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.

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.

[The current place of non-invasive large-vessel imaging in the diagnosis and follow-up of giant cell arteritis]. / Place actuelle de l'imagerie non invasive des artères de gros calibre dans l'artérite à cellules géantes: du diagnostic au suivi.

Large vessel involvement in giant cell arteritis has long been described, although its right frequency and potential prognostic value have only been highlighted for two decades. Large vessel involvement not only is associated with a high incidence of late aortic aneurysms, but also might cause greater resistance to glucocorticoids and longer treatment duration, as well as worse late cardiovascular outcomes. These data were brought to our attention, thanks to substantial progress recently made in large vessel imaging. This relies on four single, often complementary, approaches of varying availability: colour Doppler ultrasound, contrast-enhanced computed tomography with angiography and, magnetic resonance imaging, which all demonstrate homogeneous circumferential wall thickening and describe structural changes; 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET/CT), which depicts wall inflammation and assesses many vascular territories in the same examination. In addition, integrated head-and-neck PET/CT can accurately and reliably diagnose cranial arteritis. All four procedures exhibit high diagnostic performance for a large vessel arteritis diagnosis so that the choice is left to the physician, depending on local practices and accessibility; the most important is to carry out the chosen modality without delay to avoid false or equivocal results, due to early vascular oedema changes as a result of high dose glucocorticoid treatment. Yet, ultrasound study of the superficial cranial and subclavian/axillary arteries remains a first line assessment aimed at strengthening and expediting the clinical diagnosis as well as raising suspicion of large-vessel involvement. In treated patients, vascular imaging results are poorly correlated with clinical-biological controlled disease so that it is strongly recommended not to renew imaging studies unless a large vessel relapse or complication is suspected. On the other hand, a structural monitoring of aorta following giant cell arteritis is mandatory, but uncertainties remain regarding the best procedural approach, timing of first control and spacing between controls. Individuals at greater risk of developing aortic complication, e.g. those with classic risk factors for aneurysm and/or visualised aortitis, should be monitored more closely.

Concomitant association of giant cell arteritis and malignancy: a multicenter retrospective case-control study.

INTRODUCTION: Some studies suggest that there is an increased risk of malignancies in giant cell arteritis (GCA). We aimed to describe the clinical characteristics and outcomes of GCA patients with concomitant malignancy and compare them to a GCA control group. METHOD: Patients with a diagnosis of GCA and malignancy and with a maximal delay of 12 months between both diagnoses were retrospectively included in this study and compared to a control group of age-matched (3:1) patients from a multicenter cohort of GCA patients. RESULTS: Forty-nine observations were collected (median age 76 years). Malignancies comprised 33 (67%) solid neoplasms and 16 (33%) clonal hematologic disorders. No over-representation of a particular type of malignancy was observed. Diagnosis of GCA and malignancy was synchronous in 7 (14%) patients, while malignancy succeeded GCA in 29 (59%) patients. Malignancy was fortuitously diagnosed based on abnormalities observed in laboratory tests in 26 patients, based on imaging in 14 patients, and based on symptoms or clinical examination in the nine remaining patients. Two patients had a concomitant relapse of both conditions. When compared to the control group, patients with concomitant GCA and malignancy were more frequently male (p < 0.001), with an altered general state (p < 0.001), and polymyalgia rheumatica (p < 0.01). CONCLUSIONS: This study does not indicate an over-representation of any particular type of malignancy in GCA patients. Initial follow-up dictated by vasculitis may have led to an early identification of malignancy. Nevertheless, GCA male patients with an altered general state and polymyalgia rheumatica might more frequently show concomitant malignancies.

[Hemorrhagic syndrome due to a heparin-like anticoagulant in a patient with systemic lupus erythematosus]. / Syndrome hémorragique dû à un anticoagulant héparine-like chez un patient lupique.

INTRODUCTION: In systemic lupus erythematosus, hemostasis disorders are mainly thrombotic, but more rarely hemorrhagic. CASE REPORT: A 25-year-old man presented with a macrophagic activation syndrome revealing a systemic lupus erythematosus, secondarily complicated by a hemorrhagic syndrome ; biological investigations revealed an increase thrombin time and an activated partial thromboplastin time, normalized by protamin neutralization in vitro, thus confirming the presence of a heparin-like anticoagulant. The hemostasis balance normalized after the specific treatment of lupus. CONCLUSION: This rare anomaly of hemostasis balance has been described in blood cancers and solid cancers. This is the first description of a case associated with an autoimmune connective tissue disorder such as lupus. After one year of follow-up, no diagnosis of blood or solid cancer was made.

