456DOI Listing
February 2021

Renal involvement in eosinophilic granulomatosis with polyangiitis (EGPA): a multicentric retrospective study of 63 biopsy-proven cases.

Rheumatology (Oxford) 2021 Jan;60(1):359-365

Department of Nephrology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic small-vessel vasculitis characterized by asthma, hypereosinophilia and ANCA positivity in 40% of patients. Renal involvement is rare and poorly described, leading to this renal biopsy-proven based study in a large EGPA cohort.

Methods: We conducted a retrospective multicentre study including patients fulfilling the 1990 ACR criteria and/or the 2012 revised Chapel Hill Consensus Conference criteria for EGPA and/or the modified criteria of the MIRRA trial, with biopsy-proven nephropathy.

Results: Sixty-three patients [27 women, median age 60 years (18-83)] were included. Renal disease was present at vasculitis diagnosis in 54 patients (86%). ANCA were positive in 53 cases (84%) with anti-MPO specificity in 44 (83%). All patients had late-onset asthma. Peripheral neuropathy was present in 29 cases (46%), alveolar haemorrhage in 10 (16%). The most common renal presentation was acute renal failure (75%). Renal biopsy revealed pauci-immune necrotizing GN in 49 cases (78%). Membranous nephropathy (10%) and membranoproliferative GN (3%) were mostly observed in ANCA-negative patients. Pure acute interstitial nephritis was found in six cases (10%); important interstitial inflammation was observed in 28 (44%). All patients received steroids with adjunctive immunosuppression in 54 cases (86%). After a median follow-up of 51 months (1-296), 58 patients (92%) were alive, nine (14%) were on chronic dialysis and two (3%) had undergone kidney transplantation.

Conclusion: Necrotizing pauci-immune GN is the most common renal presentation in ANCA-positive EGPA. ANCA-negative patients had frequent atypical renal presentation with other glomerulopathies such as membranous nephropathy. An important eosinophilic interstitial infiltration was observed in almost 50% of cases.
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http://dx.doi.org/10.1093/rheumatology/keaa416DOI Listing
January 2021

Nephrotoxicity Associated With Niraparib.

Am J Kidney Dis 2020 12 14;76(6):898-900. Epub 2020 Jul 14.

Service de Néphrologie, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, Sorbonne Paris Cité, France; Service de Biochimie, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, Sorbonne Paris Cité, France.

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http://dx.doi.org/10.1053/j.ajkd.2020.05.021DOI Listing
December 2020

COVID-19-Related Collapsing Glomerulopathy in a Kidney Transplant Recipient.

Am J Kidney Dis 2020 10 12;76(4):590-594. Epub 2020 Jul 12.

Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Hôpital Européen Georges Pompidou, Faculté de Médecine Centre Université de Paris, Université, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.

We report a case of a kidney transplant recipient who presented with acute kidney injury and nephrotic-range proteinuria in a context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Kidney biopsy revealed collapsing glomerulopathy. Droplet-based digital polymerase chain reaction did not detect the presence of SARS-CoV-2 RNA in the biopsy fragment, and the virus was barely detectable in plasma at the time of the biopsy. SARS-CoV-2 RNAemia peaked several days later, followed by a seroconversion despite the absence of circulating CD19-positive lymphocytes at admission due to rituximab-based treatment of antibody-mediated rejection 3 months earlier. Genotyping for the 2 risk alleles of the apolipoprotein L1 (APOL1) gene revealed that the donor carried the low-risk G0/G2 genotype. This case illustrates that coronavirus disease 2019 infection may promote a collapsing glomerulopathy in kidney allografts with a low-risk APOL1 genotype in the absence of detectable SARS-CoV-2 RNA in the kidney and that podocyte injury may precede SARS-CoV-2 RNAemia.
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http://dx.doi.org/10.1053/j.ajkd.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354772PMC
October 2020

Randomized Trial Comparing Double Versus Triple Bortezomib-Based Regimen in Patients With Multiple Myeloma and Acute Kidney Injury Due to Cast Nephropathy.

J Clin Oncol 2020 08 23;38(23):2647-2657. Epub 2020 Jun 23.

Department of Hematology and Immunology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, INSERM UMR 1126, Paris, France.

Purpose: We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis.

Methods: After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group).

Results: Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died.

Conclusion: This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.
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http://dx.doi.org/10.1200/JCO.20.00298DOI Listing
August 2020

Spondyloarthritis-Associated IgA Nephropathy.

Kidney Int Rep 2020 Jun 16;5(6):813-820. Epub 2020 Mar 16.

Department of Nephrology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France.

Introduction: IgA nephropathy (IgAN) can be associated with spondyloarthritis (SpA). The course of SpA-associated IgAN remains largely unknown due to the absence of large cohorts.

