Recurrent (or episodic) fever of unknown origin (FUO) as a variant subgroup of classical FUO: A French multicentre retrospective study of 170 patients.

BACKGROUND: Recurrent FUO (fever of unknown origin) is a rare subtype of FUO for which diagnostic procedures are ill-defined and outcome data are lacking. METHODS: We performed a retrospective multicentre study of patients with recurrent FUO between 1995 and 2018. By multivariate analysis, we identified epidemiological, clinical and prognostic variables independently associated with final diagnosis and mortality. RESULTS: Of 170 patients, 74 (44%) had a final diagnosis. Being ≥ 65 years of age (OR = 5.2; p < 0.001), contributory history (OR = 10.4; p < 0.001), and abnormal clinical examination (OR = 4.0; p = 0.015) independently increased the likelihood of reaching a diagnosis, whereas lymph node and/or spleen enlargement decreased it (OR = 0.2; p = 0.004). The overall prognosis was good; 58% of patients recovered (70% of those with a diagnosis). Twelve (7%) patients died; patients without a diagnosis had a fatality rate of 2%. Being ≥ 65 years of age (OR = 41.3; p < 0.001) and presence of skin signs (OR = 9.5; p = 0.005) significantly increased the risk of death. CONCLUSION: This study extends the known yield of recurrent FUO and highlights the importance of repeated complete clinical examinations to discover potential diagnostic clues during follow-up. Moreover, their overall prognosis is excellent.

Cyclophosphamide vs rituximab for eradicating inhibitors in acquired hemophilia A: A randomized trial in 108 patients.

BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. METHODS: CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5-2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. RESULTS: Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL-1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). CONCLUSION: Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. FUNDING: French Ministry of Health. CLINICALTRIALS: gov number: NCT01808911.

French practical guidelines for the diagnosis and management of relapsing polychondritis.

Relapsing polychondritis is a rare systemic disease. It usually begins in middle-aged individuals. This diagnosis is mainly suggested in the presence of chondritis, i.e. inflammatory flares on the cartilage, in particular of the ears, nose or respiratory tract, and more rarely in the presence of other manifestations. The formal diagnosis of relapsing polychondritis cannot be established with certainty before the onset of chondritis, which can sometimes occur several years after the first signs. No laboratory test is specific of relapsing polychondritis, the diagnosis is usually based on clinical evidence and the elimination of differential diagnoses. Relapsing polychondritis is a long-lasting and often unpredictable disease, evolving in the form of relapses interspersed with periods of remission that can be very prolonged. Its management is not codified and depends on the nature of the patient's symptoms and association or not with myelodysplasia/vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS). Some minor forms can be treated with non-steroidal anti-inflammatory drugs, or a short course of corticosteroids with possibly a background treatment of colchicine. However, the treatment strategy is often based on the lowest possible dosage of corticosteroids combined with background treatment with conventional immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil, rarely cyclophosphamide) or targeted therapies. Specific strategies are required if relapsing polychondritis is associated with myelodysplasia/VEXAS. Forms limited to the cartilage of the nose or ears have a good prognosis. Involvement of the cartilage of the respiratory tract, cardiovascular involvement, and association with myelodysplasia/VEXAS (more frequent in men over 50years of age) are detrimental to the prognosis of the disease.

[Castleman-like presentation of systemic lupus: About a case report]. / Présentation « Castleman-like ¼ de lupus systémique : à propos d'un cas.

INTRODUCTION: Castleman disease is a rare lymphoproliferation, which may mimic systemic lupus. Conversely, systemic lupus sometimes presents like an hematological malignancy. In these cases, a "Castleman-like" histology has been exceptionally described. OBSERVATION: A 55-year-old female treated by methotrexate for systemic lupus with skin and joint involvement presented weight loss, polyadenopathy and clinical signs of lupus flare. Biology showed pancytopenia, complement activation, and positive anti-DNA antibodies. PET/CT showed hypermetabolic polyadenopathy. The lymph node biopsy showed "Castleman-like" features. Treatment with corticosteroids and azathioprine resulted in complete remission. CONCLUSION: Systemic lupus and Castleman disease may share common clinical, biological, and histological features. The presence of specific elements of systemic lupus flare and the remission obtained by low-dose corticosteroids results in considering the diagnosis of Castleman-like systemic lupus and avoiding treatment intensification.

Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

[TAFRO syndrome and cutaneous necrotizing vasculitis]. / Syndrome TAFRO et vascularite nécrosante cutanée : une association inédite.

INTRODUCTION: TAFRO syndrome is a systemic inflammatory syndrome in the spectrum of Castleman's disease, associating thrombocytopenia, anasarca, fever, renal failure and/or reticulin myelofibrosis and organomegaly. Its association with necrotizing cutaneous vasculitis has not yet been reported. CASE REPORT: A 69-year-old woman presented with weight loss, fever, anasarca, organomegaly, lymphadenopathy, anuria and extensive necrotic livedo occurring after acute diarrhea. Biology showed anemia, thrombocytopenia, renal failure, hypergammaglobulinemia, a circulating B-lymphocyte clone, hypoparathyroidism and autoimmune hypothyroidism. The skin biopsy showed small vessel vasculitis with fibrinoid necrosis. Methylprednisolone infusions associated with tocilizumab were ineffective and the patient became anuric. Rituximab and plasma exchanges associated to corticosteroids allowed remission for 2 months. Combination of rituximab, cyclophosphamide and dexamethasone resulted in a prolonged remission. CONCLUSION: We report here the first case of severe cutaneous necrotizing vasculitis in a patient suffering from TAFRO syndrome. The possible resistance to tocilizumab should be known.

[Development of sarcoma on a ectopic extramedullary hematopoiesis secondary to hereditary spherocytosis: Case report and literature review]. / Développement d'un sarcome sur foyer ectopique hématopoïétique secondaire à une sphérocytose héréditaire : à propos d'un cas et revue de la littérature.

INTRODUCTION: Extramedullary hematopoiesis is a complication of myeloproliferative neoplasms or of chronic hemolysis. The more frequent localizations are splenic, ganglionic or paraspinal. Rarely, extramedullary hematopoiesis is associated with solid cancer. CASE REPORT: We report an original case of sarcoma located in an extramedullary hematopoiesis mass in a 72-year-old woman suffering from hereditary spherocytosis. An asymptomatic right paravertebral mass was found in 2004; the biopsy confirmed extramedullary hematopoiesis. In 2016, the patient was hospitalized due to paravertebral pain. Computed tomography showed the extension of the right paraspinal mass to pleura and mediastinum as well as vertebral bone lysis. Positron emission tomography showed an intense hypermetabolism. The biopsy showed undifferentiated sarcoma. CONCLUSION: This case report illustrates the risk of neoplastic transformation of extramedullary hematopoiesis, and the need for a biopsy when confronted to atypical aspect.

Candida bloodstream infection in patients with systemic autoimmune diseases.

OBJECTIVES: To describe the epidemiological, clinical and microbiological characteristics and mortality of patients with Candida bloodstream infection and systemic autoimmune diseases. METHODS: We performed a retrospective multicenter study of candidemia in adults with systemic autoimmune diseases between 2010 and 2016. RESULTS: Among 1040 patients with candidemia, 36 (3.5%) had a systemic autoimmune disease. The most common systemic autoimmune disease was rheumatoid arthritis (27.8%). The most common species was Candida albicans (66.7%). Twenty-two (61.1%) patients received a corticosteroid therapy and nine (25%) received an immunosuppressive therapy at the time of candidemia. The mortality rate was 27.8%. CONCLUSIONS: Systemic autoimmune diseases are not common in patients with candidemia. The unadjusted mortality rate was comparable to other candidemia studies in the general population.

[Insufficient influenza vaccination coverage in giant cell arteritis. A French population-based study]. / Couverture vaccinale anti grippale insuffisante dans l'artérite à cellules géantes.

