Evolution and outcomes of aortic dilations in giant cell arteritis.

OBJECTIVES: To identify factors associated with the progression of giant cell arteritis (GCA)-related or associated aortic dilations. METHODS: In this retrospective study, 47 GCA patients with aortic dilation were longitudinally analyzed. Each patient underwent ≥2 imaging scans of the aorta during the follow-up. Three progression statuses of aortic dilations were distinguished: fast-progressive (FP) defined by a progression of the aortic diameter ≥5 mm/year or ≥1 cm/2 years, slow progressive (SP) by a progression of the aortic diameter >1 mm during the follow-up, and not progressive (NP) when aortic diameter remained stable. RESULTS: Among the 47 patients with aortic dilation, the thoracic section was involved in 87 % of patients. Within a total follow-up of 89 [6-272] months, we identified 13 (28 %) patients with FP dilations, and 16 (34 %) and 18 (38 %) patients with SP and NP dilations, respectively. No differences regarding baseline characteristics, cardiovascular risk factors or treatments were observed among the 3 groups. However, FP patients more frequently showed atheromatous disease (p = 0.04), with a more frequent use of statins (p = 0.04) and antiplatelet agents (p = 0.02). Among the 27 (57 %) patients with aortitis, aortic dilation developed on an inflammatory segment in 23 (85 %). Among the FP patients who underwent aortic surgery with available histology (n = 3), all presented active vasculitis. CONCLUSION: This study suggests that aortic inflammation, as well as atheromatous disease, might participate in the fast progression of aortic dilation in GCA.

A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation.

A20 haploinsufficiency (HA20) is an autoinflammatory disease caused by heterozygous loss-of-function variations in TNFAIP3, the gene encoding the A20 protein. Diagnosis of HA20 is challenging due to its heterogeneous clinical presentation and the lack of pathognomonic symptoms. While the pathogenic effect of TNFAIP3 truncating variations is clearly established, that of missense variations is difficult to determine. Herein, we identified a novel TNFAIP3 variation, p.(Leu236Pro), located in the A20 ovarian tumor (OTU) domain and demonstrated its pathogenicity. In the patients' primary cells, we observed reduced A20 levels. Protein destabilization was predicted in silico for A20_Leu236Pro and enhanced proteasomal degradation was confirmed in vitro through a flow cytometry-based functional assay. By applying this approach to the study of another missense variant, A20_Leu275Pro, for which no functional characterization has been performed to date, we showed that this variant also undergoes enhanced proteasomal degradation. Moreover, we showed a disrupted ability of A20_Leu236Pro to inhibit the NF-κB pathway and to deubiquitinate its substrate TRAF6. Structural modeling revealed that two residues involved in OTU pathogenic missense variations (i.e. Glu192Lys and Cys243Tyr) establish common interactions with Leu236. Interpretation of newly identified missense variations is challenging, requiring, as illustrated here, functional demonstration of their pathogenicity. Together with functional studies, in silico structure analysis is a valuable approach that allowed us (i) to provide a mechanistic explanation for the haploinsufficiency resulting from missense variations and (ii) to unveil a region within the OTU domain critical for A20 function.

Characteristics of ANCA-associated vasculitis with aneurysms: Case series and review of the literature.

INTRODUCTION: ANCA-associated vasculitis (AAV) is an exceptional cause of small and large vascular aneurysms. Here, we present the phenotypic characteristics of patients with AAV associated with the presence of aneurysms. METHODS: We conducted a retrospective multicenter study and a systematic review of the literature. Only AAV patients with positive ANCA results and > 1 aneurysm(s) were enrolled. Patients were recruited through a call of observations among the French Vasculitis Study Group (FVSG) and the French Internal Medicine Network. Patients with aneurysm rupture were compared to those without. RESULTS: We enrolled 51 patients in the cohort, including 31 (67%) with granulomatosis with polyangiitis. The median Birmingham Vasculitis Activity Score was 18 [6-41]. A total of 92 aneurysms were noted, 74% of which involved medium-sized arteries, particularly the renal artery. During a follow-up of 24 [6-56] months, 22 (43%) patients experienced aneurysmal rupture, 91% of which involved medium-sized vessels. Patients with aneurysmal rupture showed significantly more pulmonary infiltrates and higher creatinine levels at baseline than patients without rupture. Initial treatments did not differ between the two groups. Ten (20%) patients died during the follow-up, including three from an aneurysmal rupture. CONCLUSION: Aneurysms were more frequently observed in GPA patients and predominantly affected medium-sized vessels, especially the renal arteries. The risk of rupture was high and occurred in >40% of patients. Because of their increased mortality, further studies are required to better manage this subset of patients.