Methods: This retrospective study included patients with biopsy-proven IgAN and definite SpA. Kidney biopsies were centrally examined and scored according to the IgAN Oxford Classification. Thirty-two patients fulfilled the inclusion criteria, with a male:female ratio of 9:1 and median age of 27 and 37 years at SpA and IgAN diagnosis, respectively. HLA-B27 was positive in 90% of cases, and most patients (60%) presented with ankylosing spondylitis. The mean baseline estimated glomerular filtration rate (eGFR) was 84 ± 26 ml/min per 1.73 m, and the urine protein-to-creatinine ratio was 0.19 g/mmol.

Results: Renal biopsy revealed frequent presence of crescents (33%) and interstitial inflammation (18%). Despite almost constant use of renin-angiotensin system inhibitors, combined with steroids in 13 of 32 patients, renal outcome was particularly poor. After a median follow-up of 5.9 years, 4 patients (12.5%) reached end-stage renal disease and 41% of patients experienced a >50% decrease of eGFR. The mean annual eGFR decline rate was -4.3 ± 6.7 ml/min per 1.73 m. The risk of reaching class IV or V chronic kidney disease (CKD) stage during follow-up was associated with the presence of hypertension, level of proteinuria, and baseline S- and T-scores of the Oxford.

Conclusion: SpA-associated IgAN is associated with a poor renal outcome, despite frequent use of steroids. Tumor necrosis factor (TNF)-α blockade did not appear to influence the rate of eGFR decline in this setting.
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http://dx.doi.org/10.1016/j.ekir.2020.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271945PMC
June 2020

Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial.

Ann Intern Med 2020 08 2;173(3):179-187. Epub 2020 Jun 2.

Cochin Hospital, Paris Descartes University, Paris, France (P.C., C.V., X.P., B.T., L.M., L.G.).

Background: Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).

Objective: To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen.

Design: Randomized controlled trial. (ClinicalTrials.gov: NCT02433522).

Setting: 39 clinical centers in France.

Patients: 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy.

Intervention: Rituximab or placebo infusion every 6 months for 18 months (4 infusions).

Measurements: The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0.

Results: From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) ( = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) ( = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group.

Limitation: Potential selection bias based on previous rituximab response and tolerance.

Conclusion: Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy.

Primary Funding Source: French Ministry of Health and Hoffmann-La Roche.
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http://dx.doi.org/10.7326/M19-3827DOI Listing
August 2020

Clinicopathologic features of infection-related glomerulonephritis with IgA deposits: a French Nationwide study.

Diagn Pathol 2020 May 27;15(1):62. Epub 2020 May 27.

Université de Tours, PRES Centre-Val de Loire, Tours, France.

Background: Infection-related glomerulonephritis with IgA deposits (IRGN-IgA) is a rare disease but it is increasingly reported in the literature. Data regarding epidemiology and outcome are lacking, especially in Europe. We aimed to assess the clinical, pathologic and outcome data of IRGN-IgA.

Methods: Clinical and outcome data from patients from 11 French centers over the 2007-2017 period were collected retrospectively. We reviewed pathologic patterns and immunofluorescence of renal biopsies and evaluated C4d expression in IRGN-IgA. We analyzed the correlation between histological presentation and outcome.

Results: Twenty-seven patients (23 men, mean age: 62 ± 15 years) were included. Twenty-one (78%) had Staphylococcus aureus infection and twelve (44%) were diabetic. At the time of biopsy, 95.2% had haematuria, 48.1% had a serum creatinine level of > 4 mg/dL, and 16% had hypocomplementemia. The most common pathologic presentation included mesangial (88.9%) and endocapillary proliferative glomerulonephritis (88.9%) with interstitial fibrosis and tubular atrophy (IF/TA) (85.1%). Diffuse and global glomerular C4d expression was found in 17.8%, mostly in biopsies with acute or subacute patterns, and was associated with a short delay between infection and renal biopsy compared to segmental and focal staining. After median follow-up of 13.2 months, 23.1% died, 46.2% had persistent renal dysfunction and 15.4% reached end-stage renal disease. Renal outcome was correlated to IF/TA severity.

Conclusions: Infection-related glomerulonephritis with IgA deposits is usually associated with Staphylococcus infections and mainly affects adult men. This entity has a poor prognosis which is correlated to interstitial fibrosis and tubular atrophy severity.
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http://dx.doi.org/10.1186/s13000-020-00980-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254713PMC
May 2020

Malaria, Collapsing Glomerulopathy, and Focal and Segmental Glomerulosclerosis.

Clin J Am Soc Nephrol 2020 07 22;15(7):964-972. Epub 2020 May 22.

Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare Syndrome Néphrotique Idiopathique, Créteil, France

Background And Objectives: Malaria, a potentially life-threatening disease, is the most prevalent endemic infectious disease worldwide. In the modern era, the spectrum of glomerular involvement observed in patients after malarial infections remains poorly described.

Design, Setting, Participants, & Measurements: We therefore performed a retrospective multicenter study to assess the clinical, biologic, pathologic, and therapeutic characteristics of patients with glomerular disease demonstrated by kidney biopsy in France within 3 months of an acute malaria episode.

Results: We identified 23 patients (12 men), all but 1 of African ancestry and including 10 patients with concomitant HIV infection. All of the imported cases were in French citizens living in France who had recently traveled back to France from an endemic area and developed malaria after their return to France. Eleven patients had to be admitted to an intensive care unit at presentation. was detected in 22 patients, and was detected in 1 patient. Kidney biopsy was performed after the successful treatment of malaria, a mean of 24 days after initial presentation. At this time, all patients displayed AKI, requiring KRT in 12 patients. Nephrotic syndrome was diagnosed in 17 patients. Pathologic findings included FSGS in 21 patients and minimal change nephrotic syndrome in 2 patients. Among patients with FSGS, 18 had collapsing glomerulopathy (including 9 patients with HIV-associated nephropathy). In four patients, immunohistochemistry with an antibody targeting histidine-rich protein-2 demonstrated the presence of the malaria antigen in tubular cells but not in podocytes or parietal epithelial cells. An analysis of the apoL1 risk genotype showed that high-risk variants were present in all seven patients tested. After a mean follow-up of 23 months, eight patients required KRT (kidney transplantation in two patients), and mean eGFR for the other patients was 51 ml/min per 1.73 m.

Conclusions: In patients of African ancestry, imported infection may be a new causal factor for secondary FSGS, particularly for collapsing glomerulopathy variants in an APOL1 high-risk variant background.
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http://dx.doi.org/10.2215/CJN.00590120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341769PMC
July 2020

B-cell treatment in ANCA-associated vasculitis.

Rheumatology (Oxford) 2020 05;59(Suppl 3):iii68-iii73

Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris.

The pivotal role of B-cells in ANCA-associated vasculitis has been suggested by experimental data that demonstrate the direct pathogenicity of ANCAs. Rituximab (RTX), an anti-CD20 monoclonal antibody that targets B-cells, has proven its efficacy for induction of remission in severe ANCA vasculitis. RTX is equivalent to CYC for induction of remission, and is probably superior in relapsing patients. Long-term B cell depletion by prolonged RTX treatment has been shown to significantly reduce the relapse rate, when compared with AZA maintenance therapy. Biomarkers, such as B-cell subpopulations or ANCA monitoring, may help the clinician to determine the optimal dose and duration of RTX therapy.
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http://dx.doi.org/10.1093/rheumatology/kez605DOI Listing
May 2020

Microscopic polyangiitis: Clinical characteristics and long-term outcomes of 378 patients from the French Vasculitis Study Group Registry.

J Autoimmun 2020 08 25;112:102467. Epub 2020 Apr 25.

Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, APHP, Université Paris Descartes, Paris, France. Electronic address:

Objective: To describe characteristics and long-term outcomes of patients with microscopic polyangiitis (MPA), an antineutrophil cytoplasm antibody (ANCA)-associated small-vessel necrotizing vasculitis.

Methods: MPA patients from the French Vasculitis Study Group Registry satisfying the European Medicines Agency algorithm were analyzed retrospectively. Characteristics at diagnosis, treatments, relapses and deaths were analyzed to identify factors predictive of death or relapse.

Results: Between 1966 and 2017, 378 MPA patients (median age 63.7 years) were diagnosed and followed for a mean of 5.5 years. At diagnosis, the main clinical manifestations included renal involvement (74%), arthralgias (45%), skin (41%), lung (40%) and mononeuritis multiplex (32%), with less frequent alveolar hemorrhage (16%), cardiomyopathy (5%) and severe gastrointestinal signs (4%); mean serum creatinine was 217 μmol/L. ANCA were detected in 298/347 (86%) patients by immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA). Among the 293 patients with available ELISA specificities, 272 (92.8%) recognized myeloperoxidase and 13 (4.4%) proteinase-3. During follow-up, 131 (34.7%) patients relapsed and 78 (20.6%) died, mainly from infections. Respective 5-year overall and relapse-free survival rates were 84.2% and 60.4%. Multivariable analyses retained age >65 years, creatinine >130 μmol/L, severe gastrointestinal involvement and mononeuritis multiplex as independent risk factors for death. Renal impairment was associated with a lower risk of relapse.

