Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.

NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.

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

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

Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome in the intensive care unit: a case report.

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome is a newly discovered inflammatory disease affecting male subjects, for which few data exist in the literature. Here, we describe the case of a patient with known Sweet's syndrome admitted to the intensive care unit and for whom a vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome was diagnosed, allowing for appropriate treatment and the patient's discharge and recovery. CASE PRESENTATION: A 70-year-old male White patient was hospitalized in the intensive care unit following an intrahospital cardiac arrest. History started a year before with repeated deep vein thrombosis and episodes of skin eruption compatible with Sweet's syndrome. After a course of oral steroids, fever and inflammatory syndrome relapsed with onset of polychondritis, episcleritis along with neurological symptoms and pulmonary infiltrates. Intrahospital hypoxic cardiac arrest happened during patient's new investigations, and he was admitted in a critical state. During the intensive care unit stay, he presented with livedoid skin lesions on both feet. Vasculitis was not proven; however, cryoglobulinemia screening came back positive. Onset of pancytopenia was explored with a myelogram aspirate. It showed signs of dysmyelopoiesis and vacuoles in erythroid and myeloid precursors. Of note, new deep vein thrombosis developed, despite being treated with heparin leading to the diagnosis of heparin-induced thrombocytopenia. The course of symptoms were overlapping multiple entities, and so a multidisciplinary team discussion was implemented. Screening for UBA1-mutation in the blood came back positive, confirming the vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome. Corticosteroids and anti-IL1 infusion were started with satisfactory results supporting patient's discharge from intensive care unit to the internal medicine ward. CONCLUSIONS: Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome should be suspected in male patients presenting with inflammatory symptoms, such as fever, skin eruption, chondritis, venous thromboembolism, and vacuoles in bone marrow precursors. Patients with undiagnosed vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome may present with organ failure requiring hospitalization in intensive care unit, where screening for UBA1 mutation should be performed when medical history is evocative. Multidisciplinary team involvement is highly recommended for patient management, notably to start appropriate immunosuppressive treatments.

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

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

Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review.

Our aim was to describe the main features of amyloid goiter in adults with amyloidosis secondary to familial Mediterranean fever. Therefore, we analyzed cases from a French cohort of familial Mediterranean fever patients with amyloidosis and from literature review. Forty-two cases were identified: 9 from the French cohort and 33 from literature review. Ninety percent of patients were on hemodialysis for renal amyloidosis before the development of goiter. The goiter grew up rapidly in 88% of cases; 75.6% of patients were euthyroid, 58% displayed dyspnea, and 44.8% dysphagia. Various features were seen on ultrasound, from diffuse to multinodular goiter. When it was performed, fine-needle aspiration biopsy almost always revealed amyloidosis. Thirty-one patients underwent thyroidectomy: to manage compressive symptoms (72%) or rule out malignancy (27%). Histology showed mature adipose tissue in 64% of cases and lymphocytic infiltration in 21.4%. In conclusion, amyloid goiter in familial Mediterranean fever preferentially occurs in patients with end stage renal failure. Fine-needle aspiration biopsy seems to be a sensitive exam for diagnosis, but thyroidectomy remains sometimes necessary to rule out malignancy or release compressive symptoms.

Primary varicella-zoster virus infection of the immunocompromised associated with acute pancreatitis and hemophagocytic lymphohistiocytosis: A case report.

RATIONALE: Primary varicella-zoster virus (VZV) infection may be associated with hemophagocytic lymphohistiocytosis (HLH), as well as with acute pancreatitis. However, there is few data concerning the evolution and the optimal treatment of these rare associations. PATIENT CONCERNS: A 57-year-old immunocompromised woman, who was treated for chronic lymphocytic leukemia 3 years prior to admission, was hospitalized with abdominal pain revealing severe acute pancreatitis. The day after admission, a pruritic rash appeared on her face, trunk, and limbs, sparing the palmoplantar regions. At the same time, fever, thrombocytopenia (27 × 109/L), major hyperferritinemia (11,063 µg/mL), hypertriglyceridemia (2.56 mmol/L) and elevated lactate dehydrogenase levels (1441 IU/L) suggested HLH. DIAGNOSIS: The diagnosis of chickenpox (varicella) was established. Primary VZV infection was then confirmed: cutaneous and plasma VZV polymerase chain reactions were positives, VZV serology was negative for IgG. INTERVENTIONS: Treatment with aciclovir was started intravenously after the onset of the rash, for a total of 10 days. A 48-h surveillance in intensive care was carried out. OUTCOMES: Acute pancreatitis and biological abnormalities evolved favorably under aciclovir. Platelet count was normalized 6 days after admission to hospital. LESSONS: A favorable outcome of primary VZV infection associated with severe acute pancreatitis and probable HLH in an immunocompromised patient is possible with aciclovir alone.

Association between familial Mediterranean fever and multiple sclerosis: A case series from the JIR cohort and systematic literature review.

INTRODUCTION: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disorder; and leads to the uncontrolled production of interleukin (IL)-1ß. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system; and its development seems to be partly correlated with IL-1ß levels. It is hypothesized that FMF could be associated with MS. We aim to describe the features of patients displaying both diseases and to investigate the MEFV mutation rate in MS patients. METHODS: Patients with definite MS were retrieved from the cohort of FMF patients in the Reference Center for Rare Auto-inflammatory Diseases and Amyloidosis (CEREMAIA). We also performed a systematic literature review of articles from PubMed that were published from 1990 to 2020. RESULTS: Twenty-four patients were included in the case series: five patients (1.3%) from our cohort of 364 and 19 patients from the literature. The sex ratio was 2:1. The mean age at diagnosis of FMF was 19 years old; and that for MS was 29 years old. Seven studies investigating the MEFV mutation rate in MS patients were included. Three studies found a higher mutation rate in MS patients than in the control group. CONCLUSION: FMF and MS features were comparable to those of patients with unrelated diseases; and MEFV mutation carriage was not positively correlated with MS. However; MS prevalence in FMF patients was higher than was expected in a healthy population. To a lesser extent; FMF prevalence in MS patients was higher than expected in a healthy population and the difference might not be significant. These data suggest that FMF could be associated with MS; and further studies are needed to investigate a potential causal association.