Hematologic Involvement Research Articles

Presentation of a case with fever, lymphadenopathy and thrombocytopenia: a case report

The three primary differential diagnoses for a patient with systemic and hematological involvements (fever, lymphadenopathy, and hepatosplenomegaly), skin rashes, and sore pharynx are infections, connective tissue diseases, and malignancies. In this case report, we discuss possible illusory similarities between these categories that can aid in the diagnostic workup of primary care physicians. Practical Implications. The clinical course of (Infections mononncleosis, MI) patients with and their histopathological data rarely differ; Therefore, early testing for IM caused by EBV is recommended. This article will help physicians face similar cases

Diagnostic Value of Labial Minor Salivary Gland Biopsy: Histological Findings of a Large Sicca Cohort and Clinical Associations.

(1) Background: The aim of this study was to analyze labial minor salivary gland biopsy (MSGB) findings of a large sicca cohort and to examine their associations with Sjogren's syndrome (SS)-associated laboratory markers, phenotypic characteristics and systemic manifestations. Moreover, we sought to explore the ability of MSGB to identify SS patients among subjects with pre-diagnosed fibromyalgia (FM). (2) Methods: Included were all patients of three rheumatology departments having undergone a diagnostic MSGB within 9 years. Next to the examination of histological and immunohistochemical findings, we focused on activity and chronicity parameters of the underlying disease, autoantibodies, presence of systemic and hematologic involvement, as well as chronic pain and SS comorbidities. (3) Results: Among the 678 included patients, 306 (45.1%) had a positive focus score (FS). The remaining patients (n = 372) served as control subjects. There were significant correlations between FS and hypergammaglobulinemia (p < 0.001), ANA and rheumatoid factor positivity (both; p < 0.001), a weak significant correlation with erythrocyte sedimentation rate (rho = 0.235; p < 0.001) and a negative correlation with nicotine use (p = 0.002). Within the primary SS subgroup, FS was associated significantly with glandular enlargement (p = 0.007) and systemic hematologic manifestations (p = 0.002). Next to FS, CD20 cell staining showed an excellent diagnostic performance in the diagnosis of SS by an area under the curve of 0.822 (95%CI 0.780-0.864; p < 0.001). Interestingly, 42.1% of all patients with fibromyalgia (FM) having received an MSGB could be diagnosed with SS. (4) Conclusion: By examining one of the largest cohorts in the literature, we could show that MSGB histological and immunohistochemical findings not only play a key role in the classification and diagnosis of SS but could also provide important information regarding SS phenotype and systemic manifestations. Furthermore, MSGB may help differentiate patients with FM from patients with subclinical SS who suffer primarily from chronic pain.

Fragility fractures in lupus patients: Associated factors and comparison of four fracture risk assessment tools.

Osteoporosis (OP) and fragility fractures (FF) are common comorbidities in patients with systemic lupus erythematosus (SLE). This study aimed to (1) assess the prevalence of these conditions in a cohort of SLE patients (2) evaluate the risk factors associated with FF, and (3) compare the accuracy of four different FF risk assessment algorithms to determine which performs better in this specific rheumatologic population. We conducted a cross-sectional study with SLE women who underwent bone mineral density assessment by dual-energy X-ray absorptiometry (DEXA) within 3months of their last visit. Conventional radiology methods were used to evaluate the presence of FF. The 10-year risk of osteoporotic fractures was estimated using four tools: DeFRA, FRAX (adjusted for GC dosage), GARVAN, and QFracture. The comparison of these computational tools was analyzed by the area under the receiver operating characteristic (ROC) curves. We analyzed 86 SLE patients with a median age of 56years (IQR 12.1) and a median age at diagnosis of 34years (IQR 17.2). The median T-score values at the femoral neck and lumbar spine were -1.6 (IQR 0.9) and -1.7 (IQR 1.1), respectively. Of the patients, 33 (38.4%) had OP, with 13 patients (15.1%) experiencing FF. Univariate analysis showed that the presence of FF was associated with thrombocytopenia (p = .01), hemolytic anemia (p = .0001), and the intake of cyclosporine A (p = .002), cyclophosphamide (p = .006), and rituximab (p = .001). The median 10-year risk of major FF for the four calculation tools were as follows: DeFRA 9.85 (IQR 8.6); FRAX GC 8.8 (IQR11.7); GARVAN 12 (IQR 8.2); QFracture 4.1 (IQR 5.8). We observed a significant correlation among all instruments evaluated (p < .0001); in particular, the best correlation was recorded between the FRAX GC and the DeFRA (r = 0.85). DeFRA was the best tool for this population with an AUC of 0.94 (p < .0001, CI 0.88-1). OP is a common comorbidity in SLE patients, even in younger patients. FF appears to be more frequent in patients with hematologic involvement. The comparison of the four algorithms shows that DeFRA is the most accurate tool and should be applied to SLE patients.

