Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Susceptibility to mycobacterial infection in VEXAS syndrome.

OBJECTIVES: VEXAS is a recently described acquired auto-inflammatory and hematologic syndrome caused by somatic mutations in UBA1. To date, VEXAS is not a recognized cause of acquired immunodeficiency. PATIENTS AND METHODS: Two of our 10 VEXAS patients developed a disseminated Mycobacterium avium infection. To shed light on this observation, we retrospectively studied all patients with disseminated non-tuberculous mycobacterial infections (NTMi) seen at our institution over 13 years. Inclusion criteria were a positive blood/bone marrow culture, or 2 positive cultures from distinct sites, or one positive culture with 2 involved sites. RESULTS: patient 1 presented with fever, rash, orbital cellulitis and lung infiltrates. Patient 2 presented with fever and purpura. In both cases, Mycobacterium avium was identified on bone marrow culture. Twenty cases of disseminated NTMi were reviewed. Among 11 HIV-negative patients, three had chronic immune-mediated disease; three had untreated myeloid neoplasm; two had VEXAS; one had undergone kidney transplantation; one had GATA-2 deficiency; and one had no identified aetiology. None had lymphoid neoplasia or had undergone bone marrow transplantation. HIV-negative cases had higher CD4 counts than HIV-positive patients (median CD4: 515/mm3  vs 38/mm3, p< 0.001). Monocytopenia was present in seven cases. At 2 years, six patients had died, including both VEXAS patients. DISCUSSION: VEXAS patients have an intrinsic susceptibility to disseminated NTMi, which may result from monocytic dysfunction. NTMi can mimic VEXAS flare. Clinicians should maintain a high suspicion for opportunistic infections before escalating immunosuppressive therapy. Further studies are needed to confirm and better decipher the herein reported observations.

Characteristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease: A Retrospective Multicenter Study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical presentation, severity, and mortality of PcP has not been adequately evaluated. RESEARCH QUESTION: Does the underlying disease and immunosuppression causing PcP impact the outcome and clinical presentation of the disease? STUDY DESIGN AND METHODS: In this multicenter retrospective observational study, conducted from January 2011 to December 2021, all consecutive patients admitted with a proven or probable diagnosis of PcP according to the European Organisation for Research and Treatment of Cancer consensus definitions were included to assess the epidemiology and impact of underlying immunosuppressive diseases on overall and 90-day mortality. RESULTS: Overall, 481 patients were included in the study; 180 (37.4%) were defined as proven PcP and 301 (62.6%) were defined as probable PcP. Patients with immune-mediated inflammatory diseases (IMIDs) or solid tumors had a statistically poorer prognosis than other patients with PcP at day 90. In multivariate analysis, among the HIV-negative population, solid tumor underlying disease (OR, 5.47; 95% CI, 2.16-14.1; P < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; P = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; P = .045), cysts in sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; P = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; P < .001) were independently associated with 90-day mortality. Prior corticotherapy was the only immunosuppressant associated with 90-day mortality (OR, 1.67; 95% CI, 1.03-2.71; P = .035), especially for a prednisone daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; P = .010). INTERPRETATION: Among patients who were HIV-negative, long-term corticosteroid prior to PcP diagnosis was independently associated with increased 90-day mortality, specifically in patients with IMIDs. These results highlight both the needs for PcP prophylaxis in patients with IMIDs and to early consider PcP curative treatment in severe pneumonia among patients with IMIDs.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Dysregulation of neutrophil oxidant production and interleukin-1-related cytokines in granulomatosis with polyangiitis.

OBJECTIVES: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of the inflammasome and IL-1-related cytokines. We aimed to analyse the ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen proteinase 3 (PR3). METHODS: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production was evaluated in whole blood of patients with active GPA and compared with the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analyzed. RESULTS: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. CONCLUSION: Our data suggests that ROS production and regulation of the inflammasome in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT01862068, clinicaltrials.gov, https://www.clinicaltrials.gov.

Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Invasive fungal diseases in patients with autoimmune diseases: a case series from the French RESSIF network.

