Giant cell arteritis (GCA) is a systemic vasculitis with a direct and indirect increased risk of acute and chronic vascular events, affecting large and medium vessels, and responsible for most of the ...morbidity and mortality of this disease. We aimed in this review to provide an updated synthesis of knowledge regarding cardiovascular events observed in GCA. By definition, GCA patients are over 50 and often over 70 years old, and subsequently also present age-related cardiovascular risk factors. In addition, the systemic and vascular inflammation as well as glucocorticoids (GC) probably contribute to an accelerated atherosclerosis and to vascular changes leading to arterial stenoses and aortic dilations and/or dissections. GCA-related ischemic complications, especially ophthalmologic events, stroke or myocardial infarcts are mostly observed within the first months after the diagnosis, being mainly linked to the vasculitic process. Conversely, aortic complications, including dilations or dissections, generally occur several months or years after the diagnosis, mainly in patients with large-vessel vasculitis. In these patients, other factors such as atherosclerosis, GC-related endothelial damage and vascular wall remodeling/healing probably contribute to the vascular events. GCA management includes the detection and treatment of these previous and newly induced cardiovascular risk factors. Hence, the use of cardiovascular treatments (e.g., aspirin, anticoagulation, statins, anti-hypertensive treatments) should be evaluated individually. Aortic structural changes require regular morphologic evaluations, especially in patients with previous aortitis. The initial or secondary addition of immunosuppressants, especially tocilizumab, an anti-IL-6 receptor antibody, is discussed in patients with GCA-related cardiovascular complications and, more consensually, to limit GC-mediated comorbidities.
Objective
The literature supporting the role of a specific drug in the onset of drug‐induced antineutrophil cytoplasmic antibody–associated vasculitis (AAV) mainly relies on case reports or short ...series and implicates old treatments. The advent of new treatments may have modified the epidemiology of these adverse drug reactions. This study was undertaken to update the list of drugs associated with AAV by using a pharmacovigilance‐based data mining approach.
Methods
We collected data on adverse drug reactions reported using the Medical Dictionary for Regulatory Activities preferred term “anti‐neutrophil cytoplasmic antibody positive vasculitis” up to November 2020 from the World Health Organization pharmacovigilance database (VigiBase). For each retrieved drug, a case–noncase analysis was performed, and disproportionate reporting was calculated by using the information component (IC). A positive IC025 value, which is the lower end of the 95% credibility interval, was considered significant.
Results
A total of 483 deduplicated individual case safety reports of drug‐induced AAV involving 15 drugs with an IC025 >0 were retrieved. Of the individuals with drug‐induced AAV for whom data on sex were available (n = 371), 264 (71.2%) were women. The median age at onset of drug‐induced AAV was 62 years (quartile 1 Q1–Q3 45–72 years), and the median time from the introduction of the suspected drug to the onset of drug‐induced AAV was 9 months (Q1–Q3 1–36 months). Drug‐induced AAV was considered serious in 472 (98.1%), and was fatal in 43 (8.9%), of 481 cases. The drugs associated with the highest disproportionate reporting were hydralazine, propylthiouracil, thiamazole, sofosbuvir, minocycline, carbimazole, mirabegron, and nintedanib.
Conclusion
Our findings strengthen the evidence of an association of AAV with previously suspected drugs, but also identify 3 new drugs that may cause drug‐induced AAV. Particular attention should be given to these drugs by prescribers and in experimental studies.
Recent data suggest the existence of a complement alternative pathway activation in the pathogenesis of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a condition that ...remains poorly understood. This study aims to assess the clinical characteristics and outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with regard to their plasma complement levels at diagnosis. A retrospective monocentric study carried out at Caen University Hospital led to the identification of proteinase-3- or myeloperoxidase-ANCA-positive GPA and MPA patients from January 2000 to June 2016 and from September 2011 to June 2016, respectively. All patients with available C3 and C4 levels at diagnosis were included. Patients were categorized in the hypocomplementemia group if their C3 and/or C4 levels at diagnosis were below the lower limit of the normal range. Among the 76 AAV patients (43 GPA, 33 MPA), 4 (5%) had hypocomplementemia, and the 72 remaining patients exhibited normal plasma complement levels. All 4 hypocomplementemia patients had renal involvement. Hypocomplementemia was followed in 1 patient whose post-treatment complement level normalized within 1 month. Among all clinical and ANCA specificity, including relapse-free survival (p = 0.093), only overall and renal survival rates were significantly lower in the hypocomplementemia group (p = 0.0011 and p<0.001, respectively). Hypocomplementemia with low C3 and/or C4 levels at GPA or MPA diagnosis may be responsible for worse survival and renal prognosis. These results argue for larger and prospective studies to better determine the epidemiology of the disease and to assess complement-targeting therapy in these patients.