PURPOSE: To evaluate the rate of seasonal influenza vaccination coverage (IVC) in incident giant cell arteritis (GCA) patients compared with controls. METHODS: The vaccination rate was estimated from vaccine dispensation. IVC was compared between GCA and their controls using longitudinal multivariate Poisson regression. RESULTS: During the influenza campaigns from 2005-2006 to 2010-2011, the IVC rates in the GCA group and the control group ranged from 60.8 to 74.7% vs. 56.6 to 70.4%, respectively. Incident GCA influenza vaccination rate was 20% higher than controls (RR=1.20 ; IC 1.09 to 1.32, P<0.001). CONCLUSION: Although suboptimal, IVC in incident GCA was statistically better than controls.

[Febrile myalgia revealing Propionibacterium acnes endocarditis]. / Myalgies fébriles révélant une endocardite infectieuse à Propionibacterium acnes.

INTRODUCTION: Propionibacterium acnes endocarditis is rare and difficult to diagnose. We report a case of Propioniacterium acnes endocarditis revealed by a lower limb fasciitis. CASE REPORT: A 54-year-old patient presented with recurrent febrile myalgia of the lower limbs, that appeared three years after an aortic surgery (aortic valve sparing reimplentation and ascending aortic prosthesis implantation). Computer tomography showed fasciitis of both legs. Positron emission tomography showed 18Fluorodeoxyglucose intake of the aortic prosthesis and in muscles of the lower limbs. Ten days after blood sample drawing, cultures showed the presence of Propionibacterium acnes. The aortic prosthesis was surgically removed, whose culture confirmed infection by Propionibacterium acnes. The diagnosis of infective endocarditis revealed by lower limb emboli was made. Evolution was favorable. CONCLUSION: In patients with vascular prostheses, Propionibacterium acnes infection must be evoked face to an atypical inflammatory process. Very prolonged blood culture incubation is needed to identify the pathogen.

Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: The aim of our study was to assess major cardiovascular event incidence, predictors, and mortality in ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective cohort study of all GPA or MPA, according to Chapel Hill Consensus Conference classification criteria, diagnosed between 1981 and 2015. Major cardiovascular event was defined as acute coronary artery disease, or ischemic stroke, or peripheral vascular disease requiring a revascularization procedure. We calculated the comparative morbidity/mortality figure (CMF) and we used Cox proportional hazards regression models to assess the risk of coronary artery disease, ischemic stroke associated with AAV, after adjusting for covariates. RESULTS: 125 patients, 99 GPA (79,2%) and 26 MPA (20,8%), were followed 88.4 ±â€¯78.3 months. Ischemic stroke incidence was four times higher than in the general population (CMF 4,65; 95% CI 4,06-5,31). Coronary artery disease incidence was four times higher than in the general population (CMF 4,22; 95% CI 1,52-11,68). Smoking habits and history of coronary artery disease were strongly associated with coronary artery disease occurrence (adjusted HR 8.8; 95% CI 2.12-36.56, and adjusted HR 10.3; 95% CI 1.02-104.5, respectively). ENT flare-up was an independent protective factor for coronary artery disease occurrence. We did not identify factors significantly associated with stroke occurrence. The age-adjusted mortality rate was 22.5 per 1000 person-years. Mortality in AAV was 1.5 times higher than in the general population (CMF 1.56; 95% CI 1.34-1.83). CONCLUSION: AAV have a significantly increased risk of mortality, ischemic stroke, and coronary artery disease.

[Postural tachycardia syndrome (PoTS): An up-to-date]. / Le syndrome de tachycardie posturale (PoTS) : une maladie pour l'interniste.

Postural tachycardia syndrome (PoTS) is a multifactorial syndrome defined by an increase in heart rate ≥30bpm, within 10minutes of standing (or during a head up tilt test to at least 60°), in absence of orthostatic hypotension. It is associated with symptoms of cerebral hypoperfusion that are worse when upright and improve in supine position. Patients have an intense fatigue with a high incidence on quality of life. This syndrome can be explained by many pathophysiological mechanisms. It can be associated with Ehlers-Danlos disease and some autoimmune disorders. The treatment is based on nonpharmacological measures and treatment with propranolol, fludrocortisone or midodrine.