OBJECTIVES: We aimed to describe patients with autoimmune diseases (AID) developing invasive fungal disease (IFD) and identify factors associated with short-term mortality. METHODS: We analysed cases of IFD associated with AID from the surveillance network of invasive fungal diseases (Réseau de surveillance des infections fongiques invasives, RESSIF) registry of the French national reference centre for invasive mycoses. We studied association of AID-specific treatments with 30-day mortality. We analysed total lymphocyte and CD4-T cell counts in patients with Pneumocystis jirovecii pneumonia (PCP). RESULTS: From 2012 to 2018, 549 individuals with IFD and AID were included, mainly with PCP (n=227, 41.3%), fungemia (n=167, 30.4%) and invasive aspergillosis (n=84, 15.5%). Rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) were the most frequent AID in PCP (n=55 and 25, respectively) and invasive aspergillosis (n=15 and 10, respectively), inflammatory bowel diseases (IBDs) were predominant in fungemia (n=36). At IFD diagnosis, 365 (66.5%) patients received glucocorticoids (GCs), 285 (51.9%) immunosuppressants, 42 (7.7%) tumor necrosis factor (TNF)-α blockers, 75 (13.7%) other biologics. Mortality at 30 days was 28.1% (143/508). Fungemia and high-dose GCs were independently associated with higher 30-day mortality. In PCP patients, lymphopenia <1500/mm3 was frequent (132/179, 73.7%) even if CD4+T cell count exceeded 200/mm3 in 56/78 patients (71.8%) (median 472.5/mm3, IQR 160-858). CONCLUSION: IFD associated with AID occurs primarily in RA, AAV and IBD, especially when treated with GCs and immunosuppressants. Mortality is high, especially for patients on high-dose GCs. Lymphopenia may help identify risk of PCP, but normal CD4+T cell count does not rule out the risk. Further studies are needed to assess the individual risk factors for IFD.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Regulation of CD8 T cell by B-cells: A narrative review.

Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.

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.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

Localized versus systemic granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe the main features at diagnosis and evolution over time of patients with localized granulomatosis with polyangiitis (L-GPA) compared with those of systemic GPA (S-GPA). METHODS: EULAR definitions of L-GPA, i.e. upper and/or lower respiratory tract involvement, and S-GPA were applied to patients from the French Vasculitis Study Group Registry. L-GPA and S-GPA patients' characteristics at diagnosis and long-term outcomes were analysed and compared. RESULTS: Among the 795 Registry patients, 79 (10%) had L-GPA. Their main clinical manifestations were rhinitis, lung nodules, sinusitis and otitis. L-GPA vs S-GPA patients at diagnosis, respectively, were younger, more frequently had saddle nose deformity or subglottic stenosis and were less often PR3-ANCA-positive. L-GPA vs S-GPA induction therapy less frequently included CYC but more often a combination of MTX and glucocorticoids; 64% of MTX-treated patients experienced disease progression within 18 months post-diagnosis. L- and S-GPA patients' estimated relapse-free-survival probabilities, relapse rates and refractory disease rates at each time point were comparable, but L-GPA patients had more frequent ENT and lung relapses, and higher overall survival rates (P<0.02). Over a median follow-up of 3.5 years, 18 (22.8%) L-GPA progressed to S-GPA, either as a relapse after a period in remission or more frequently in the context of refractory disease. L-GPA patients experienced more ENT-related damage. CONCLUSIONS: The relapse risks of L-GPA and S-GPA were similar, but relapse patterns differed and L-GPA overall survival rate was higher. About one-quarter of L-GPA patients developed S-GPA over time, but without end-stage organ involvement.

Risk factors for symptomatic vascular events in giant cell arteritis: a study of 254 patients with large-vessel imaging at diagnosis.