A20 haploinsufficiency (HA20) is an autoinflammatory disease caused by heterozygous loss-of-function variations in
, the gene encoding the A20 protein. Diagnosis of HA20 is challenging due to its ...heterogeneous clinical presentation and the lack of pathognomonic symptoms. While the pathogenic effect of
truncating variations is clearly established, that of missense variations is difficult to determine. Herein, we identified a novel
variation, p.(Leu236Pro), located in the A20 ovarian tumor (OTU) domain and demonstrated its pathogenicity. In the patients' primary cells, we observed reduced A20 levels. Protein destabilization was predicted in silico for A20_Leu236Pro and enhanced proteasomal degradation was confirmed in vitro through a flow cytometry-based functional assay. By applying this approach to the study of another missense variant, A20_Leu275Pro, for which no functional characterization has been performed to date, we showed that this variant also undergoes enhanced proteasomal degradation. Moreover, we showed a disrupted ability of A20_Leu236Pro to inhibit the NF-κB pathway and to deubiquitinate its substrate TRAF6. Structural modeling revealed that two residues involved in OTU pathogenic missense variations (i.e. Glu192Lys and Cys243Tyr) establish common interactions with Leu236. Interpretation of newly identified missense variations is challenging, requiring, as illustrated here, functional demonstration of their pathogenicity. Together with functional studies, in silico structure analysis is a valuable approach that allowed us (i) to provide a mechanistic explanation for the haploinsufficiency resulting from missense variations and (ii) to unveil a region within the OTU domain critical for A20 function.
Purpose
The purpose of our study was to assess the concordance of aortic CT angiography (CTA) and FDG-PET/CT in the detection of large-vessel involvement at diagnosis in patients with giant-cell ...arteritis (GCA).
Methods
We created a multicenter cohort of patients with GCA diagnosed between 2010 and 2015, and who underwent both FDG-PET/CT and aortic CTA before or in the first ten days following treatment introduction. Eight vascular segments were studied on each procedure. We calculated concordance between both imaging techniques in a per-patient and a per-segment analysis, using Cohen’s kappa concordance index.
Results
We included 28 patients (21/7 women/men, median age 67 56–82). Nineteen patients had large-vessel involvement on PET/CT and 18 of these patients also presented positive findings on CTA. In a per-segment analysis, a median of 5 1–7 and 3 1–6 vascular territories were involved on positive PET/CT and CTA, respectively (
p
= 0.03). In qualitative analysis, i.e., positivity of the procedure suggesting a large-vessel involvement, the concordance rate between both procedures was 0.85 0.64–1. In quantitative analysis, i.e., per-segment analysis in both procedures, the global concordance rate was 0.64 0.54–0.75. Using FDG-PET/CT as a reference, CTA showed excellent sensitivity (95%) and specificity (100%) in a per-patient analysis. In a per-segment analysis, sensitivity and specificity were 61% and 97.9%, respectively.
Conclusions
CTA and FDG-PET/CT were both able to detect large-vessel involvement in GCA with comparable results in a per-patient analysis. However, PET/CT showed higher performance in a per-segment analysis, especially in the detection of inflammation of the aorta’s branches.
Large-vessel involvement (LVI) in giant cell arteritis (GCA) includes different clinical and imaging patterns that are rarely described separately at diagnosis and whose specific cardiovascular ...outcomes are unknown.
We conducted a nationwide retrospective study and included GCA patients with LVI demonstrated on imaging at diagnosis between 2007 and 2017. We analyzed the prognosis of three different imaging patterns of LVI present at diagnosis, with some of them overlapping but with the first one present in all patients: 1) inflammation of the aorta and/or its branches; 2) dilation of the aorta; and 3) stenosis of the aortic branches. A control group of GCA patients without LVI was constituted.
We included 183 patients with LVI and 105 controls without LVI. Altogether, among the 183 patients who all showed inflammation of the aorta and/or its main branches, concomitant aortic dilation and large-vessel stenosis were observed in 27 (15%) and 55 (30%) patients, respectively. During the follow-up period, new cardiovascular events occurred in 49% and 11% of LVI patients and controls, respectively (p < 0.0001). Inflammation of the aorta and/or its branches (HR: 3.42 2.09–5.83, p < 0.0001) and large-artery stenosis (HR: 2.75 1.80–4.15, p < 0.0001) were independent predictive factors of new cardiovascular events. Conversely, the use of an immunosuppressant besides corticosteroids was a protective factor against new cardiovascular events (HR: 0.44 0.29–0.66, p < 0.0001) and the development of aortic dilation (HR: 0.43 0.23–0.77, p = 0.005).
This study suggests different forms of cardiovascular events according to the initial imaging pattern of LVI.
•Large-vessel involvements include aortitis, aorta dilation and vascular stenoses.•These patterns exhibit different outcomes and prognoses.•More cardiovascular events occur in patients with initial large-vessel involvement.•Large-vessel stenosis was associated with the poorest outcomes.•Immunosuppressants might have a protective impact on new cardiovascular events.
We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. In this controlled, open-label trial, we enrolled adults with ...COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. Between 27.sup.th April and 6.sup.th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.