French practical guidelines for the diagnosis and management of AA amyloidosis.

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.

Disease patterns and specific trajectories of anti-MDA5-related disease: a multicentre retrospective study of 70 adult patients.

Introduction: This study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. Methods: Among a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up. Results: Among the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21-22], p<0.0001), the occurrence of thromboembolic events (HR: 5.22 [1.61-14.77], p=0.008) and the presence of any malignancy (HR: 19.73 [6.67-60], p<0.0001) were the three factors independently associated with poor outcomes. Discussion: This new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors.

Role of non-invasive methods in detecting liver impairment in familial Mediterranean fever adult patients with persistent hepatic cytolysis.

Familial Mediterranean fever (FMF) patients may have hepatic cytolysis, although its origin is not formally elucidated. We aimed to evaluate liver involvement in familial Mediterranean fever (FMF) using non-invasive methods. All adult FMF patients harboring two non-ambiguous mutations of the MEFV gene with hepatic cytolysis were identified in a French tertiary adult center for FMF. Liver impairment was explored with FibroMax (a non-invasive method to estimate hepatic steatosis, necrosis, inflammation and fibrosis) and liver ultrasound. Among 520 FMF adult patients, 43 had persistent hepatic cytolysis and 20 patients were included (11 women, median age at inclusion: 49.5 years). According to the FibroMax results, patients were classified as having steatosis, fibrosis, and possible or definite nonalcoholic steato-hepatitis in 10 (50%), 9 (45%) and 7 (35%) of cases, respectively. The score of steatosis did not seem associated with the usual metabolic risk factors. No significant association was found between the cumulated dose of colchicine and any of the scores included in FibroMax. In adult FMF patients with persistent hepatic cytolysis, steatosis is the first cause to consider even in the absence of usual metabolic risk factors, suggesting other mechanisms. Colchicine did not seem to be involved in this toxicity.

Drugs associated with systemic sclerosis: An updated list of suspected drugs using the WHO pharmacovigilance database.

OBJECTIVE: The pathophysiological mechanisms involved in systemic sclerosis (SSc), especially the triggering factor, are poorly understood. The literature supporting the role of drugs in the onset of SSc primarily relies on case reports, short series or previous studies of old drugs. We aimed to update the list of suspected drugs associated with SSc (DASSc). METHODS: Analyzing the World Health Organization (WHO) pharmacovigilance database (Vigibase®), we collected all individual case safety reports (ICSRs) of drugs putatively associated with SSc reported since 1967 using the Medical Dictionary for Regulatory Activities preferred terms "systemic sclerosis" and "scleroderma". For each drug, a disproportionality analysis was performed by calculating the information component (IC). An identified drug was considered significant if the IC025 was >0. RESULTS: A total of 2800 deduplicated ICSRs of DASSc were identified, accounting for 509 ICSRs and 38 suspected DASSc after exclusion of protopathic and indication biases. Anticancer drugs were the most represented drug class, accounting for 16/38 (42%) of DASSc and 317/509 (62.3%) of ICSRs, which occurred mostly in the first years after the introduction of the drugs. Among these, taxane-based agents, bleomycin, vinblastine, imatinib, dacarbazine, pembrolizumab and pemetrexed were associated with the highest disproportionate reporting. Hormone replacement therapy, romiplostim and eculizumab were associated with a significant signal. DASSc was considered a serious adverse drug reaction in 404 (92%, n = 441) cases with 41 (9%) cases resulting in death. CONCLUSION: Several new drugs with significant disproportionality signals were identified as potential drugs implicated the development of SSc, particularly anticancer drugs.

