Frequency and characteristics of severe relapse in giant cell arteritis.

OBJECTIVES: To assess the frequency and characteristics of severe relapse in patients with giant cell arteritis (GCA) in a real-life setting. METHODS: In a monocentric database of 530 patients, we retrospectively analysed patients who experienced at least one relapse and distinguished severe from nonsevere relapses. Severe relapse was defined by the occurrence of an ischaemic event (ophthalmologic, neurologic, digestive, limb ischaemia), the occurrence of an aortic complication (i.e. new or worsening of aortic dilation, aortic dissection), or new or worsening of vascular stenosis. RESULTS: From the cohort of 530 patients, 242 (45.7%) patients experienced relapse at least once, including 13 (2.5% of the cohort) who experienced severe relapse. Among the 464 recorded relapses, 14 (3% of all relapses) were severe. Severe relapse corresponded to the following vascular events: a peripheral limb ischaemia in 6 patients, a visual event in 3 patients (including 2 acute anterior ischaemic anterior neuropathies), an aortic complication in 3 patients, a mesenteric ischaemia in one patient and an ischaemic stroke in one patient.When compared with the 229 patients who experienced nonsevere relapses, severe relapse patients were younger at diagnosis (p= 0.02), more frequently showed limb claudication at baseline (p< 0.0001) and fewer GCA-related cranial signs (p< 0.0001). At diagnosis, more large-vessel vasculitis on imaging (82% vs 36%, p= 0.002) were observed in patients with severe relapse. The death rate did not differ between patients with severe and nonsevere relapses. CONCLUSION: In a real-life setting, relapse affects nearly half of GCA patients, but severe relapse is rare.

Drug-associated acquired hemophilia A: an analysis based on 185 cases from the WHO pharmacovigilance database.

INTRODUCTION: Acquired hemophilia A (AHA) is a rare autoimmune hemorrhagic disease occurring in several underlying conditions. Drug-associated AHA (D-AHA) is poorly addressed nowadays. AIM: This work aims to identify and characterize which drugs are associated with AHA using the WHO global database of reported potential effects of medicinal products (VigiBase). METHODS: First, we realized a disproportionality analysis using the information component (IC) to identify D-AHA in VigiBase. IC compares observed- and expected-values in order to find associations between drugs and adverse drug reactions (ADRs) using disproportionate Bayesian reporting. IC025 is the lower end of a 95% credibility interval for the IC. Then, we collected cases of drugs significantly associated with AHA from July 2004 to November 2021. RESULTS: 14 drugs with IC025 > 0 were identified representing a total of 185 cases. D-AHA occurred more frequently in men (59%) than women (41%). The median (min-max) age at onset was 75 years (8-98). The median [Q1-Q3] time to onset of D-AHA from the start of the suspected drug was 30 days [9.5-73.75] and 10% of cases resulted in a fatality. The drugs associated with the highest IC025 (IC025 > 2) were Clopidogrel, Alemtuzumab, Omalizumab. This study retrieved for the first time three usually used drugs (3/14) that exhibit a significant pharmacovigilance signal for D-AHA. CONCLUSION: This worldwide pharmaco-epidemiologic study updates the list of the drugs associated with AHA. The clinician should be aware of these possible severe ADR, which might require larger epidemiological and pathophysiologic studies.

Tolerance of glucocorticoids in giant cell arteritis: a study of patient-reported adverse events.

OBJECTIVE: To assess patients' self-reported glucocorticoid (GC)-related adverse events (AEs) in a GCA population. METHODS: A questionnaire was sent to the 100 patients most recently diagnosed with GCA in a tertiary centre. This questionnaire included open- and close-ended questions on the disease and GC effects. Eight primary AE areas were analysed: cardiovascular, metabolic, muscle, cognitive and psychologic, bone, cutaneous and hairiness, infective and visual complications. Including derivative subitems from preceding areas, a total of 18 GC-related AEs were analysed separately and according to GC duration. RESULTS: Ninety patients were analysed and 89 (99%) reported at least one GC-related AE [median 6 (range 1-11)]. Cognitive and psychological changes, primarily insomnia (72%), affected 90% of patients. Cutaneous changes and muscle loss affected 70% of patients, with frequent impairment of physical autonomy (P = 0.007) associated with this event. Metabolic issues, especially weight gain (40%) and diabetes mellitus (20%), affected 49% of patients. Conversely, vision troubles and bone fractures were mentioned by 42% and 9% of patients, respectively, and more frequently in patients who received GCs for >18 months (P = 0.01 and P = 0.007, respectively). Cardiovascular changes and infections affected 30% and 26% of patients, respectively. CONCLUSION: This real-life study of GC tolerance assessed using a self-evaluation provides pragmatic and updated data reminding us that GC tolerance remains more noteworthy than ever. This study suggests carefully monitoring GC-related AEs during follow-up and encourages GC-sparing strategies in some patients.

