Intravenous immunoglobulins for the treatment of prolonged COVID-19 in immunocompromised patients: a brief report.

Primary humoral deficiency and secondary B-cell depletion may lead to prolonged Sars-Cov-2 infection due to a decreased viral clearance. Prolonged infection is mainly driven by the lack of anti-Sars-Cov-2 immunoglobulin (IVIg) especially in patients with no vaccine response. Anti-spike immunoglobulin can be provided by infusion of convalescent patients' plasma: recent studies highlighted that commercial immunoglobulin show high titers of neutralizing IgG. We conducted a single center retrospective cohort. We included 9 patients (6 males, median age 74 years old): one patient with X-linked agammaglobulinemia and 8 patients treated with rituximab (2 granulomatosis with polyangiitis, 1 neuromyelitis optica, 4 low grade B-cell lymphoma and 1 EBV post-transplant lymphoproliferative disorder). Mean serum globulin was 4 ± 1.6 g/L. 7/8 had received at least 3 doses of mRNA anti-Sars-Cov-2 vaccine (median 4) with no response (anti-Spike IgG 0 for 6 patients). In this specific population requiring oxygen therapy but no intensive care support, the administration of IVIg was well tolerated and provided a swift improvement of clinical status, a significant decrease of inflammation associated to the an improvement of radiological patterns. Our results suggest that immunoglobulin could be used as a salvage therapy as an alternative to convalescent plasma but highly stringent patient selection is required due to the worldwide shortage of IVIg.

Eicosanoids and oxylipin signature in HH patients are similar to DIOS patients but are impacted by dietary iron absorption.

INTRODUCTION: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype the effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients. METHODS: LC-MS/MS based method to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 hours after an iron-rich meal in HH patients. RESULTS: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal. DISCUSSION: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism.

Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry.

INTRODUCTION: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors. METHODS: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models. RESULTS: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV-2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections. CONCLUSION: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency.

Treatment strategy for acquired pure red cell aplasia: a systematic review and meta-analysis.

The treatment of autoimmune acquired pure red cell aplasia (aPRCA) is challenging. Guidelines are based on expert recommendations in the absence of controlled trials. We assessed the efficacy of the main treatment strategy through a systematic review and meta-analysis using MEDLINE, EMBASE, and the Cochrane Library up to September 2022. The overall response rate (ORR) was pooled using random-effects models. In total, 24 observational studies (19 retrospective, median follow-up of 48 months) encompassing 753 patients (49% male) were included. Primary aPRCA represented 57% of the cases. The risk of bias was moderate to high using the ROBINS-I tool. Substantial heterogeneity (I2 > 50%) was retrieved. Corticosteroids as monotherapy as first-line treatment (186 patients, 13 studies) provided an ORR of 47% (95% confidence interval [CI], 34-60). Cyclosporine A was the most frequently used immunosuppressant agent (384 patients, 18 studies), providing an ORR of 74% (95% CI, 66-82) with a similar ORR in first- (73%) and second-line (76%) treatment and when cyclosporin was used as monotherapy (83%) or with corticosteroids (77%). A total of 112 patients (10 studies) received cyclophosphamide, with an ORR of 49% (95% CI, 35-64), which was higher when cyclophosphamide was combined with corticosteroids (48%) and used in second-line treatment (58%) than in monotherapy (31%), and in first-line treatment (44%). Sirolimus use was reported only after cyclosporine A failure and provided an ORR of 87% (95% CI, 68-100; 64 patients, 3 studies). Substantial uncertainty remains regarding the best treatment strategy in the absence of high-quality evidence. This study was registered on the PROPERO database as #CRD42022360452.

Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

BACKGROUND: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a newly identified autoinflammatory disorder related to somatic UBA1 mutations. Up to 72% of patients may show lung involvement. RESEARCH QUESTION: What are the pleuropulmonary manifestations in VEXAS syndrome? STUDY DESIGN AND METHODS: One hundred fourteen patients were included in the French cohort of VEXAS syndrome between November 2020 and May 2021. Each patient included in the study who had an available chest CT scan was discussed in an adjudication multidisciplinary team and classified as showing potentially pleuropulmonary-specific involvement of VEXAS syndrome or others. RESULTS: Fifty-one patients had a CT scan available for review and 45 patients (39%) showed pleuropulmonary abnormalities on chest CT scan that were considered related to VEXAS syndrome after adjudication. Most patients were men (95%) with a median age 67.0 years at the onset of symptoms. Among these 45 patients, 44% reported dyspnea and 40% reported cough. All 45 patients showed lung opacities on chest CT scan (including ground-glass opacities [87%], consolidations [49%], reticulation [38%], and septal lines [51%]) and 53% of patients showed pleural effusion. Most patients showed improvement with prednisone, but usually required > 20 mg/d. The main clinical and biological features as well the median survival did not differ between the 45 patients with pleuropulmonary involvement and the rest of the cohort, suggesting that the prevalence of pleuropulmonary involvement might have been underdiagnosed in the rest of the cohort. INTERPRETATION: Pulmonary manifestations are frequent in VEXAS syndrome, but rarely are at the forefront. The initial outcome is favorable with prednisone and does not seem to lead to pulmonary fibrosis.

[Pure red cell aplasia: Diagnosis, classification and treatment]. / L'érythroblastopénie : diagnostic, classification, traitement.

Pure red cell aplasia (PRCA) is a rare anemia characterised by profound reticulocytopenia caused by a marked reduction in bone marrow erythroblasts, without abnormalities in other blood lineages. Blackfan-Diamond anemia is an inherited ribosomopathy responsible for a hereditary form of PRCA. Acquired PRCA are separated in primary and secondary forms, including Parvovirus B19 infection, thymoma, lymphoproliferative disorders, autoimmune diseases (lupus) and drug-induced PRCA. The pathophysiology of PRCA is not fully understood and involves both humoral and T lymphocyte autoreactive cells. In Parvovirus B19-related PRCA, treatment is based on polyvalent immunoglobulins. Thymectomy for thymoma is mandatory but results in prolonged remission in a limited number of cases. The therapeutic strategy is based on expert opinion: corticosteroids in monotherapy provide few sustained responses. The choice of an additional immunosuppressant drug is guided by the presence of an underlying disease. In most cases, cyclosporine A is the first choice providing the best response rate but requires a concentration monitoring (150 to 250 ng/mL). The second choice is cyclophosphamide in large granular lymphocyte leukaemia. Sirolimus (mTOR inhibitor) seems to be a promising option especially in refractory cases. Transfusion independence is the main objective. If the patient receives numerous red blood cell transfusions (> 20 packs), iron overload assessment is crucial to initiate an iron chelation. A retrospective and prospective national cohort (EPIC-F) has been set up and is now available to include each case of PRCA to improve the knowledge of this disease and to optimize the therapeutic strategy.

Indirect Comparison of Glucocorticoid-Sparing Agents for Remission Maintenance in Giant Cell Arteritis: A Network Meta-analysis.