[Gastroparesis may be the cause of unexplained dyspepsia in patients with primary Sjögren syndrome]. / La gastroparésie peut être à l'origine de symptômes digestifs hauts inexpliqués chez les patients souffrant d'un syndrome de Goujerot-Sjögren.

INTRODUCTION: Upper digestive symptoms may be present in up to 50% of patients with primary Sjögren syndrome (pSS). We report a retrospective cohort of gastroparesis in a population of pSS presenting unexplained dyspepsia. Delayed gastric emptying was defined by a gastric emptying time above 113min or by a retention percentage at 4h more than 10% on scintigraphy. RESULTS: Eleven patients with primary Sjögren syndrome and gastroparesis were included in a retrospective study. Every patients were women of age 48±18y. The average time of gastric emptying was 725,18±704,45min. 64% of patients had abdominal pain or gastric heaviness. A central or peripheral neurologic involvement was described in respectively 9 and 27% of cases. The diagnostic delay of gastroparesis was higher than 24 months. CONCLUSION: In primary Sjögren syndrome, gastroparesis should be suspected in case of unexplained dyspepsia, and a scintigraphy performed to prove the diagnosis. A neurologic involvement could explain gastroparesis, but prospective studies are needed for a better understanding of this disorder.

Management of giant cell arteritis: Recommendations of the French Study Group for Large Vessel Vasculitis (GEFA).

PURPOSE: Management of giant cell arteritis (GCA, Horton's disease) involves many uncertainties. This work was undertaken to establish French recommendations for GCA management. METHODS: Recommendations were developed by a multidisciplinary panel of 33 physicians, members of the French Study Group for Large Vessel Vasculitis (Groupe d'étude français des artérites des gros vaisseaux [GEFA]). The topics to be addressed, selected from proposals by group members, were assigned to subgroups to summarize the available literature and draft recommendations. Following an iterative consensus-seeking process that yielded consensus recommendations, the degree of agreement among panel members was evaluated with a 5-point Likert scale. A recommendation was approved when ≥ 80% of the voters agreed or strongly agreed. RESULTS: The 15 retained topics resulted in 31 consensus recommendations focusing on GCA nomenclature and classification, the role of temporal artery biopsy and medical imaging in the diagnosis, indications and search modalities for involvement of the aorta and its branches, the glucocorticoid regimen to prescribe, treatment of complicated GCA, indications for use of immunosuppressants or targeted biologic therapies, adjunctive treatment measures, and management of relapse and recurrence. CONCLUSIONS: The recommendations, which will be updated regularly, are intended to guide and harmonize the standards of GCA management.

[Adult-onset Still's disease as a manifestation of malignancy: report of a patient with melanoma and literature review]. / Pseudomaladie de Still et néoplasie : une observation de mélanome et revue de la littérature.

INTRODUCTION: A malignancy must be carefully excluded before ruling in the diagnosis of adult onset Still's disease (AOSD). However, an occult or poorly symptomatic malignancy can easily be overlooked. CASE REPORT: We report a 50-year-old female patient who presented with features of adult onset Still's disease (AOSD), in fact heralding a malignant melanoma with fatal outcome since discovered lately, at a metastatic stage. In retrospect, the only significant atypical feature was cholestatic hepatitis, which soon disappeared upon institution of glucocorticoid treatment. The literature review identified 27 additional cases of AOSD-like disease associated with malignancy published since 1980 including solid cancer in 61% of the cases (especially breast and lung) and haematological malignancies in 39% of the cases (especially malignant lymphoma). The interval between OASD-like symptoms and malignancy averaged 8 months, and AOSD most often preceding malignancy. Although idiopathic AOSD and neoplastic AOSD-like disease are often indistinguishable initially, some features could point toward the latter: an onset of AOSD after the age of 40 years, the presence of atypical clinical, biological, or immunological features in less than one third of the cases, and a poor response to NAIDS or systemic glucocorticoids in 61% of the cases. CONCLUSION: Making the differential diagnosis of malignancy-associated AOSD in a timely fashion remains a primary goal, even in the most typical cases and those showing good initial therapeutic response.

[Pathophysiology of giant cell arteritis]. / Physiopathologie de l'artérite à cellules géantes.

Giant cell arteritis is a large-vessel vasculitis affecting all three layers of the arterial wall. Histopathology of this vasculitis consists of an inflammatory infiltrate with CD4(+) T cells, macrophages, multinucleated giant cells, forming granulomas in the media. This infiltrate is associated with a destruction of the arterial wall, a fragmentation of the internal elastic lamina and a vascular remodeling leading to intimal hyperplasia. Recent studies have clarified the role of Th17 cells in the initial phase of the disease, pro-inflammatory cytokines and vascular smooth muscle cells in vascular remodeling. This review aims to update data on giant cell arteritis pathogenesis and to propose clues of investigation for a better understanding of this condition.

