Screening for primary immune deficiency among patients with bronchiectasis.

INTRODUCTION: To assess frequency and methods of PID (primary immune deficiency) screening among patients with bronchiectasis by pneumologists in clinical practice. METHODS: All the patients hospitalized in the department of pneumology of the Poitiers University Hospital between April 2013 and April 2020 with a diagnosis of bronchiectasis on chest computerized tomography were included. Patients aged 70 and over and those with already known PID were excluded. Primary endpoint was the proportion of patients having had serum immunoglobulin (Ig) assay and serum protein electrophoresis (SPE) analysis. Secondary endpoints were factors associated with prescription of SPE and/or Ig assay, proportion of patients with newly diagnosed PID and their characteristics and factors associated with repeated courses of antibiotics. RESULTS: Among the 133 patients included, 43% had SPE+Ig assay, 34% SPE only and 23% neither. The proportion of patients with asthma was higher in the "SPE+Ig assay" group (33.3%) compared to the "SPE only" (11.1%) and the "Neither SPE nor Ig assay" groups (6.4%) (P=0.002). Four patients were newly diagnosed for PID of whom 3 had subclass IgG deficiency. Factors associated with repeated courses of antibiotics were generalized bronchiectasis (P=0.02) and asthma (P=0.04). CONCLUSION: PID is underscreened by pneumologists among patients with bronchiectasis. Association of SPE+Ig assay+IgG subclass assay appears as the most accurate combination.

Belimumab corticosteroid-sparing treatment in systemic lupus erythematosus: a real-life observational study (BESST study).

Data about the impact of Belimumab on corticosteroid sparing in real life are scarce. To assess the corticosteroid-sparing effect among patients with systemic lupus erythematosus (SLE) treated with Belimumab in real-life settings. Multicentric observational retrospective study including patients with SLE and having received Belimumab for at least 6 months between 2011 and 2020, in eight French hospitals. "Low dose" referred to patients receiving up to 7.5 mg of prednisone a day and "Very low dose" to those receiving strictly ≤ 5 mg prednisone a day The primary endpoint was the reduction of daily prednisone dose after six months of Belimumab. The secondary endpoint was a change in the proportion of patients with low or very low dose of prednisone as well as those without prednisone during the Belimumab course. Censoring occurred for patients who stopped Belimumab. Bivariate analyses were performed using the Wilcoxon signed-rank test. The threshold for statistical significance was set at p < 0.05. Thirty patients were included. All were female with a median age of 38 years. A significant reduction in prednisone dose was observed at month 6 (10 [7-20] vs 6.75 [2-9] mg, p < 0.0001), continued until month 12 (10 [7-20] mg vs 5 [0-7.12] mg, p < 0.001) and was sustained until month 24. The proportion of patients with very low dose of prednisone and those without prednisone progressively increased during the Belimumab course. Introducing Belimumab in patients with SLE, in real-life conditions, is associated with early and sustained corticosteroid-sparing effect.

[Mobilization and conditioning protocols actualization for autologous stem cell transplantation for autoimmune diseases: Guidelines from MATHEC-SFGM-TC]. / Actualisation des protocoles de mobilisation et conditionnement pour la pratique des autogreffes de cellules souches hématopoïétiques chez les patients atteints de maladies auto-immunes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (MATHEC-SFGM-TC).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 13th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures in September 2022 in Lille, France. The aim of this workshop is to update the mobilization and conditioning protocols for autologous hematopoietic stem cell transplantation for autoimmune diseases, and to specify contraindications for transplant, conditioning regimen selection, immunosuppressive treatment discontinuation before mobilization and disease-specific surveillance.

Clinical features and long-term outcomes of patients with systemic polyarteritis nodosa diagnosed since 2005: Data from 196 patients.

BACKGROUND: The landscape of polyarteritis nodosa (PAN) has substantially changed during the last decades. Recent data regarding causes, characteristics, and prognosis of systemic PAN in the modern era are lacking. METHODS: This retrospective study included patients with systemic PAN referred to the French Vasculitis Study Group between 2005 and 2019. Characteristics, associated conditions and outcomes were collected, and predictors of relapse and death were analyzed. RESULTS: 196 patients were included. Main clinical symptoms were constitutional (84%), neurological (59%), skin (58%) and musculoskeletal (58%) manifestations. Secondary PAN accounted for 55 (28%) patients, including myelodysplastic syndrome (9%), solid cancer (7%), lymphoma (4%) and autoinflammatory diseases (4%). No patient had active HBV infection. All treated patients (98.5%) received glucocorticoids (GCs), alone (41%) or in combination with immunosuppressants (59%), with remission achieved in 90%. Relapses were independently associated with age >65 years (HR 1.85; 95% CI1.12-3.08), gastrointestinal involvement (1.95; 95% CI1.09-3.52) and skin necrotic lesions (HR 1.95; 95%CI 1.24-3.05). One-, 5- and 10-year overall survival rates were 93%, 87% and 81%, respectively. In multivariate analyses, age >65 years (HR 2.80; 95%CI 1.23-6.37), necrotic purpura (HR 4.16; 95%CI 1.62-10.70), acute kidney injury (HR 4.89; 95% 1.71-13.99) and secondary PAN (HR 2.98; 95%CI 1.29-6.85) were independently associated with mortality. CONCLUSION: Landscape of PAN has changed during the last decades, with the disappearance of HBV-PAN and the emergence of secondary PAN. Relapse rate remains high, especially in aged patients with gastrointestinal and cutaneous necrosis, as well as mortality.

