Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis).

Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH. Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival. Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p = 0.014), central nervous system (51 vs. 34%, p = 0.007), facial/orbit (52 vs. 38%, p = 0.031), lungs (43 vs. 28%, p = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p < 0.001), skin (61 vs. 29%, p < 0.001), and lymph nodes (15 vs. 7%, p = 0.028); the BRAFV600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p < 0.001) or as any line (75 vs. 24%, p < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432). Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAFV600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH. Funding: None.

Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.

Introduction: Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Results: Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). Discussion: This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.

Prognostic value of hypermetabolic bone sarcoidosis observed by 18F-fluorodeoxyglucose positron emission tomography.

OBJECTIVES: Sarcoidosis is a multisystemic granulomatosis diagnosed mainly in young adults.18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) is useful in sarcoidosis cases to search for a biopsiable site or assess disease activity.18F-FDG PET-CT can reveal bone hypermetabolism in sarcoidosis patients, even in the absence of osteoarticular symptoms. The aim of this study was to describe metabolic bone involvement in sarcoidosis patients and to evaluate its prognostic impact. METHODS: This was an observational, comparative, retrospective, monocentric study. Inclusion criteria were a confirmed diagnosis of sarcoidosis according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria and at least one 18F-FDG PET-CT scan during follow-up. Metabolic bone involvement of sarcoidosis was defined as focal bone hypermetabolism with no argument for a differential diagnosis of bone 18F-FDG uptake. Patients with and without bone involvement were compared. RESULTS: Among the 175 included patients, 32 (18%) had metabolic bone involvement of sarcoidosis. The metabolic bone involvement was mainly axial and mostly without bone abnormalities on CT. Metabolic bone involvement was associated with intrathoracic and extrathoracic lymph node involvement and with a higher number of organs involved. Patients with metabolic bone involvement more frequently received corticosteroids, methotrexate and tumor necrosis factor (TNF)-α inhibitors and a higher number of treatments. Relapse of sarcoidosis occurred sooner in patients with metabolic bone involvement. CONCLUSION: These results suggest that metabolic bone involvement is associated with more diffuse and more severe sarcoidosis.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Epidemiology and geographic clustering of Erdheim-Chester disease in Italy and France.

This geoepidemiological study, performed in Italy and France, shows that Erdheim-Chester disease is increasingly diagnosed and cases cluster in specific geographic areas, namely southern Italy and central France. Disease frequency inversely correlates with the Human Development Index.

Sinonasal and ear manifestations of Erdheim-Chester disease.

To calculate the prevalence of sinonasal and ear involvement in an Erdheim-Chester disease (ECD) population, to describe the different ear, nose and throat (ENT) manifestations and to study the association between ENT involvement, other organ involvement, and BRAF mutations. We led a retrospective monocentric study in the national referral center for ECD. One hundred and sixty-two patients with ECD and ENT data were included between January 1, 1980 and December 31, 2020. Ear and nose clinical and radiological findings were noted. We described and studied the prevalence of ENT involvement in ECD population. The association between sinonasal and ear involvement, other organ involvement, and BRAF mutations was calculated. The prevalence of ENT manifestations is around 45%. No clinical rhinologic or otologic signs were specific to ECD. Sinus imaging was abnormal in 70% of cases. A bilateral maxillary sinus frame osteosclerosis was highly specific of ECD. Associations were found between the sinus MRI imaging type and BRAF status, central nervous system involvement, cerebellum involvement and xanthelasma. Sinonasal or ear involvement is frequent in ECD and has specific imaging features for sinuses. Trial registration: #2011-A00447-34.

Identification of natural killer markers associated with fatal outcome in COVID-19 patients.

Introduction: Increasing evidence has shown that coronavirus disease 19 (COVID-19) severity is driven by a dysregulated immunological response. Previous studies have demonstrated that natural killer (NK) cell dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of NK cell markers as a driver of death in the most critically ill patients. Methods: We enrolled 50 non-vaccinated hospitalized patients infected with the initial virus or the alpha variant of SARS-CoV-2 with moderate or severe illness, to evaluate phenotypic and functional features of NK cells. Results: Here, we show that, consistent with previous studies, evolution NK cells from COVID-19 patients are more activated, with the decreased activation of natural cytotoxicity receptors and impaired cytotoxicity and IFN-γ production, in association with disease regardless of the SARS-CoV-2 strain. Fatality was observed in 6 of 17 patients with severe disease; NK cells from all of these patients displayed a peculiar phenotype of an activated memory-like phenotype associated with massive TNF-α production. Discussion: These data suggest that fatal COVID-19 infection is driven by an uncoordinated inflammatory response in part mediated by a specific subset of activated NK cells.

Psychiatric disorders, personality and neuropsychological alterations in Erdheim-Chester disease.