OBJECTIVE: To compare and rank the effect of glucocorticoid-sparing agents in giant cell arteritis (GCA), for which several drugs have been evaluated but with a benefit-risk balance that remains uncertain. METHODS: The MEDLINE and Clinical Trials databases were searched up to November 2021; all randomized controlled trials investigating glucocorticoids in GCA were included. The glucocorticoid regimen was dichotomized into short (≤6 months) or prolonged (>6 months) use. Risk of relapse and safety were estimated using network meta-analysis with frequentist random effects models. RESULTS: Of the 96 records screened, 8 trials were included (572 patients). The trials compared glucocorticoids and a sparing agent: tocilizumab (2 trials), oral methotrexate (3 trials), infliximab (1 trial), etanercept (1 trial), and adalimumab (1 trial). The pooled prevalence of GCA relapse was 52.6% (95% CI, 38.1 to 66.9). The risk of relapse was significantly lower with tocilizumab compared with methotrexate (relative risk [RR], 0.41; 95% CI, 0.17 to 0.97) and prolonged (RR, 0.41; 95% CI, 0.20 to 0.83) and short (RR, 0.32; 95% CI, 0.16 to 0.66) glucocorticoid use. The risk of relapse was not significantly different with methotrexate compared with short (RR, 0.79; 95% CI, 0.48 to 1.31) and prolonged (RR, 0.95; 95% CI, 0.31 to 2.89) glucocorticoid use. The frequency of serious adverse events and serious infection was comparable between the different drugs. The certainty of the evidence was low to very low. CONCLUSION: This meta-analysis suggests that tocilizumab may be superior to other sparing agents to prevent GCA relapse, but with a low to very low certainty of evidence, and that safety is comparable to the other drugs. REGISTRATION: The protocol of the meta-analysis is registered in the international prospective register of systematic reviews PROSPERO (https://www.crd.york.ac.uk/prospero/; registration CRD42020112387).

A New Pathogenic Missense Variant in a Consanguineous North-African Family Responsible for a Highly Variable Aceruloplasminemia Phenotype: A Case-Report.

Aceruloplasminemia is a rare autosomal recessive inherited disorder. Mutations in the ceruloplasmin gene cause depressed ferroxidase activity leading to iron accumulation. The clinical phenotype is highly variable: anemia, retinopathy, diabetes mellitus, psychiatric disorders, and neurological symptoms including parkinsonian disorders and dementia are the main features of this disease. Characterized by high serum ferritin with low transferrin saturation, aceruloplasminemia uniquely combines brain, liver and systemic iron overload. We report here four new cases of aceruloplasminemia in a consanguineous North-African family. Genetic sequencing revealed a homozygous missense variant c.656T>A in exon 4 of the ceruloplasmin gene, which had been described previously as of "unknown significance" in the dbSNP database and never associated with ACP in the HGMD database. Ferroxidase activity was strongly depressed. Clinical manifestations varied among cases. The proband exhibited mild microcytic anemia, diabetes mellitus, psychosis and parkinsonism, whereas the other cases were asymptomatic or mildly anemic, although high serum ferritin and brain iron deposition were documented in all of them. Therapeutic management was complex. The proband started deferoxamine treatment when already symptomatic and he rapidly declined. In the asymptomatic cases, the treatment was associated with poor tolerance and was discontinued due to anemia requiring red blood cell transfusion. Our series illustrates the need for new therapeutic approaches to aceruloplasminemia.

Iron Deficiency in Cystic Fibrosis: A Cross-Sectional Single-Centre Study in a Referral Adult Centre.

Iron deficiency (ID) diagnosis in cystic fibrosis (CF) is challenging because of frequent systemic inflammation. We aimed to determine the prevalence and risk factors of ID in adult patients with CF. We conducted a single-centre prospective study in a referral centre. ID was defined by transferrin saturation ≤16% or ferritin ≤20 (women) or 30 (men) µg/L, or ≤100 µg/L in the case of systemic inflammation. Apparent exacerbation was an exclusion criterion. We included 165 patients (78 women), mean age­31.1 ± 8.9 years. ID prevalence was 44.2%. ID was significantly associated with female gender (58.9% vs. 38%), lower age (29.4 ± 8.5 vs. 32.5 ± 9.1), lower body mass index (20.5 ± 2.2 vs. 21.3 ± 2.5), and Pseudomonas aeruginosa colonization (70.8% vs. 55.1%). Diabetes mellitus, antiacid drug use and low pulmonary function were more frequent in patients with ID with no statistical significance. The use of CFTR correctors was not associated with ID. In the multivariate analysis, ID was associated with female gender (OR 2.64, CI95% 1.31−5.31), age < 30 years (OR 2.30, CI95% 1.16−4.56), and P. aeruginosa (OR 2.09, CI95% 1.04−4.19).