Low total gamma globulin level discovery at diffuse large B-cell lymphoma diagnosis predicts high risk of infection-related death: data from a monocentric retrospective study.

OBJECTIVE: Diffuse large B-cell lymphoma can complicate the course of B-cell primary immunodeficiencies or induce lowering of total gamma globulin levels, whose clinical status as an effective secondary immunodeficiency remains unspecified. This study aimed to assess the frequency, and clinical and prognostic relevance of the low total gamma-globulin levels discovered at diagnosis of diffuse large B-cell lymphoma. RESULTS: In a 2-year monocentric retrospective study, 96 patients diagnosed with diffuse large B-cell lymphoma who had a serum electrophoresis were included. Patients were divided into those with lower (L-TGL and higher (H-TGL) total gamma-globulin levels (total gamma-globulin levels ≤5.5 g/l and >5.5 g/l) and compared for outcomes, including fatal infectious events. Twelve (12.5%; 8 males; age median 68 years, range 55-82 years) exhibited L-TGL. There was no difference between the both groups regarding demographics, Ann Arbor lymphoma stage, inflammatory parameters or chemotherapy regimen. However, overall death rates (10/12, 83.3% versus 22/96, 26.2%; p = 0.03) and infection-related death rates (10/12, 83% versus 6/96, 6.2%; p <0.001) were significantly higher in the L-TGL group. CONCLUSION: We demonstrate for the first time the strong negative impact of L-TGL on overall and infection-related mortality in diffuse large B-cell lymphoma. Prospective studies should distinguish immunodeficiencies secondary to the lymphoma from pre-existing humoral primary immunodeficiencies, using biomolecular testing and post-treatment total gamma-globulin level monitoring, to determine the best management strategy for infectious risk during diffuse large B-cell lymphoma treatment in the context of L-TGL.

AA Amyloidosis in the Course of HIV Infection: A Report of 19 Cases Including 4 New French Cases and a Comprehensive Review of Literature.

INTRODUCTION: HIV infection has been recently retained as an unclear cause of AA amyloidosis. Our aim was to investigate cases of AA amyloidosis associated with HIV infection to understand if it could be considered as a cause of AA amyloidosis. METHODS: A comprehensive literature review was conducted as well as retrospective study from French cases collected from our national reference center for AA amyloidosis. RESULTS: Altogether, 19 patients with AA amyloidosis and HIV infection were found with 68% of men and median age at amyloidosis diagnosis of 38 years (range 28-75 years). Clinical presentation was nephrotic syndrome in 94% (n = 17/18). Among patients with renal involvement and assessable outcome (n = 17), 11 (64.7%) progressed to chronic kidney disease, with 6 (35%) end-stage renal disease. Seventy-five percent of patients had uncontrolled HIV infection and 71.4% CD4 counts <400/mm3 at amyloidosis diagnosis. Repeated or chronic bacterial or fungal infection was found in 47% of cases and a history of parenteral drug use in 55% of patients. Three patients had no classical or at least no suspected AA amyloidosis cause found or reported. CONCLUSIONS: AA Amyloidosis is a rare condition in HIV patients with common renal involvement and significant risk of progression to chronic renal insufficiency. Because of the frequency related to other inflammatory conditions in this population, HIV is probably not an independent risk factor for AA amyloidosis.

ANCA and anti-glomerular basement membrane double-positive patients: A systematic review of the literature.