•Giant-cell arteritis-related aortic dissection occurs earlier in patients with aortitis than in those without.•70% of patients presented Stanford type A aortic dissection.•Half of patients with type ...a dissection had a previous thoracic aorta dilation.•Aortic surgery is the single predictive factor for survival in patients with GCA-related aortic dissection.
To describe characteristics and outcomes of patients with giant cell arteritis (GCA)-related aortic dissection.
We retrospectively included, through a nationwide GCA network, all patients who had an aortic dissection either revealing GCA or occurring during follow-up.
A total of 46 patients were included in this study. Aortic dissection was inaugural and led to GCA diagnosis in 21 patients, whereas it occurred during follow-up in the 25 others, at a median of 53 1–265 months after GCA diagnosis.
Large-vessel vasculitis (LVV) was diagnosed through imaging before or at the time of aortic dissection in 31 (67%) patients. In patients who developed an aortic dissection during follow-up, the aortic event occurred 22 1–143 months post GCA diagnosis in the patients with previous aortitis, whereas it occurred after 72 19–265 months in patients without previously diagnosed aortitis (p = 0.005).
Aortic surgery was performed in 27 (59%) patients and 23 of them survived. A total of 15 (32%) patients died following the aortic dissection, including 11 who were not operated on. In a multivariate analysis, aortic surgery was the single predictor of survival (HR: 4.3; 95% CI: 1.47— 15.7; p = 0.007).
Patients with prior LVV are more prone to develop early aortic dissection and require close monitoring of aortic morphology. One third of patients died from the aortic dissection. Surgery remains the best predictive factor for survival.
Abstract
Objectives
To describe the clinical presentation, treatments and prognosis of gastrointestinal (GI) involvement in adult IgA vasculitis (IgAV).
Methods
Data from 260 adults with IgAV ...included in a French multicentre retrospective survey were analysed. Presentation and outcomes of patients with (GI+) and without (GI-) GI involvement were compared.
Results
One hundred and thirty-seven (53%) patients had GI involvement. Initial manifestations were abdominal pain in 99%, intestinal bleeding in 31%, diarrhoea in 26% and acute surgical abdomen in only 4%. Abdominal imaging revealed thickening of intestinal wall in 61%, and endoscopies revealed abnormalities in 87%, mostly mucosal ulcerations. GI+ vs GI- patients were younger (46 ± 18 vs 54 ± 18 years; P = 0.0004), had more constitutional symptoms (43% vs 23%; P = 0.0005) and joint involvement (72 vs 50%; P = 0.0002), and higher CRP levels (3.7 vs 1.9 mg/dl; P = 0.001). Clinical response and relapse rates were comparable between groups, and all causes mortality (2 vs 4%) and IgAV-related mortality (1% vs 2%) as well. GI-related deaths were due to intestinal perforation and mesenteric ischaemia.
Conclusion
GI involvement is frequent in adult IgAV. GI involvement is frequent in adult IgAV. Mortality is not uncommon but does not seem to be specifically related to GI. Immunosuppressants should not be preferred as first-line therapy for GI+ patients but may be required in case of acute surgical abdomen.
Background & Aims
Secondary to tumour necrosis factor‐alpha induced protein 3 (TNFAIP3) mutations, A20 haploinsufficiency (HA20) is a recently described autoinflammatory disease with clinical ...features similar to those of Behçet's and Crohn's diseases but with a constantly expanding clinical spectrum. Here, we describe HA20 liver involvement in three new patients from the same family.
Methods
We retrospectively assessed clinical, biological and/or histological findings for eight patients over three generations of the same family with heterozygous mutations in the TNFAIP3 gene (c.259C > T, p.Arg87*).
Results
The eight patients exhibited the following: aphthous ulcers (8/8, bipolar in 7), autoimmune features (6/8, including 5 with definitive autoimmune disease diagnoses, ie, type I diabetes, Hashimoto thyroiditis, pernicious anaemia, and/or 5 with antinuclear antibodies ≥320), pustulosis/folliculitis (5/8), abdominal pain (4/8), arthralgia (3/8), enlarged cervical lymph nodes (3/8) and pericarditis (1/8). In addition, three patients (twin sisters and their grandmother aged 23 and 70 years, respectively) exhibited persistent mild hepatic cytolysis associated with splenomegaly (n = 3), hepatomegaly (n = 1) and/or liver atrophy (n = 1) on echography. We could not detect any other causes of chronic liver diseases. Liver biopsies from three patients displayed hepatic fibrosis, hepatocyte injury and/or CD4+/CD8+ T lymphocyte infiltration, and patterns of inflammatory cells and NLRP3 or NF‐κB immunostaining differed from the predominant neutrophil infiltration observed in skin or some digestive tract biopsies.
Conclusions
This study reinforces the dual involvement of innate and adaptive immunity in HA20 according to both acute and chronic injury and the organ involved and widens its clinical spectrum to include chronic hepatic involvement.
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