Epidemiology of major relapse in giant cell arteritis: A study-level meta-analysis.

OBJECTIVE: The relapse rate of giant cell arteritis (GCA) is around 48%. Major relapse of GCA is defined by the European League Against Rheumatism as severe ischemic or aortic (stenosis, aneurysm, or aortic dissection) disease of GCA. The objective of the present study was to determine the prevalence and incidence, as well as the spectrum of major relapse in GCA using published data. METHODS: The MEDLINE and Cochrane databases were searched up to March 2020. Studies that included patients with newly diagnosed or relapsed GCA receiving glucocorticoids (GC) alone and/or GC-sparing therapy, detailing the number of relapsing patients and the characteristics of relapses were included. The prevalence and incidence of major relapse were pooled using a random-effects model. RESULTS: Twenty-six studies (including eight randomised controlled trials) involving 2754 patients with GCA were included. The prevalence and incidence of major relapse in this population was 3.3% (95%CI [1.7;5.6]; I2 = 86%) and 14.5/100 patient-years (95%CI [5.2;27.2]; I2 = 90%). The clinical manifestations were jaw claudication (44.3%), ophthalmological involvement (32.7%), peripheral limb ischemia (12.5%), aortic (7.7%), and neurological involvements (4.8%). In the meta-regression analysis, the duration of follow-up was negatively associated with the incidence of major relapse (Beta = -0.015, 95%CI [-0.026; -0.0042]; p = 0.0063). The incidence of major relapse was significantly higher in prospective studies (55.2/100 person-years, 95%CI [15.3;114.3] than in retrospective studies (4.1/100 patient-years, 95%CI[1.1;8.4]; pinteraction = 0.000.2). CONCLUSION: This study found that there was heterogeneity among studies, and this is partially related to study design. Jaw claudication was frequent and increases the prevalence and incidence of relapses major.

Immune thrombocytopenia with clinical significance in systemic lupus erythematosus: a retrospective cohort study of 90 patients.

OBJECTIVES: To describe the characteristics, treatment and outcome of patients with immune thrombocytopenia with clinical significance (ITPCS) associated with SLE. METHODS: This retrospective multicentre study included SLE patients who experienced ≥1 ITPCS (defined as ITP with attributable bleeding disorders and/or a platelet count <30×109/l). Other causes of secondary thrombocytopenia were excluded. Major bleeding event (MBG) was defined as Khellaf score >8 and/or WHO score >2. RESULTS: A total of 90 patients were included, the median (range) follow-up duration was 80 (6-446) months. ITP was diagnosed before SLE in 25 patients. They presented a high rate of autoimmune haemolytic anaemia (15%), antiphospholipid antibody (62%) and antiphospholipid syndrome (19%). The 25 (28%) patients who experienced MBG had significantly more bleedings at ITP diagnosis and higher bleeding scores, and serositis and thrombosis during follow-up. They required significantly more treatment lines, transfusions and hospitalizations. The 11 (12%) patients who experienced no bleeding event presented a significantly more restricted SLE phenotype (cutaneous and/or articular). Patients received a mean (range) of 4.2 (1-11) treatment lines. Corticosteroids and HCQ allowed ITPCS overall response in one-third of patients. The median relapse-free survival of rituximab (n = 34), AZA (n = 19), MMF (n = 8), thrombopoietin-receptor agonists (n = 16) and splenectomy (n = 19) were 53, 31.5, 61, 24.5 and 78 months, respectively. Four patients experienced thrombotic events after splenectomy and one occurred under thrombopoietin-receptor agonist treatment. CONCLUSION: SLE-ITCS patients displayed a high rate of haematological abnormalities and MBG patients exhibited higher morbidity. Management of thrombocytopenia was highly heterogeneous and many options seem viable.