VEXAS syndrome: Current clinical, diagnostic and treatment approaches.

VEXAS syndrome, is a hemato-inflammatory chronic disease characterized with predominantly rheumatic and hematologic systemic involvement. It was first described in 2020 by a group of researchers in the United States. VEXAS syndrome is a rare condition that primarily affects adult males and is caused by a mutation in the UBA1 gene located on the X chromosome. Its pathogenesis is related to the somatic mutation affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. Mutant gene lead to decreased ubiquitination and activated innate immune pathways and systemic inflammation occur. The specific mechanism by which the UBA1 mutation leads to the clinical features of VEXAS syndrome is not yet fully understood. VEXAS is a newly define adult-onset inflammatory syndrome manifested with treatment-refractory fevers, arthritis, chondritis, vasculitis, cytopenias, typical vacuoles in hematopetic precursor cells, neutrophilic cutaneous and pulmonary inflammation. Diagnosing VEXAS syndrome can be challenging due to its rarity and the overlap of symptoms with other inflammatory conditions. Genetic testing to identify the UBA1 gene mutation is essential for definitive diagnosis. Currently, there is no known cure for VEXAS syndrome, and treatment mainly focuses on managing the symptoms. This may involve the use of anti-inflammatory medications, immunosuppressive drugs, and supportive therapies tailored to the individual patient's needs. Due to the recent discovery of VEXAS syndrome, ongoing research is being conducted to better understand its pathogenesis, clinical features, and potential treatment options. In this review article, the clinical, diagnostic and treatment approaches of VEXAS syndrome were evaluated in the light of the latest literature data.

Characteristics and treatment responses of immune thrombocytopenia in patients with primary Sjögren syndrome

ObjectiveThis study aims to describe patients' characteristics and treatment responses with primary Sjögren's syndrome (pSS) who experience immune thrombocytopenia (ITP) and ITP with clinical significance (ITPCS). MethodsA retrospective study was conducted involving 164 patients diagnosed with pSS-related ITP after excluding secondary ITP. Patients were categorized into subgroups based on the risk of bleeding: major bleeding event (MBG), non-hemorrhagic group (NHG), and hematological involvement-only SS group (HOSG). Results57 (34.8%) were diagnosed with ITP simultaneously with pSS, while 60 (36.6%) were diagnosed with ITP before pSS. ITP patients exhibited a high prevalence of interstitial lung disease (19.5%), and an up to 96.3% positive presence of anti-SSA/Ro-52 antibody. ITPCS was identified in 58.5% of patients, with 22.0% experiencing high-risk hemorrhagic events. A median (range) of 2 (1, 3) treatment lines for maintenance therapies were administered. Corticosteroids and hydroxychloroquine (HCQ) led to an ITP response in 76.1% of patients. Ciclosporin A (CsA) and other medicines contributed to a 76.6% response. The MBG, NHG, and HOSG groups consisted of 36 (22.0%), 68 (41.5%) and 53 (32.3%) patients, respectively. Notably, patients of MBG were more frequently diagnosed before SS onset (p = 0.035). They required more treatment lines (p = 0.001) with a lower risk of relapse (p < 0.001), which is confirmed in patients with only hematological involvement (HOSG group). ConclusionPatients with pSS-related ITP face an increased risk of bleeding, particularly in the MBG group, which necessitates more extensive treatment. Heterogeneous treatment regimens were observed for pSS-related ITP, and combinations involving corticosteroids, HCQ, and/or CsA appear viable options.

Predictive Factors of the Use of Rituximab and Belimumab in Spanish Lupus Patients.