INTRODUCTION: Double-positive patients (DPP) exhibiting anti-glomerular basement membrane (GBM) and anti-neutrophil cytoplasmic antibodies (ANCAs) belong to an entity that is newly and poorly described, mainly in short series. We aimed to better characterize the epidemiological features, clinical presentation and therapeutic outcomes of these patients through a systematic review. METHODS: We performed a systematic review of English-, German-, Spanish- and French-written publications from February 1987 to March 2020 reporting cases of DPP using the following databases: PubMed, Scielo, ScienceDirect, Google Scholar, The Cochrane Library, Open Grey, The Grey Literature Report, Clinicaltrials.gov and International Clinical Trial Registry Platform of the World Health Organization. RESULTS: In total, 538 DPP were identified from 90 articles. Their clinical presentations were often severe, and the majority exhibited acute kidney failure (91.8%) with a median initial serum creatinine level of 873 µmol/L; 50.7% had alveolar haemorrhage. Other manifestations were present in 30.3% of DPP, mainly ear, nose, throat and articular manifestations. ANCAs were predominantly directed against MPO (n = 377/523; 72.1%) compared to PR3 (n = 107/523; 20.5%), with rare cases of triple positivity (n = 15/538; 2.9%). Although most patients received initial immunosuppressive therapy (n = 285/317; 89.9%), the one-year overall, renal and relapse-free survival rates were 64.8%, 38.7% and 71.1%, respectively. CONCLUSION: DPP are associated with the characteristics of two eponymous vasculitis types, responsible for a poor overall and renal prognosis. Thus, simultaneous testing of both antibodies and systematic renal biopsy should be recommended in every patient with rapidly progressive glomerulonephritis to recognize this difficult-to-treat and rare disease.

Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency.

BACKGROUND & AIMS: Secondary to tumour necrosis factor-alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family. METHODS: We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*). RESULTS: The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4+ /CD8+ T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF-κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies. CONCLUSIONS: This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement.

Real-life analysis of the causes of death in patients consecutively followed for giant cell arteritis in a French centre of expertise.

OBJECTIVES: To describe, in a real-life setting, the direct causes of death in a cohort of consecutive patients with GCA. METHODS: We retrospectively analysed the deaths that occurred in a cohort of 470 consecutive GCA patients from a centre of expertise between January 2000 and December 2019. Among the 120 patients who died, we retrieved data from the medical files of 101 patients. RESULTS: Cardiovascular events were the dominant cause of death (n = 41, 41%) followed by infections (n = 22, 22%), geriatric situations (i.e. falls or senile deterioration; n = 17, 17%) and cancers (n = 15, 15%). Patients in each of these four groups were compared with the other deceased patients pooled together. Patients who died from cardiovascular events were more frequently male (46 vs 27%; P = 0.04) with a past history of coronary artery disease (29 vs 8%; P = 0.006). Patients who died from infections mostly had ongoing glucocorticoid treatment (82 vs 53%; P = 0.02) with higher cumulative doses (13 994 vs 9150 mg; P = 0.03). Patients who died from geriatric causes more frequently had osteoporosis (56 vs 17%; P = 0.0009) and had mostly discontinued glucocorticoid treatment (76 vs 33%; P = 0.001). The predictive factors of death in multivariate analysis were a history of coronary disease [hazard ratio (HR) 2.39; 95% CI 1.27, 4.21; P = 0.008], strokes at GCA diagnosis (HR 2.54; 95% CI 1.05, 5.24; P = 0.04), any infection during follow-up (HR 1.93; 95% CI 1.24, 2.98; P = 0.004) and fever at GCA diagnosis (HR 1.99; 95% CI 1.16, 3.28; P = 0.01). CONCLUSION: Our study provides real-life insight on the cause-specific mortality in GCA patients.

Giant cell arteritis-related aortic dissection: A multicenter retrospective study.

PURPOSE: To describe characteristics and outcomes of patients with giant cell arteritis (GCA)-related aortic dissection. PATIENTS AND METHODS: We retrospectively included, through a nationwide GCA network, all patients who had an aortic dissection either revealing GCA or occurring during follow-up. RESULTS: A total of 46 patients were included in this study. Aortic dissection was inaugural and led to GCA diagnosis in 21 patients, whereas it occurred during follow-up in the 25 others, at a median of 53 [1-265] months after GCA diagnosis. Large-vessel vasculitis (LVV) was diagnosed through imaging before or at the time of aortic dissection in 31 (67%) patients. In patients who developed an aortic dissection during follow-up, the aortic event occurred 22 [1-143] months post GCA diagnosis in the patients with previous aortitis, whereas it occurred after 72 [19-265] months in patients without previously diagnosed aortitis (p = 0.005). Aortic surgery was performed in 27 (59%) patients and 23 of them survived. A total of 15 (32%) patients died following the aortic dissection, including 11 who were not operated on. In a multivariate analysis, aortic surgery was the single predictor of survival (HR: 4.3; 95% CI: 1.47- 15.7; p = 0.007). CONCLUSION: Patients with prior LVV are more prone to develop early aortic dissection and require close monitoring of aortic morphology. One third of patients died from the aortic dissection. Surgery remains the best predictive factor for survival.

Tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS)-related AA amyloidosis: a national case series and systematic review.

OBJECTIVES: TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review. METHODS: This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, familial hibernian fever and hibernian familial fever. RESULTS: A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept). CONCLUSION: TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.

Infections and AA amyloidosis: An overview.

BACKGROUND: Amyloidoses are a heterogeneous group of systemic diseases characterised by extracellular accumulation of insoluble amyloid fibrils derived from unfolded proteins. Inflammatory (AA) amyloidosis can complicate various inflammatory disorders that are associated with a sustained acute phase response and serum amyloid A (SAA) protein overproduction. Chronic infections were the first recognised cause of amyloidoses. However, with the better management of underlying diseases, the frequency of AA amyloidosis is decreasing. PURPOSE: The aim of this overview was to discuss the several infections associated with AA amyloidosis and the relative frequency of infections as aetiological factors. METHODS: A search of the literature was performed using the PubMed database using the MeSH terms "Amyloidosis" and "Infections," from inception to December 31st, 2019. Articles written in other languages than English or French were excluded. RESULTS: The frequency of AA amyloidosis secondary to infections decreased from more than 50% to less than 20% after the 2000s, with a parallel increase in the frequency of AA amyloidosis secondary to inflammatory diseases and to an unknown cause. CONCLUSION: Whereas new antibiotics have been developed and sanitary conditions are better, infections still represent 5%-30% of the causes of AA amyloidosis, including in developed countries. These data argue for better screening of chronic infections to prevent AA amyloidosis and the development of new strategies to manage recurrent infections.

AA amyloidosis associated with Fabry disease.

BACKGROUND: Fabry disease (FD) is the second most common lysosomal storage disorder, carrying a large morbidity and mortality. It has been recently reported that lysosomal storage disorders could cause inflammation and, subsequently, AA amyloidosis (AAA). Our aim was to describe AAA cases occurring in the course of FD. PATIENTS AND METHODS: We described two patients displaying both AAA and FD and an additional case from the literature. RESULTS: Three female patients originating from Europe (n = 2) and Algeria (n = 1) harboured heterozygous GLA mutations. The median age at AAA diagnosis was 61 years old. The diagnosis of Fabry was made before the diagnosis of AAA (n = 1) or concomitantly (n = 2). At AAA diagnosis, two patients displayed a nephrotic syndrome; all had inflammation. CONCLUSION: Fabry disease can be associated with AAA, suggesting that an inflammatory component could exist in this genetic disease.

Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: Results at 5 years from the French prospective registry ITP-ritux.

Rituximab is a second-line option in adults with immune thrombocytopenia (ITP), but the estimated 5-year response rate, only based on pooled retrospective data, is about 20%, and no studies have focused on long-term safety. We conducted a prospective multicenter registry of 248 adults with ITP treated with rituximab with 5 years of follow-up to assess its long-term safety and efficacy. The median follow-up was 68.4 [53.7-78.5] months. The incidence of severe infections was only 2/100 patient-years. Profound hypogammaglobulinemia (<5 g/L) developed in five patients at 15 to 31 months after the last rituximab infusion. In total, 25 patients died at a median age of 80 [69.5-83.9] years, corresponding to a mortality rate of 2.3/100 patient-years. Only three deaths related to infection that occurred 12 to 14 months after rituximab infusions could be due in part to rituximab. At 60 months of follow-up, 73 (29.4%) patients had a sustained response. On univariate and multivariate analysis, the only factor significantly associated with sustained response was a previous transient response to corticosteroids (P = .022). Overall, 24 patients with an initial response and then relapse received retreatment with rituximab, which gave a response in 92%, with a higher duration of response in 54%. As a result of its safety profile and its sustained response rate, rituximab remains an important option in the current therapeutic armamentarium for adult ITP. Retreatment could be an effective and safe option.