Risk Factors for Venous Thromboembolism in Severe COVID-19: A Study-Level Meta-Analysis of 21 Studies.

Venous thromboembolism (VTE) in patients with COVID-19 in intensive care units (ICU) is frequent, but risk factors (RF) remain unidentified. In this meta-analysis (CRD42020188764) we searched for observational studies from ICUs reporting the association between VTE and RF in Medline/Embase up to 15 April 2021. Reviewers independently extracted data in duplicate and assessed the certainty of the evidence using the GRADE approach. Analyses were conducted using the random-effects model and produced a non-adjusted odds ratio (OR). We analysed 83 RF from 21 studies (5296 patients). We found moderate-certainty evidence for an association between VTE and the D-dimer peak (OR 5.83, 95%CI 3.18-10.70), and length of hospitalization (OR 7.09, 95%CI 3.41-14.73) and intubation (OR 2.61, 95%CI 1.94-3.51). We identified low-certainty evidence for an association between VTE and CRP (OR 1.83, 95% CI 1.32-2.53), D-dimer (OR 4.58, 95% CI 2.52-8.50), troponin T (OR 8.64, 95% CI 3.25-22.97), and the requirement for inotropic drugs (OR 1.67, 95% CI 1.15-2.43). Traditional VTE RF (i.e., history of cancer, previous VTE events, obesity) were not found to be associated to VTE in COVID-19. Anticoagulation was not associated with a decreased VTE risk. VTE RF in severe COVID-19 correspond to individual illness severity, and inflammatory and coagulation parameters.

Pure red cell aplasia in systemic lupus erythematosus, a nationwide retrospective cohort and review of the literature.

OBJECTIVES: To characterize the clinical and biological course, management and response to treatment in SLE-associated pure red cell aplasia (PRCA). METHODS: This was a nationwide, multicentre, retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection. RESULTS: We enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level, and reticulocyte and differential erythroblast count were 39.2 (13.2) years, 62 ( 20) g/l, 9.1 (7.6) × 109/l and 2.8 ( 2.5)%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range 2-11). CS therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, 5 (21%) partial response and 2 (8%) treatment failure. In total, 21 (87%) patients required red blood cell transfusion; 5 had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization. CONCLUSION: SLE-associated PRCA is a severe condition. Repeated red blood cell transfusions and several lines of immunosuppressant therapy are mostly required, with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined.

Arterial and venous thromboembolism in COVID-19: a study-level meta-analysis.

BACKGROUND: The prevalence of venous thromboembolic event (VTE) and arterial thromboembolic event (ATE) thromboembolic events in patients with COVID-19 remains largely unknown. METHODS: In this meta-analysis, we systematically searched for observational studies describing the prevalence of VTE and ATE in COVID-19 up to 30 September 2020. RESULTS: We analysed findings from 102 studies (64 503 patients). The frequency of COVID-19-related VTE was 14.7% (95% CI 12.1% to 17.6%, I2=94%; 56 studies; 16 507 patients). The overall prevalence rates of pulmonary embolism (PE) and leg deep vein thrombosis were 7.8% (95% CI 6.2% to 9.4%, I2=94%; 66 studies; 23 117 patients) and 11.2% (95% CI 8.4% to 14.3%, I2=95%; 48 studies; 13 824 patients), respectively. Few were isolated subsegmental PE. The VTE prevalence was significantly higher in intensive care unit (ICU) (23.2%, 95% CI 17.5% to 29.6%, I2=92%, vs 9.0%, 95% CI 6.9% to 11.4%, I2=95%; pinteraction<0.0001) and in series systematically screening patients compared with series testing symptomatic patients (25.2% vs 12.7%, pinteraction=0.04). The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively. Metaregression and subgroup analyses failed to explain heterogeneity of overall ATE. High heterogeneity limited the value of estimates. CONCLUSIONS: Patients admitted in the ICU for severe COVID-19 had a high risk of VTE. Conversely, further studies are needed to determine the specific effects of COVID-19 on the risk of ATE or VTE in less severe forms of the disease.