AIMS: To identify factors associated with vascular events in patients with giant cell arteritis (GCA). METHODS: We performed a retrospective study of GCA patients diagnosed over a 20-year-period, who all underwent vascular imaging evaluation at diagnosis. Symptomatic vascular events were defined as the occurrence of any aortic event (aortic dissection or symptomatic aortic aneurysm), stroke, myocardial infarction, limb or mesenteric ischemia and de novo lower limbs arteritis stage 3 or 4. Patients with symptomatic vascular event (VE+) and without were compared, and risk factors were identified in a multivariable analysis. RESULTS: Thirty-nine (15.4%) of the 254 included patients experienced at least one symptomatic vascular event during follow-up, with a median time of 21.5 months. Arterial hypertension, diabetes, lower limbs arteritis or vascular complication at diagnosis were more frequent in VE+ patients (p < 0.05), as an abnormal computed tomography (CT)-scan at diagnosis (p = 0.04), aortitis (p = 0.01), particularly of the descending thoracic aorta (p = 0.03) and atheroma (p = 0.03). Deaths were more frequent in the VE+ group (37.1 versus 10.3%, p = 0.0003). In multivariable analysis, aortic surgery [hazard ratio (HR): 10.46 (1.41-77.80), p = 0.02], stroke [HR: 22.32 (3.69-135.05), p < 0.001], upper limb ischemia [HR: 20.27 (2.05-200.12), p = 0.01], lower limb ischemia [HR: 76.57 (2.89-2027.69), p = 0.009], aortic atheroma [HR: 3.06 (1.06-8.82), p = 0.04] and aortitis of the descending thoracic aorta on CT-scan at diagnosis [HR: 4.64 (1.56-13.75), p = 0.006] were independent predictive factors of a vascular event. CONCLUSION: In this study on GCA cases with large vessels imaging at diagnosis, aortic surgery, stroke, upper or lower limb ischemia, aortic atheroma and aortitis of the descending thoracic aorta on CT-scan, at GCA diagnosis, were independent predictive factors of a vascular event. PLAIN LANGUAGE SUMMARY: Risk factors for symptomatic vascular events in giant cell arteritisThis study was performed to identify the risk factors for developing symptomatic vascular event during giant cell arteritis (GCA) because these are poorly known.We performed a retrospective study of GCA patients diagnosed over a 20-year-period, who all underwent vascular imaging evaluation at diagnosis.Patients with symptomatic vascular event (VE+) and without (VE-) were compared, and risk factors were identified in a multivariable analysis.Thirty-nine patients experienced at least one symptomatic vascular event during follow-up, with a median time of 21.5 months.Arterial hypertension, diabetes, lower limbs arteritis or vascular complication at diagnosis were significantly more frequent in VE+ patients, as an abnormal CT-scan at diagnosis, aortitis, particularly of the descending thoracic aorta and atheroma. Deaths were more frequent in the VE+ group.Among 254 GCA patients, 39 experienced at least one vascular event during follow-up.Aortic surgery, stroke, upper and lower limb ischemia were vascular event risk factors.Aortic atheroma and descending thoracic aorta aortitis on CT-scan were vascular event risk factors.This study on GCA cases with large vessels imaging at diagnosis, showed that aortic surgery, stroke, upper or lower limb ischemia, aortic atheroma and aortitis of the descending thoracic aorta on CT-scan, at GCA diagnosis, were independent predictive factors of a vascular event.

Large-vessel involvement is predictive of multiple relapses in giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis. Relapses are frequent. The aim of this study was to identify relapse risk factors in patients with GCA with complete large-vessel imaging at diagnosis. METHODS: Patients with GCA followed in our institution between April 1998 and April 2018 were included retrospectively. We included only patients who had undergone large vascular imaging investigations at diagnosis by computed tomography (CT)-scan and/or positron emission tomography (PET)-scan and/or angio-magnetic resonance imaging (MRI). Clinical, biological, and radiological data were collected. Relapse was defined as the reappearance of GCA symptoms, with concomitant increase in inflammatory markers, requiring treatment adjustment. Relapsing patients (R) and non-relapsing patients (NR) were compared. Relapse and multiple relapses (>2) risk factors were identified in multivariable Cox analyses. RESULTS: This study included 254 patients (73.2% women), with a median age of 72 years at diagnosis and a median follow up of 32.5 months. At diagnosis, 160 patients (63%) had an inflammatory large-vessel involvement on imaging, 46.1% (117 patients) relapsed at least once, and 21.3% (54 patients) had multiple relapses. The median delay of first relapse after diagnosis was 9 months. The second relapse delay was 21.5 months. NR patients had more stroke at diagnosis than R (p = 0.03) and the brachiocephalic trunk was involved more frequently on CT-scan (p = 0.046), as carotids (p = 0.02) in R patients. Multivariate Cox model identified male gender [hazard ratio (HR): 0.51, confidence interval (CI) (0.27-0.96), p = 0.04] as a relapse protective factor, and peripheral musculoskeletal manifestations [HR: 1.74 (1.03-2.94), p = 0.004] as a relapse risk factor. Peripheral musculoskeletal manifestations [HR: 2.78 (1.23-6.28), p = 0.014], negative temporal artery biopsy [HR: 2.29 (1.18-4.45), p = 0.015], large-vessel involvement like upper limb ischemia [HR: 8.84 (2.48-31.56), p = 0.001] and inflammation of arm arteries on CT-scan [HR: 2.39 (1.02-5.58), p = 0.04] at diagnosis were risk factors of multiple relapses. CONCLUSION: Male gender was a protective factor for GCA relapse and peripheral musculoskeletal manifestations appeared as a relapsing risk factor. Moreover, this study identified a particular clinical phenotype of multi-relapsing patients with GCA, characterized by peripheral musculoskeletal manifestations, negative temporal artery biopsy, and large-vessel involvement with upper limb ischemia or inflammation of arm arteries. PLAIN LANGUAGE SUMMARY: At giant cell arteritis diagnosis, large-vessel inflammatory involvement is predictive of multiple relapses 46.1% of patients with GCA relapse, and 21.3% undergo multiple relapses;Male gender appears as a protective factor for relapsing in GCA;Peripheral musculoskeletal manifestations are a relapse and multiple relapses risk factor;A negative temporal artery biopsy is predictive of multiple relapses;Large-vessel involvement is predictive of multiple relapses.

Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic).

BACKGROUND: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE. METHODS: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS). RESULTS: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4). CONCLUSIONS: A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01738360  registered 30 November 2012.

Inflammatory optic neuropathy in granulomatosis with polyangiitis can mimick isolated idiopathic optic neuritis.

OBJECTIVE: We describe a clinico-radiological presentation of inflammatory optic neuropathy that mimicked optic neuritis. METHODS: Retrospective single-center case series and literature review of optic neuropathy without orbital pseudotumor. RESULTS: Five local patients fulfilled the inclusion criteria. Clinical presentation revealed rapidly progressive severe unilateral visual loss, retrobulbar pain (n = 4), and paralytic strabismus (simultaneous = 2, protracted = 2) without proptosis. Optic nerve abnormality was not appreciated on initial scan review. Patients did not have any general activity of the granulomatosis with polyangiitis. Upon follow-up magnetic resonance imaging and initial imaging review, all patients revealed orbital apex anomalies. Visual acuity improved in three patients who received high-dose intravenous glucocorticosteroids immediately. Relapse was frequent and visual outcome was poor (final vision > 20/40 in two patients only). Literature review identified 16 well-documented cases of granulomatosis with polyangiitis-related isolated optic neuropathies. Magnetic resonance imaging revealed no abnormality (n = 6), optic nerve and/or sheath involvement (n = 9), apex infiltration (n = 3), and/or pachymeningitis (n = 7). CONCLUSION: Granulomatosis with polyangiitis is a rare yet potentially blinding cause of inflammatory optic neuropathy. Optic neuropathy in granulomatosis with polyangiitis may occur in the absence of systemic symptoms of disease activity and is challenging to distinguish from other inflammatory and non-inflammatory disorders affecting visual acuity. Several clinical and imaging clues suggest that optic neuropathy results from the development of an extravascular granulomatous process within the optic nerve sheath in the orbital apex, a place that is difficult to image. In a granulomatosis with polyangiitis patient with unexplained visual loss and a seemingly normal workup (fundoscopy, biology, and imaging), clinician should keep a high index of suspicion.

Muscle biopsy in anti-neutrophil cytoplasmic antibody-associated vasculitis: diagnostic yield depends on anti-neutrophil cytoplasmic antibody type, sex and neutrophil count.

OBJECTIVES: This study aimed to examine the sensitivity of muscle biopsy (MB) in ANCA-associated vasculitis (AAV), identify factors predicting MB positivity and assess the prognostic value of a positive MB. METHODS: We conducted a single-centre retrospective study of AAV with an MB performed at diagnosis. AAV classification [granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA)] followed the European Medicines Agency algorithm. A logistic regression model was used to identify the factors associated with MB positivity. Survival curves were generated using the Kaplan-Meier method. RESULTS: Among 276 AAV patients (1995-2018), 101 had an MB. Seventy-eight patients were included: 33 with GPA, 25 with MPA and 20 with EGPA. MB samples were positive in 45 cases (58%): 17 GPA, 16 MPA and 12 EGPA. Univariate analysis focussed on GPA and MPA, revealed that the MB yield was higher in females [22/31 (71%) vs 11/27 (41%); P = 0.02] and in anti-MPO patients [25/37 (68%) vs 6/19 (32%) for anti-PR3; P = 0.01]. By multivariate analysis, three factors predicted MB positivity: anti-MPO ANCA [odds ratio (OR) 10.67 (CI 2.09, 81.68)], female sex [OR 5.3 (CI 1.16, 32.35)] and neutrophil count [OR 1.33 (CI 1.07, 1.8)]. MB positivity had no impact on relapse, death or end-stage renal disease-free survival. CONCLUSIONS: MB is a safe and efficient diagnostic tool for AAV. Predictors of MB yield include ANCA type, sex and neutrophil count. MB cannot substitute for kidney biopsy when indicated, but should be considered in other cases.