Conclusion: Non-renal manifestations and several risk factors for death or relapse were frequent in this nationwide cohort. While mortality was low, and mainly due to treatment-related complications, relapses remained frequent, suggesting that MPA management can be further improved.
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http://dx.doi.org/10.1016/j.jaut.2020.102467DOI Listing
August 2020

Reducing the initial number of rituximab maintenance-therapy infusions for ANCA-associated vasculitides: randomized-trial post-hoc analysis.

Rheumatology (Oxford) 2020 10;59(10):2970-2975

Centre de Référence Maladies Systémiques et Auto-Immunes Rares, Université Paris Descartes, APHP, Hôpital Cochin, Paris.

Objective: The randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter's titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12.

Methods: MAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV.

Results: At M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV.

Conclusions: We were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups.
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http://dx.doi.org/10.1093/rheumatology/kez621DOI Listing
October 2020

Lymphomas with kidney involvement: the French multicenter retrospective LyKID study.

Leuk Lymphoma 2020 04 10;61(4):887-895. Epub 2020 Feb 10.

Hémato-Oncologie, APHP, Hôpital Saint-Louis, Paris, France.

The LyKID study is a nationwide survey in France of lymphoma patients with renal involvement based on biopsy and/or imaging, to evaluate its impact on disease outcome and renal function. A total of 87 adult cases of B or T-cell lymphomas were retrospectively analyzed. Interstitial topography was observed in most of the kidney biopsies (54/66; 80%). Kidney failure (glomerular filtration rate <60 mL/min/1.73 m) was present in 47% of patients and was associated with non-significantly different outcome. After lymphoma treatment, 44% of patients had persistent chronic kidney failure (CKF); kidney failure at diagnosis was the only parameter associated with CKF in multivariate analysis. DLBCL (diffuse large B-cell lymphomas) represented half of the series, with noticeably CNS (central neurological system) relapse in 17% patients, while fewer than one of two patients had received CNS prophylaxis. To our knowledge, the LyKID study represents the largest published non-autopsy lymphoma series with renal involvement.
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http://dx.doi.org/10.1080/10428194.2019.1697811DOI Listing
April 2020

Acute interstitial nephritis: aetiology and management.

Nephrol Dial Transplant 2020 Jan 25. Epub 2020 Jan 25.

Department of Renal Transplantation, Hôpital de La Pitié Salpêtrière, AP-HP, Sorbonne Université, Paris, France.

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http://dx.doi.org/10.1093/ndt/gfz262DOI Listing
January 2020

Predictive factors of severe infections in patients with systemic necrotizing vasculitides: data from 733 patients enrolled in five randomized controlled trials of the French Vasculitis Study Group.

Rheumatology (Oxford) 2020 09;59(9):2250-2257

Department of Internal Medicine.

Objectives: Infections remain a major cause of morbidity and mortality in systemic necrotizing vasculitides (SNV). We aimed to identify factors predicting severe infections (SI) in SNV.

Methods: Data from five randomized controlled trials (RCTs) enrolling 733 patients were pooled. The primary end point was the occurrence of SI, defined by the need of a hospitalization and/or intravenous anti-infectious treatment and/or leading to death.

Results: After a median follow-up of 5.2 (interquartile range 3-9.7) years, 148 (20.2%) patients experienced 189 SI, and 98 (66.2%) presented their first SI within the first 2 years. Median interval from inclusion to SI was 14.9 (4.3-51.7) months. Age ≥65 years (hazard ratio (HR) 1.49 [1.07-2.07]; P=0.019), pulmonary involvement (HR 1.82 [1.26-2.62]; P=0.001) and Five Factor Score ≥1 (HR 1.21 [1.03-1.43]; P=0.019) were independent predictive factors of SI. Regarding induction therapy, the occurrence of SI was associated with the combination of GCs and CYC (HR 1.51 [1.03-2.22]; P = 0.036), while patients receiving only GCs were less likely to present SI (HR 0.69 [0.44-1.07]; P = 0.096). Finally, occurrence of SI had a significant negative impact on survival (P<0.001).

Conclusion: SI in SNV are frequent and impact mortality. Age, pulmonary involvement and Five Factor Score are baseline independent predictors of SI. No therapeutic regimen was significantly associated with SI but patients receiving glucocorticoids and CYC as induction tended to have more SI.
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http://dx.doi.org/10.1093/rheumatology/kez575DOI Listing
September 2020

Risk of malignancy in patients treated for systemic necrotising vasculitis.

Ann Rheum Dis 2020 03 25;79(3):431-433. Epub 2019 Nov 25.

Department of Internal Medicine, Cochin Hospital, Paris, France

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http://dx.doi.org/10.1136/annrheumdis-2019-216452DOI Listing
March 2020