[Ocular complications of giant cell arteritis]. / Manifestations ophtalmologiques de la maladie de Horton.

Permanent visual loss (PVL) is the most dreaded complication of giant cell arteritis (GCA). It results from anterior ischemic optic neuropathy or, less commonly, retinal artery occlusion. This complication still occurs in 14 to 20% of patients and is typically devastating and permanent, although it is highly preventable by an early diagnosis of giant cell arteritis and appropriate glucocorticoid treatment. Transient ischemic symptoms such as amaurosis fugax, episodes of blurred vision or diplopia may occur, either heralding visual loss or remaining isolated. In studies, the main predictors of PVL are jaw claudication, amaurosis fugax, lack of systemic "B" symptoms, a modestly increased ESR and a higher haemoglobin level. The evaluation of a GCA patient with PVL includes emergency fundoscopy completed by fluorescein angiography, immediate erythrocyte sedimentation rate, C-reactive protein, and complete blood count. Treatment is extremely urgent mainly because, if left untreated, GCA is associated with visual loss in the fellow eye within days in up to 50% of individuals. Treatment may begin with high-dose intravenous methylprednisolone, followed by oral prednisone administered at 1 mg/kg per day. Daily adjunctive aspirin orally may be added since it has been shown, in retrospective studies, to protect against stroke and visual loss. Although treatment duration of complicated GCA is not codified, an initial PVL deserves close monitoring of patient's systemic symptoms, ESR and CRP to avoid relapses due to a significant risk of late recurrence of visual loss during steroid tapering.

[Acute necrotizing pancreatitis and complete atrioventricular block complicating the course of ascaris infection in an adult patient]. / Pancréatite aiguë nécrosante et bloc auriculo-ventriculaire complet compliquant une ascaridiose de l'adulte.

Ascaris lumbricoides, a large round nematode, which causes human ascariasis, is the most prevalent helminth in the world. Ascariasis is usually asymptomatic but can cause serious complications, with a mortality rate of 5%. We report a 55-year-old woman from Comoros who presented with ascariasis complicated by occult cholangitis, severe acute pancreatitis, and transient complete heart-block. Cardiac damage due to migrating ascaris larvae was the likely explanation of the transient heart-block in this patient, although such a complication had never been described previously.

[Vasculitis assessment with [18F]FDG positron emission tomography]. / Place de la tomographie par émission de positrons (TEP) au [18F]FDG dans l'exploration et la surveillance des vascularites.

[18F]fluorodeoxyglucose positron emission tomography (PET) is a noninvasive metabolic imaging modality that is well-suited to the assessment of activity and extent of large vessel vasculitis. PET imaging has demonstrated its usefulness in diagnosing giant cell arteritis (notably in its silent form), Takayasu's arteritis, and unclassified aortitis. PET imaging could be more effective than magnetic resonance imaging in detecting the earliest stages of vascular wall inflammation. The visual grading of vascular [18F]FDG uptake makes it possible to discriminate arteritis from active atherosclerosis, providing therefore high specificity. High sensitivity can also be achieved provided scanning is performed during active inflammatory phase, preferably before starting corticosteroid treatment. Prospective studies are needed to determine the exact value of PET imaging in assessing other vasculitis subsets, infectious aortitis, and large vessel vasculitis outcome and response to immunosuppressive treatment.

DBH deficiency in an elderly patient: efficacy and safety of chronic droxidopa.

We describe the effects of chronic droxidopa in a patient with Dopamine beta-hydroxylase deficiency diagnosed at the age of 73. Investigations were performed to assess sympathetic activity (MIBG scintigraphy, catecholamines) and cardiovascular droxidopa safety.

Familial aggregation in giant cell arteritis and polymyalgia rheumatica: a comprehensive literature review including 4 new families.