Although neurological manifestations and changes in brain volumes have been described in Erdheim-Chester disease (ECD), it remains unknown whether ECD may be associated with psychiatric symptoms and cognitive dysfunctions. We assessed the presence of psychiatric disorders, changes in temperaments and characters, and neuropsychological performances in 32 ECD patients (mean age = 59) younger than 70, not treated with interferon alpha during the last 6 months, and without other serious illnesses. ECD patients exhibited high level of past depressive disorder (80%) and anxiety disorder, especially agoraphobia (29%). They revealed personality changes, especially with high agreeableness (t = 3.18, p < 0.005) and high conscientiousness (t = 3.81, p < 0.001). Neuropsychological assessments showed impairments in attention (GZ: t = 16.12, p < 0.0001, KL: t = 37.01, p < 0.0001) and episodic memory performances (STIR: t = - 3.01, p = 0.006, LTFR: t = - 2.87, p = 0.008, LTIR: t = - 3.63, p = 0.001). Executive functions, such as flexibility, inhibitory control, were unimpaired. Although it remains to be clarified whether these psychiatric symptoms and cognitive impairments may impact the daily functioning and the quality of life, the present study highlights the need to consider cognitive and emotional states in ECD management.

Cutaneous vasculitis occurring in the setting of systemic lupus erythematosus: a multicentre cohort study.

OBJECTIVES: To describe the clinical and pathological features of biopsy-proven cutaneous vasculitis (CV) associated with SLE, focusing on diagnosis classification and impact on overall SLE activity. METHODS: Retrospective multicentric cohort study including SLE patients with biopsy-proven CV identified by (i) data from pathology departments of three university hospitals and (ii) a national call for cases. SLE was defined according to 1997 revised ACR and/or 2019 ACR/EULAR criteria. CV diagnosis was confirmed histologically and classified by using the dermatological addendum of the Chapel Hill classification. SLE activity and flare severity at the time of CV diagnosis were assessed independently of vasculitis items with the SELENA-SLEDAI and SELENA-SLEDAI Flare Index. RESULTS: Overall, 39 patients were included; 35 (90%) were female. Cutaneous manifestations included mostly palpable purpura (n = 21; 54%) and urticarial lesions (n = 18; 46%); lower limbs were the most common location (n = 33; 85%). Eleven (28%) patients exhibited extracutaneous vasculitis. A higher prevalence of Sjögren's syndrome (51%) was found compared with SLE patients without CV from the French referral centre group (12%, P < 0.0001) and the Swiss SLE Cohort (11%, P < 0.0001). CV was mostly classified as urticarial vasculitis (n = 14, 36%) and cryoglobulinaemia (n = 13, 33%). Only 2 (5%) patients had no other cause than SLE to explain the CV. Sixty-one percent of patients had inactive SLE. CONCLUSION: SLE-related vasculitis seems very rare and other causes of vasculitis should be ruled out before considering this diagnosis. Moreover, in more than half of patients, CV was not associated with another sign of active SLE.

Severe Libman-Sacks endocarditis complicating antiphospholipid syndrome: a retrospective analysis of 23 operated cases.

OBJECTIVE: Data on severe heart valve disease (HVD), including Libman-Sacks endocarditis, associated with SLE and/or APS requiring valvular surgery are scarce. We thus conducted a retrospective study, aimed at describing and clarifying clinical, laboratory, echocardiographic, histopathological and evolutional features of SLE and/or APS patients with severe associated-HVD. METHODS: An observational retrospective multicentric analysis of 23 adults with SLE and/or APS and HVD between 1996 and 2019 and available histopathological report evaluating long-term follow-up. RESULTS: Twenty-three individuals (20 females, median age 37 [range 17-76] years) were included. All had APS (thrombotic in 22, with an arterial phenotype in 15 and with catastrophic APS [CAPS] in six), and 11 (47%) had SLE. Systemic underlying disease had been diagnosed prior to HVD in 12 (52%). In 10 patients (43%), HVD was complicated by cerebral stroke prior to surgery. Twenty patients (87%) had only one pathological valve, the mitral valve in 18 patients (78%). Valvular thickening (n = 19) and valvular regurgitation (n = 19) were the most frequently reported lesions. Fifteen (62%) patients underwent mechanical valve replacement, six (26%) conservative valve repair (five were later re-operated after a median time of 1 [0-4] year), and two (9%) underwent biological valve replacement. Nine patients (39%) presented early-onset post-operative complications, including three CAPS immediately after surgery and one death. After surgery, 18 patients (78%) had normal postoperative valvular function, but almost half of the patients (43%) had post-operative neurological sequelae (median follow-up of 6 [2-20] years). CONCLUSION: Severe HVD leading to surgery was strongly associated with thrombotic APS, especially arterial phenotypes. Half of the reported patients presented cerebral stroke complicating the HVD. Valvular surgery carried a significant risk of CAPS.

Prevalence, patterns and outcomes of cardiac involvement in Erdheim-Chester disease.

AIMS: Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. METHODS AND RESULTS: All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]. CONCLUSION: Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.