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

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

Steroid-sparing effect of anakinra in giant-cell arteritis: a case series with clinical, biological and iconographic long-term assessments.

OBJECTIVES: The treatment of GCA relies on corticosteroids but is burdened by a high rate of relapses and adverse effects. Anti-IL-6 treatments show a clear benefit with a significant steroid-sparing effect, but late relapses occur after treatment discontinuation. In addition to IL-6, IL-1 also appears to play a significant role in GCA pathophysiology. We report herein the efficacy of anakinra, an IL-1 receptor antagonist, in six GCA patients exhibiting corticosteroid dependence or resistance, specifically analysing the outcome of aortitis in four of them. METHODS: This retrospective study analysed the cases of all GCA patients treated with anakinra from the French Study Group for Large Vessel Vasculitis. RESULTS: After a median duration of anakinra therapy of 19 (18-32) months, all six patients exhibited complete clinical and biological remission. Among the four patients with large-vessel involvement, one had a disappearance of aortitis under anakinra and three showed a decrease in vascular uptake. After a median follow-up of 56 (48-63) months, corticosteroids were discontinued in four patients, and corticosteroid dosage could be decreased to 5 mg/day in two patients. One patient relapsed 13 months after anakinra introduction in the context of increasing the daily anakinra injection interval to every 48 h. Three patients experienced transient injection-site reactions, and one patient had pneumonia. CONCLUSION: In this short series, anakinra appears to be an efficient and safe steroid-sparing agent in refractory GCA, with a possible beneficial effect on large-vessel involvement.

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

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

Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency.

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

Infections and AA amyloidosis: An overview.

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

Second-line and beyond: treatment options for primary persistent and chronic immune thrombocytopenia.

Less than 40% of patients with newly diagnosed adult immune thrombocytopenia will show spontaneous recovery within 12 months. Therefore, second-line treatments are frequently used to maintain a hemostatic platelet count or at best to cure the disease, with as few adverse effects as possible. Nevertheless, we lack head-to-head comparison studies of the different available treatments. Moreover, physicians have no robust predictors of response to guide decision-making on an individual basis. Therefore, there is no consensus, and decisions when to treat and with which drug must be individualized and shared with the patient based on factors related to the patient and the available second-line treatments. The main treatments used, based on their good benefit-risk ratio, are splenectomy, rituximab, and thrombopoietin-receptor agonists, but their prescription should be avoided in some situations and can be limited due to cost or to health authorities' restrictions on funding the last two drugs. This review presents the various second-line treatments used in primary persistent or chronic immune thrombocytopenia in adults and discusses their prescription in general and specific situations.

AA amyloidosis associated with Fabry disease.

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

Specific changes in faecal microbiota are associated with familial Mediterranean fever.

OBJECTIVES: Familial Mediterranean fever (FMF) can be complicated by AA amyloidosis (AAA), though it remains unclear why only some patients develop amyloidosis. We examined the gut microbiota composition and inflammatory markers in patients with FMF complicated or not by AAA. METHODS: We analysed the gut microbiota of 34 patients with FMF without AAA, 7 patients with FMF with AAA, 19 patients with AAA of another origin, and 26 controls using 16S ribosomal RNA gene sequencing with the Illumina MiSeq platform. Associations between bacterial taxa and clinical phenotypes were evaluated using multivariate association with linear models statistical method. Blood levels of interleukin (IL)-1ß, IL-6, tumour necrosis factor-α and adipokines were assessed by ELISA; indoleamine 2,3-dioxygenase (IDO) activity was determined by high-performance liquid chromatography. RESULTS: Compared with healthy subjects, specific changes in faecal microbiota were observed in FMF and AAA groups. Several operational taxonomic units (OTUs) were associated with FMF. Moreover, two OTUs were over-represented in FMF-related AAA compared with FMF without AAA. Additionally, higher adiponectin levels and IDO activity were observed in FMF-related AAA compared with FMF without AAA (p<0.05). CONCLUSION: The presence of specific changes in faecal microbiota in FMF and in FMF-related AAA suggests that intestinal microorganisms may play a role in the pathogenesis of these diseases. These findings may offer an opportunity to use techniques for gut microbiota manipulation.