[Epidemiology and pharmacoepidemiology of immune thrombocytopenia]. / Épidémiologie et pharmacoépidémiologie du purpura thrombopénique immunologique.

During the last decade, the development of large clinical and population-based cohorts led to new findings in the epidemiology and the pharmacoepidemiology of immune thrombocytopenia (ITP). The incidence is estimated to 3-4 for 105 inhabitants/year, with a slight female predominance and peaks in children and patients after 60 years. The incidence rate is 9 for 105 inhabitants/year in males after 75 years. Variations across ethnic groups are discussed. In France, there is a North-South gradient and a peak of incidence during winter suggesting the role of viruses in ITP pathophysiology. Myelodysplastic syndromes are an emergent cause of secondary ITP. The incidence of intracranial bleeding is about 1% by year and the risk increases with aging. Exposure to splenectomy decreases while rituximab and thrombopoietin receptor agonists (TPO-RA) are the most used second-line drugs for persistent ITP. Mortality is slightly increased in primary ITP as compared with the general population. ITP patients have an increased risk of infection, thrombosis and hemorrhage. Aging, lung diseases, splenectomy, corticosteroids and rituximab are risk factors for infection while influenza and pneumococcal vaccines are associated with a 50% decrease of infection risk. Aging, cardiovascular risk factors, lupus anticoagulant and splenectomy are risk factors for thrombosis. The risk of thrombosis associated with corticosteroids and TPO-RAs must be further investigated.

Infections in non-splenectomized persistent or chronic primary immune thrombocytopenia adults: risk factors and vaccination effect.

Essentials The risk factors for infection in immune thrombocytopenia are not well known. We conducted a national pharmacoepidemiological study. Pulmonary disease, corticosteroids and rituximab were the main risk factors for infections. Pneumococcal and influenza vaccines were protective against infections. SUMMARY: Introduction Risk factors for infection and protective effect of vaccines in immune thrombocytopenia (ITP) patients in the era of rituximab therapy are unknown. Objectives To assess the risk factors for serious and non-serious infections (respectively, SIs and NSIs) in non-splenectomized adults treated for persistent or chronic primary ITP, including the effect of pneumococcal and influenza vaccines. Patients/Methods The population was the 2009-2012 FAITH cohort (n = 1805), which is the cohort of all incident (newly diagnosed) primary ITP adults treated > 3 months in France built into the national health insurance database (SNIIRAM). SIs were hospitalizations with any infection as the primary diagnosis code. NSIs were identified using out-of-hospital antibiotic dispensing. Cox models were performed. Results Incidence rates were 6.3/100 patient-years (95% confidence interval [CI], 5.4-7.4) for SIs (lower respiratory tract in 42.8% of the cases) and 100.5/100 patient-years (95% CI, 95.0-106.3) for NSIs. In multivariate analyses, increasing age and chronic pulmonary disease were associated with both SI and NSI occurrence. The hazard ratios (HRs) for corticosteroids and rituximab were, respectively, 3.83 (95% CI, 2.76-5.31) and 2.60 (95% CI, 1.67-4.03) for SIs and 2.46 (95% CI, 2.19-2.76) and 1.49 (95% CI, 1.28-1.74) for NSIs. Pneumococcal vaccine showed a protective effect for both SIs and NSIs (0.38 [95% CI, 0.20-0.73] and 0.52 [95% CI, 0.43-0.65], respectively), as did influenza vaccine (0.42 [95% CI, 0.27-0.64] and 0.49 [95% CI, 0.41-0.59], respectively). Conclusions Chronic pulmonary disease, corticosteroids and rituximab are the main risk factors for infections, whereas pneumococcal and influenza vaccines are protective against SIs and NSIs.