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study.

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Polyclonal hypergammaglobulinaemia: towards definition of a threshold.

BACKGROUND: Polyclonal hypergammaglobulinaemia (PH) represents a classic diagnosis problem in internal medicine. However, there is no consensus threshold for PH. The aim of this study was to define a threshold for PH. METHODS: We conducted a retrospective multicentric study using laboratory biological databases between 1 January 2016 and 31 December 2016 in two university hospitals and one non-university hospital. All patients 18 years old or over and with at least one serum protein electrophoresis (SPE) available in 2016 were included. Exclusion criteria were monoclonal, biclonal, or oligoclonal spikes or, in case of hypogammaglobulinaemia, proven free light chain gammopathy. The main endpoint was to define the threshold values for PH in this population. Another objective was to define the 95th percentile of the distribution. RESULTS: 20 766 SPEs were included in this cohort. The PH threshold on 95th percentile was 18.9 g/L. The threshold varied according to geographical areas. CONCLUSIONS: This is the first study to scientifically define a PH threshold. The main limitation is that our threshold is only biological. The study was not designed to associate this threshold with a clinically active disease. In conclusion, while the 19 g/L cut-off seems the most relevant threshold, but it will need to be validated by prospective studies.

Prognosis of immune checkpoint inhibitors-induced myocarditis: a case series.

BACKGROUND: Immune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening. METHODS: We conducted a multicenter cross-sectional retrospective study with the aim of better characterizing ICI-related myocarditis. Myocarditis diagnosis was based on the recent consensus statement of the International Cardio-Oncology Society. RESULTS: Twenty-nine patients were identified, from six different referral centers. Most patients (55%) were treated using anti-programmed-death 1, rather than ICI combination (35%) or anti-programmed-death-ligand 1 (10%). Transthoracic echocardiography was abnormal in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as severe. Compared with other patients, they had more frequently pre-existing systemic autoimmune disease (45% vs 6%, p=0.018), higher troponin level on admission (42-fold the upper limit vs 3.55-fold, p=0.001), and exhibited anti-acetylcholine receptor autoantibodies (p=0.001). Seven patients (24%) had myocarditis-related death, and eight more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received intravenous immunoglobulins, and 5 other immunosuppressants. ICI rechallenge was performed in six patients, with only one myocarditis relapse. DISCUSSION: The management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI rechallenge for some patients with smoldering presentation, after an accurate evaluation of benefit-risk balance.

Immune Checkpoint Inhibitor-Related Cytopenias: About 68 Cases from the French Pharmacovigilance Database.

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

Risk factors for biliary stent infections in malignant biliary obstruction secondary to unresectable malignancies.

BACKGROUND: Palliative biliary drainage in patients with unresectable malignant biliary obstruction (MBO) frequently leads to biliary stent infection (BI), which could impact medical care. The aim of this study was to assess the risk factors for BI occurrence in patients after stenting procedure and the impact of BI on patient survival. METHODS: All consecutive patients hospitalized from 2014 to 2018 for MBO and biliary stenting were retrospectively included. Demographic, clinical, and microbiological characteristics of each BI episode during a 1-year follow-up were described. Documented BI was defined as the association of BI episode and confirmed blood stream infection (BSI). Univariate and multivariate analyses were performed to evaluate risk factors for the first BI occurrence. RESULTS: Among 180 patients, 56% were men (mean age of 69±12), and 54% have pancreatic cancer, 16% biliary cancer, 2% hepatic cancer, and 28% lymph node or metastatic compression; metallic stent was placed in 92%. A total of 113 BI episodes occurred in 74 patients, 55% of the first episodes occurring within 3 months after stenting. BI was documented in 56% of the episodes. Enterobacteriaceae were the most frequent pathogens found, while no yeasts were documented. Mortality rate in patients with BI was 64%. Multivariate analysis showed a significant difference in BI occurrence for two criteria: WHO score 3-4 (OR=8.79 [1.79-42.89]; p=0.007) and transpapillary stenting location (OR=3.72 [1.33-10.44]; p=0.013). CONCLUSION: Since transpapillary stenting is a risk factor for BI, preserving the papilla as much as possible is a priority so as to avoid BI.

Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis, the Ottawa Protocol.

Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat patients with highly active multiple sclerosis (MS) refractory to disease-modifying therapy. Briefly, cyclophosphamide and filgrastim are used to mobilize autologous hematopoietic stem cells (HSC) into the circulation. HSC are harvested by leukapheresis, purified using a CD34 immunomagnetic selection process, and cryopreserved. Busulphan, cyclophosphamide, and rabbit anti-thymocyte globulin are used to destroy the patient's autoreactive immune system, followed by infusion of the previously collected HSC, which reconstitute a naïve and self-tolerant immune system. Many MS patients experience durable remissions with no evidence of new disease activity following aHSCT. Treatment-related toxicity is rare, but potentially life-threatening complications necessitate appropriate patient selection by MS neurologists and HSCT physicians. AHSCT must be performed with a highly trained multidisciplinary team expert to minimize morbidity and mortality. We present the current aHSCT procedure for an MS indication at The Ottawa Hospital, developed from our program's 20-year experience. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Candidate selection Basic Protocol 2: Autologous hematopoietic stem cell mobilization, collection, purification, and cryopreservation Basic Protocol 3: Autologous hematopoietic stem cell transplantation Basic Protocol 4: Supportive care following recovery from aHSCT (Beyond 100 days) Basic Protocol 5: Ongoing evaluation of multiple sclerosis.

Immune Checkpoint Inhibitors and Venous Thromboembolism: An Analysis of the WHO Pharmacovigilance Database.

Data on venous thromboembolic events (VTEs) in patients receiving immune checkpoint inhibitors (ICIs) are scarce and conflicting. This study investigated the risk of reporting VTEs associated with ICIs in comparison with all other anticancer drugs. The World Health Organization pharmacovigilance database (VigiBase), comprising >30 million individual case safety reports, was queried. All reports on patients with cancer, involving at least one anticancer drug as a suspect or interacting drug and registered from January 1, 2008, to May 31, 2021, were included. The association between ICIs and the risk of reporting VTEs was estimated using the reporting odds ratio (ROR) as a measure of disproportionality with all other anticancer drugs as comparators. RORs were estimated as crude and adjusted RORs for age, sex, and other medications (excluding anticancer drugs) associated with risk of VTEs. Among 1,196 patients experiencing VTEs after ICI treatment, the median age was 65 years and 57.6% were men. Anti-PD-1 agents (62.5%) were the most frequently reported. ICIs were not associated with higher reporting of VTEs when compared with other anticancer drugs (crude ROR 0.63, 95% confidence interval (CI) 0.60 to 0.67 and adjusted ROR 0.70, 95% CI 0.65-0.74). No signal of disproportionate reporting was found when considering each class of ICIs. In conclusion, ICIs were not associated with higher reporting of VTEs, in comparison with all other anticancer drugs in a large-scale pharmacovigilance database. Owing to the limitations inherent to pharmacovigilance studies, prospective studies, including an adequate comparison group, are needed to assess the risk of VTEs in ICI-treated patients.

Safety of Immune Checkpoint Inhibitor Resumption after Interruption for Immune-Related Adverse Events, a Narrative Review.

Immune checkpoint inhibitors (ICIs) have become the standard of care for several types of cancer due to their superiority in terms of survival benefits in first- and second-line treatments compared to conventional therapies, and they present a better safety profile (lower absolute number of grade 1-5 adverse events), especially if used in monotherapy. However, the pattern of ICI-related adverse events is totally different, as they are characterized by the development of specific immune-related adverse events (irAEs) that are unique in terms of the organs involved, onset patterns, and severity. The decision to resume ICI treatment after its interruption due to irAEs is challenged by the need for tumor control versus the risk of occurrence of the same or different irAEs. Studies that specifically assess this point remain scarce, heterogenous and mostly based on small samples of patients or focused only on the recurrence rate of the same irAE after ICI resumption. Moreover, patients with grade ≥3 irAEs were excluded from many of these studies. Herein, we provide a narrative review on the field of safety of ICI resumption after interruption due to irAE(s).

Myeloproliferative neoplasms and clonal haematopoiesis in patients with giant cell arteritis: a case-control and exploratory study.