Clinical impact of subgrouping ANCA-associated vasculitis according to antibody specificity beyond the clinicopathological classification.

OBJECTIVES: In ANCA-associated vasculitis (AAV), classifications have emerged to individualize homogeneous clinical and outcomes patterns, including the recently defined anti-MPO granulomatosis with polyangiitis (GPA) subgroup. This study aimed to retrospectively evaluate the impacts of re-classification based on clinicopathological criteria and/or ANCA specificity. METHODS: A retrospective monocentric study conducted at Caen University Hospital led to the identification of PR3 or MPO-ANCA AAV patients from January 2000 or September 2011, respectively, to June 2016. Eosinophilic GPA patients were excluded. AAVs were thereby also classified either as GPA or microscopic polyangiitis (MPA) according to the European Medicines Agency vasculitis algorithm. RESULTS: A total of 150 AAV patients were included (94 GPA, 56 MPA; 87 anti-PR3 and 63 anti-MPO patients). GPA patients exhibited a worse relapse-free survival but a better renal survival (P < 0.001 and P = 0.021, respectively) than MPA patients. Overall, relapse-free and renal survival rates were similar between anti-PR3 and anti-MPO patients (P = 0.35, 0.17 and 0.15, respectively). Similarly, the prognosis was identical between anti-MPO MPA patients and anti-PR3 MPA patients (P = 0.33, 0.19 and 0.65, respectively), and between anti-MPO GPA patients and anti-PR3 GPA patients (P = 0.06, 0.99 and 0.64, respectively). Moreover, anti-PR3 GPA and anti-MPO GPA patients exhibited no differences in clinical manifestations or BVAS score. CONCLUSION: Clinicopathological classification appeared to be the strongest criterion for distinguishing among homogeneous prognoses of AAV. Individualizing the anti-MPO GPA subgroup does not appear to bring additional value to clinical practice, but multicentre studies are required to confirm this trend.

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

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

Interest of immunodeficiency screening in adult after admission in medical intensive care unit for severe infection, a retrospective and a prospective study: the Intensive Care Unit and Primary and Secondary Immunodeficiency (ICUSPID) study.

BACKGROUND: Primary immunodeficiency (PID) in adults is rare and mostly revealed by infections. MATERIAL AND METHODS: Adults without predisposing factors who were admitted to an intensive care unit (ICU) for infection were screened for PID. RESULTS: Six PID cases were diagnosed, mostly revealed by encapsulated bacterial infections. CONCLUSION: Investigation of PID after ICU discharge should be considered to improve early detection.

Late-onset refractory hemolytic anemia in siblings treated for methionine synthase reductase deficiency: A rare complication possibly prevented by hydroxocobalamin dose escalation?

Methionine synthase reductase deficiency (cblE) is a rare autosomal recessive inborn error of cobalamin metabolism caused by pathogenic variants in the methionine synthase reductase gene (MTRR). Patients usually exhibit early-onset bone marrow failure with pancytopenia including megaloblastic anemia. The latter can remain isolated or patients may present developmental delay and rarely macular dysfunction. Treatment mostly includes parenteral hydroxocobalamin to maximize the residual enzyme function and betaine to increase methionine concentrations and decrease homocysteine accumulation. We report herein 2 cblE siblings diagnosed in the neonatal period with isolated pancytopenia who, despite treatment, exhibited in adulthood hemolytic anemia (LDH >11 000 U/L, undetectable haptoglobin, elevated unconjugated bilirubin) which could finally be successfully treated by hydroxocobalamin dose escalation. There was no obvious trigger apart from a parvovirus B19 infection in one of the patients. This is the first report of such complications in adulthood. The use of LDH for disease monitoring could possibly be an additional useful biomarker to adjust hydroxocobalamin dosage. Bone marrow infection with parvovirus B19 can complicate this genetic disease with erythroblastopenia even in the absence of an immunocompromised status, as in other congenital hemolytic anemias. The observation of novel hemolytic features in this rare disease should raise awareness about specific complications in remethylation disorders and plea for hydroxocobalamin dose escalation.

Evolution and outcomes of aortic dilations in giant cell arteritis.

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