Clinical phenotypes and long-term outcome of kidney involvement in Erdheim-Chester histiocytosis.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that frequently infiltrates the peri-kidney space ("hairy kidney" appearance), kidney pelvis and proximal ureters, leading to obstructive uropathy. Here, we analyzed the clinical characteristics, imaging findings and long-term kidney outcome of a large multicenter cohort comprising 195 consecutive patients with ECD. Retroperitoneal peri-kidney or peri-ureteral involvement was detected at diagnosis in 147 patients. Of them, 70 had hydronephrosis (bilateral in 47), and 16 with kidney atrophy (unilateral in 14). Kidney vascular peduncle infiltration was found in 60 patients, and kidney artery stenosis in 31. The estimated glomerular filtration rate (eGFR) at diagnosis was significantly lower in patients with than in those without peri-kidney involvement (median 74 vs. 98 mL/min/1.73 m2). Ureteral stenting often failed to achieve kidney function recovery. A total of 181 patients received medical therapies: first-line treatments included interferon-α (61%), BRAF-inhibitors (17%), mTOR-inhibitors (7%), or other drugs (15%). These therapies were efficacious for ECD but rarely induced kidney function improvement (one-year eGFR increase over 25% in under 10% of patients). After a median of 43 months, 19% of patients died and 5% developed kidney failure. Among patients with peri-kidney involvement, 44% developed chronic kidney disease (CKD) 3-5 at five years vs. 5% of those without. Unadjusted predictors of advanced CKD and kidney failure/death were age over 50 years, hypertension, BRAFV600E mutation, and baseline eGFR. At multivariable analysis, cardiovascular comorbidities were associated with advanced CKD, and age over 50 years with kidney failure/death. Thus, kidney involvement is common in ECD and can lead to CKD or kidney failure despite effective medical therapies or urological procedures.

Serum vascular endothelial growth factor is associated with cardiovascular involvement and response to therapy in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 [95% confidence interval: 2.39-13.62], P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 [95% confidence interval: 1.34-7.83], P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD.

Cardiac adipose tissue volume assessed by computed tomography is a specific and independent predictor of early mortality and critical illness in COVID-19 in type 2-diabetic patients.

BACKGROUND: Patients with type 2-diabetes mellitus (T2D), are characterized by visceral and ectopic adipose tissue expansion, leading to systemic chronic low-grade inflammation. As visceral adiposity is associated with severe COVID-19 irrespective of obesity, we aimed to evaluate and compare the predictive value for early intensive care or death of three fat depots (cardiac, visceral and subcutaneous) using computed tomography (CT) at admission for COVID-19 in consecutive patients with and without T2D. METHODS: Two hundred and two patients admitted for COVID-19 were retrospectively included between February and June 2020 and distributed in two groups: T2D or non-diabetic controls. Chest CT with cardiac (CATi), visceral (VATi) and subcutaneous adipose tissue (SATi) volume measurements were performed at admission. The primary endpoint was a composite outcome criteria including death or ICU admission at day 21 after admission. Threshold values of adipose tissue components predicting adverse outcome were determined. RESULTS: One hundred and eight controls [median age: 76(IQR:59-83), 61% male, median BMI: 24(22-27)] and ninety-four T2D patients [median age: 70(IQR:61-77), 70% male, median BMI: 27(24-31)], were enrolled in this study. At day 21 after admission, 42 patients (21%) had died from COVID-19, 48 (24%) required intensive care and 112 (55%) were admitted to a conventional care unit (CMU). In T2D, CATi was associated with early death or ICU independently from age, sex, BMI, dyslipidemia, CRP and coronary calcium (CAC). (p = 0.005). Concerning T2D patients, the cut-point for CATi was > 100 mL/m2 with a sensitivity of 0.83 and a specificity of 0.50 (AUC = 0.67, p = 0.004) and an OR of 4.71 for early ICU admission or mortality (p = 0.002) in the fully adjusted model. Other adipose tissues SATi or VATi were not significantly associated with early adverse outcomes. In control patients, age and male sex (OR = 1.03, p = 0.04) were the only predictors of ICU or death. CONCLUSIONS: Cardiac adipose tissue volume measured in CT at admission was independently predictive of early intensive care or death in T2D patients with COVID-19 but not in non-diabetics. Such automated CT measurement could be used in routine in diabetic patients presenting with moderate to severe COVID-19 illness to optimize individual management and prevent critical evolution.

Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases).

OBJECTIVES: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases. METHODS: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019. RESULTS: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued. CONCLUSION: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.

Vasculitis and familial Mediterranean fever: Description of 22 French adults from the juvenile inflammatory rheumatism cohort.

Objective: The frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases. Methods: Patients with vasculitis were selected from patients followed for FMF in the French JIR-cohort. Results: Twenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications. Conclusion: This study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.

Abdominal Extrarenal Involvement in Erdheim-Chester Disease in a Cohort of 304 Patients.

This cohort study estimates the prevalence of nonretroperitoneal abdominal organ involvement in Erdheim-Chester disease in a large cohort of patients.

Fatigue is independently associated with disease activity assessed using the Physician Global Assessment but not the SLEDAI in patients with systemic lupus erythematosus.

OBJECTIVES: To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA). METHODS: Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0-3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA. RESULTS: A total of 350 patients (89% female; median age: 42 years, IQR: 34-52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2-6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models. CONCLUSION: Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.