OBJECTIVES: GCA is a large vessel vasculitis for which triggering factors remain unknown. Clonal haematopoiesis (CH) was associated with atherosclerosis through the induction of inflammation in myeloid cells, and data suggest that CH expansion and inflammation may support each other to induce a pro-inflammatory loop. Our objective was to describe the impact of JAK2p.V617F-mutated myeloproliferative neoplasms (MPNs) on GCA and to screen MPN-free patients for CH mutations. METHODS: We performed a retrospective case-control study comparing the characteristics of 21 GCA patients with MPN and 42 age- and gender-matched GCA patients without MPN. Also, 18 GCA patients were screened for CH through next-generation sequencing (NGS). RESULTS: The most frequent associated MPN was essential thrombocythaemia (ET; n = 11). Compared with controls, GCA patients with MPN had less-frequent cephalic symptoms (71.4 vs 97.6%; P = 0.004) and higher platelet counts at baseline [485 × 109/l (interquartile range 346-586) vs 346 (296-418); P = 0.02]. There was no difference between groups for other clinical features. Overall survival was significantly shorter in patients with MPN compared with controls [hazard ratio 8.2 (95% CI 1.2, 56.6); P = 0.03]. Finally, screening for CH using NGS in 15 GCA patients without MPN revealed CH in 33%. CONCLUSION: GCA patients with MPN display higher platelet counts and shorter overall survival than controls. This association is not fortuitous, given the possible pathophysiological relationship between the two diseases. CH was found in one-third of GCA patients, which may be higher than the expected prevalence for a similar age, and should be confirmed in a larger cohort.

Polyclonal hypergammaglobulinaemia: towards definition of a threshold.

BACKGROUND: Polyclonal hypergammaglobulinaemia (PH) represents a classic diagnosis problem in internal medicine. However, there is no consensus threshold for PH. The aim of this study was to define a threshold for PH. METHODS: We conducted a retrospective multicentric study using laboratory biological databases between 1 January 2016 and 31 December 2016 in two university hospitals and one non-university hospital. All patients 18 years old or over and with at least one serum protein electrophoresis (SPE) available in 2016 were included. Exclusion criteria were monoclonal, biclonal, or oligoclonal spikes or, in case of hypogammaglobulinaemia, proven free light chain gammopathy. The main endpoint was to define the threshold values for PH in this population. Another objective was to define the 95th percentile of the distribution. RESULTS: 20 766 SPEs were included in this cohort. The PH threshold on 95th percentile was 18.9 g/L. The threshold varied according to geographical areas. CONCLUSIONS: This is the first study to scientifically define a PH threshold. The main limitation is that our threshold is only biological. The study was not designed to associate this threshold with a clinically active disease. In conclusion, while the 19 g/L cut-off seems the most relevant threshold, but it will need to be validated by prospective studies.

[Autologous hematopoietic cells for severe autoimmune diseases: Guidelines of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) for immune monitoring and biobanking]. / Suivi immunologique et collection biologique en vue de l'analyse de la réponse clinique après autogreffe de moelle pour maladies auto-immunes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Autologous hematopoietic cell transplantation (AHCT) is a new treatment option for patients with severe autoimmune diseases (AD), based on the use of intensive or myeloablative chemotherapy to eradicate the pathogenic autoreactive immune cells and to allow the installation of a new and tolerant immune system during immune reconstitution process. Immune reconstitution analysis after AHCT is required for patients clinical follow-up and to further identify biological and immunological markers of the clinical response to develop individualized AHCT protocols. These MATHEC-SFGM-TC good clinical practice guidelines were developed by a multidisciplinary group of experts including members of the french reference center for stem Cell Therapy in Auto-immune Diseases (MATHEC), hematologists from the French speaking Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and experts in immune monitoring and biobanking. The objectives are to provide practical recommandations for immune monitoring and biobanking of samples in patients with AD undergoing AHCT, for routine care purposes and investigational studies.

Long term outcomes of the French ASTIS systemic sclerosis cohort using the global rank composite score.

Two randomised trials (ASTIS, SCOT) of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) versus monthly Cyclophosphamide for severe Systemic Sclerosis (SSc) patients used similar inclusion criteria, but different primary endpoints: event-free-survival (EFS) at 24 months in ASTIS versus the global rank composite score (GRCS) at 54 months in SCOT. Here we analysed the French ASTIS cohort (n = 49) outcome using the same GRCS endpoint as reported in SCOT. All patients, randomised to AHSCT (n = 26) or Cyclophosphamide (n = 23), were evaluated for the non-parametric GRCS endpoint based on: death, EFS, forced vital capacity (FVC), Health Assessment Questionnaire Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 60 months. Secondary endpoints were: EFS, overall survival (OS), HAQ DI and organ status. In intention-to-treat analysis, the GRCS demonstrated superiority for AHSCT (median: 9 versus -19, p = 0.018), mRSS (Δ mRSS: -16 versus -9, p = 0.02), and HAQ-DI (ΔHAQ-DI: -0.89 versus -0.2, p = 0.05) with no significant difference in OS, EFS, lung, heart and kidney function between the groups. In conclusion, this study demonstrates long term benefits of non-myeloablative AHSCT when assessed by the five longitudinal measures within GRCS affording direct primary endpoint comparison between ASTIS and SCOT.