OBJECTIVE: To review personal and published observations of giant cell (temporal) arteritis (GCA) or polymyal-gia rheumatica (PMR) with familial or conjugal aggregation and emphasise on epidemiological, clinical and genetic features of such cases. METHODS: We pooled data obtained from all cases of GCA or PMR with familial aggregation recruited in the department since 1976 and those from reports of familial or conjugal GCA or PMR published in the French-English literature since 1970. RESULTS: During the study period, we diagnosed 460 patients (128 with isolated PMR, 227 with isolated GCA, 105 with PMR/CGA). No conjugal couples were observed in the whole series. No familial cases were identified among PMR patients, whereas the prevalence of familial GCA was 1 in 83 (1 in 250 to 500 expected by chance), as we identified 4 patients (brother-brother, sister with history of affected sister, and daughter with priory affected mother). An additional pair of sisters with TA, recruited several months after diagnosis, is also presented. Pooling data from 85 patients (74 with GCA) including our patients, representing 32 families and 8 conjugal pairs, enabled us to draw the following observations: 1) partial or full agreement in the clinical picture (GCA, PMR, or GCA/PMR) was observed in 96% of the siblings pairs, suggesting a common pathogenic mechanism; 2) five kindred were described in whom at least three members were affected; 3) the lag between manifested diseases in familial or conjugal pairs averaged 5.7 years, with synchronous or close disease occurrence in only 26% of the pairs; 4) 18 of 32 assessed patients (56%) carried the DR4 antigen. CONCLUSION: Our survey on familial aggregation of GCA and PMR accumulated data pointing to a genetic predisposition. However, environmental contagious factors could have trigger synchronous disease onset in up to one-fourth of the cases.

Primary Sjogren's syndrome in men.

OBJECTIVE: To determine whether there were any clinical and biological differences between male and female patients with primary Sjogren's syndrome (pSS) in a large bicentric series of patient. METHODS: We studied 419 consecutive patients (mean age at onset 53.6 years, mean disease outcome 73 months) with pSS according to American-European criteria, attending two different Departments of Internal Medicine in France. The 42 (9%) male patients in this cohort comprised the male group described in this study. RESULTS: Extraglandular manifestations during the course of the disease were present in 37 (89%) of our male patients with pSS. The extraglandular manifestations were similar among the two groups except that the male patients showed a lower frequency of depression or asthaenia (5% vs. 20%, p = 0.014) compared with the females. A significantly greater percentage of women reported lymphopaenia (26% vs. 8%, p = 0.02) and leucopaenia (18% vs. 3%, p = 0.015) at onset, but thrombopaenia was more common in the male patients (21% vs. 6%, p = 0.001). Lymphoma development was slightly more common in the male patients, but with no statistical significance (10% vs. 3%, p = 0.06), and occurred earlier after the SS diagnosis (log rank test p = 0.04). CONCLUSION: Although pSS is typically a disease affecting women, clinicians should be aware that it may be diagnosed in male patients. Except for haematological presentation, we could not find any notable differences in clinical and immunological characteristics between male and female patients with pSS.

Evaluation of at-home phlebotomy for iron overload: feasibility and satisfaction of patients and healthcare workers.

OBJECTIVE: This study aimed to evaluate at-home phlebotomy and the satisfaction of iron-overload patients and healthcare workers with the procedure. METHODS: Forty-two patients underwent at-home phlebotomy between 2003 and 2006. The phlebotomy was performed by the patient's nurse, who was trained by the private healthcare firm that also took charge of the disposal of the blood products. Data concerning these phlebotomies were collected via telephone interviews with all 42 patients, as well as 35 nurses and 40 primary-care physicians. The Limousin Regional Health Observatory processed the data collection. RESULTS: Ninety percent (38/42) of the patients, 80% (28/35) of the nurses and 67% (27/40) of the primary-care physicians responded. For 80% of the patients, phlebotomy volume and frequency were as prescribed. Patients chose home phlebotomy for personal reasons, or because of the limited availability of French Blood Establishment facilities (68%), or in response to being offered it by their hospital physician (32%). For 81.6% of the patients, at-home phlebotomy was more satisfactory than phlebotomy in hospital or at the French Blood Establishment and, for 84%, the constraints required were fully acceptable. The nurses considered that these homecare procedures were within their area of responsibility (100%), but felt that the remuneration was insufficient (65%). Ninety-six percent of the primary-care physicians said they were correctly informed, but only 40% felt that they were truly committed to the procedure. CONCLUSION: At-home phlebotomy is feasible, less costly than institutional phlebotomy and improves patient comfort.

[Multinodular goitre with widespread vasculitis of thyroid arteries revealing temporal giant cell arteritis]. / Goitre multinodulaire et artérite à cellules géantes intrathyroïdienne diffuse révélatrice d'une maladie de Horton.

We describe a 62-year-old woman with slowly growing usual nodular goitre in whom diffuse giant cell arteritis (GCA) of the thyroid arteries was found upon thyroidectomy, revealing otherwise unsuspected biopsy-proven temporal arteritis. To our knowledge, this association had been previously reported in only three instances. In each case, GCA of the thyroid arteries appeared clinically silent, did not produce significant glandular dysfunction, and was uncovered thanks to a planned thyroidectomy for nodular goitre. These observations highlight that thyroid artery involvement by GCA, even widespread, as in our patient, may be overlooked clinically and may produce little or no thyroid dysfunction.