Rituximab for rheumatoid arthritis-associated large granular lymphocytic leukemia, a retrospective case series.

OBJECTIVES: To assess the efficacy and tolerance profile of rituximab in rheumatoid arthritis (RA)-associated large granular lymphocyte leukemia (LGLL). METHODS: Multicenter retrospective case series. Inclusion criteria were RA defined by the ACR/EULAR 2010 criteria and LGLL defined by absolute LGL count ≥ 0.3 × 109/L with evidence of an expanded clonal LGL population (flow cytometry, TCR-γ polymerase chain reaction, or Stat3 mutation). RESULTS: Fourteen patients (10 women, mean age 55.2 ± 14.2 years) included; 13 were seropositive for anti-cyclic citrullinated peptides (n = 11) or rheumatoid factor (n = 10). LGLL diagnosis was made 9.5 [IQR: 3.25;15.5] years after RA diagnosis. Thirteen patients had T-LGLL. Rituximab was the first-line therapy for LGLL for 4 patients. Previous treatment lines included methotrexate (n = 7), cyclophosphamide (n = 2), cyclosporin A (n = 1), or granulocyte colony-stimulating factor (n = 4). Rituximab was used in monotherapy (n = 8) or associated to methotrexate (n = 3), granulocyte colony-stimulating factor (n = 2), or alkylating agents (n = 1). The number of rituximab cycles ranged from 1 to 11 (median 6), with high heterogeneity in dosing regimens. Median duration response after rituximab initiation was 35 [IQR: 23.5;41] months. The overall response rate was 100%: 8 patients experienced complete response (normalization of blood count and LGL ≤ 0.3 × 109/L) and 6 experienced partial responses (improvement in blood counts without complete normalization). The tolerance profile was good, with no infectious complications. CONCLUSION: rituximab appears as a valuable therapeutic option for RA-associated LGLL.

Severe infections in patients with anti-neutrophil cytoplasmic antibody-associated vasculitides receiving rituximab: A meta-analysis.

INTRODUCTION: The efficacy of rituximab (RTX) for remission induction and maintenance in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) is now established, but the safety, particularly concerning severe infection risk, is not well known. OBJECTIVE: The purpose of this meta-analysis is to assess the prevalence and incidence of severe infections and the factors explaining heterogeneity in AAV patients treated with RTX. METHODS: PubMed and Embase were searched up to December 2017. Prevalence and incidence was pooled using a random-effects model in case of significant heterogeneity (I2 > 50%). Severe infection was defined as severe when it led to hospitalization, intravenous antibiotics therapy, and/or death. The heterogeneity was explored by subgroup analyses and meta-regression. RESULTS: The included studies encompassed 1434 patients with a median age of 51.9 years. The overall prevalence and incidence of severe infections was 15.4% (95% CI [8.9; 23.3], I2 = 90%, 33 studies) and 6.5 per 100 person-years (PY) (95% CI [2.9; 11.4], I2 = 76%, 18 studies), respectively. The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]). The prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1], I2 = 58%) including pneumocytis jirovecii infections (0.2%, 95% CI [0.0; 0.6], I2 = 0), irrespective of prophylaxis administration. Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I2 = 27%). The RTX cumulative dose was positively associated with prevalence of infections (13 studies, prevalence increase of 4% per 100 mg, p < .0001). The incidence of infection was negatively associated with duration of follow-up (8 studies, incidence decrease of 9% per year, p = .03). CONCLUSION: Prevalence and incidence of severe infections, mainly bacterial ones, were high in AAV patients treated with RTX. This meta-analysis highlights the need for prospective studies to stratify infectious risk and validate cumulative RTX dose and duration of follow-up as modifying factors.