Objectives: To analyze the characteristics and the predictive factors of the use of rituximab and belimumab in daily practice in patients from the inception cohort Registro Español de Lupus (RELES). Material and methods: The study included 518 patients. We considered patients treated with biologics who received at least one dose of rituximab or belimumab, and possible indications of those manifestations registered at the same time or in the previous 2 months of the start of the therapy. Results: In our cohort, 37 (7%) patients received at least one biological treatment. Rituximab was prescribed in 26 patients and belimumab in 11. Rituximab was mainly prescribed for hemolytic anemia or thrombocytopenia (11 patients, 42%), lupus nephritis and neuropsychiatric lupus (5 patients each, 19%). Belimumab was mostly used for arthritis (8 patients, 73%). In the univariate analysis, the predictive factors at diagnosis for the use of biologic therapy were younger age (p = 0.022), a higher SLEDAI (p = 0.001) and the presence of psychosis (p = 0.011), organic mental syndrome (SOCA) (p = 0.006), hemolytic anemia (p = 0.001), or thrombocytopenia (p = 0.01). In the multivariant model, only younger age, psychosis, and hemolytic anemia were independent predictors of the use of biologics. Conclusions: Rituximab is usually given to patients with hematological, neuropsychiatric and renal involvement and belimumab for arthritis. Psychosis, hemolytic anemia and age at the diagnosis of lupus were independent predictive factors of the use of biological agents. Their global effects are beneficial, with a significant reduction in SLE activity and a low rate of side effects.

A neonatal lupus syndrome with pericardial tamponade due to maternal Sjögren’s syndrome

Neonatal lupus syndrome (NLS) is a rare disease with dermatological, cardiac, hepatic and hematologic involvement due to placental transfer of anti-Ro/ SSA and anti-La/ SSB antibodies in infants of mothers with autoimmune diseases. Multisystemic involvement is common in infants. Here we present a baby with neonatal lupus syndrome whose mother had Sjögren's syndrome. He presented with thrombocytopenia, then convulsion and cardiac arrest due to pericardial tamponade. So, the risk of NLS should be kept in mind in infants of mothers with autoimmune diseases.

Multiple autoimmune syndrome: Clinical, immunological and genotypic characterization

IntroductionThe existence of subphenotypes common to several autoimmune diseases (AIDs) suggests a shared physiopathology - autoimmune tautology. Multiple Autoimmune Syndrome (MAS) - the coexistence of three or more AIDs in one person-, best illustrates that polyautoimmunity is more than a coincidence. ObjectivesCharacterize and compare the monoautoimmune and MAS patients. Understand if clustering of AIDs leads to differences in disease severity, autoantibodies expression or genetic polymorphisms that could be markers for polyautoimmunity. MethodsCurrently adult patients were selected from unit cohort. MAS was assumed when ≥3 AIDs were present. 343 patients were included after exclusion criteria: having two AIDs or undetermined diagnosis. Clinical and immunological data were collected from medical files. HLA-DRB1 was genotyped by PCR-SSP methodology and PTPN22(rs2476601) polymorphisms by TaqMan Real Time PCR. Data were analysed using Chi-Square, Fisher's exact tests and logistic regression. Odds ratios (OR) and 95% confidence intervals were calculated. ResultsIn comparison with control population: Elevated frequenciesHLA-DRB1*03 in study cohort (OR=3.68,p<0.001) and in monoautoimmune SLE (OR=2.79,p<0.001) and SjS (OR=8.27,p<0.001); HLA-DRB1*15 in monoautoimmune SjS (OR=2.39,p = 0.011); HLA-DRB1*16 in MAS SLE (OR=2.67,p = 0.031); PTPN22_T in all groups except monoautoimmune SjS and triple positive systemic MAS. Diminished frequenciesHLA-DRB1*11 in study cohort (OR=0.57,p = 0.013), in MAS SLE (OR=0.39,p = 0.031) and monoautoimmune SjS (OR=0.10,p = 0.005); HLA-DRB1*13 in study cohort (OR=0.52,p = 0.001) and in monoautoimmune SLE (OR=0.53,p = 0.009) and SjS (OR=0.38,p = 0.031); HLA-DRB1*14 in study cohort (OR=0.32,p = 0.013) and monoautoimmune SLE (OR=0.21,p = 0.021); SLE group: HLA-DRB1*07 frequency was higher in monoautoimmune patients (OR=0.43,p = 0.023). MAS patients had significantly more NPSLE (OR=2.99,p<0.001), subacute cutaneous lesions (OR=2.30,p = 0.037), muscle&tendon (OR=2.00,p = 0.045), and haematological (OR=3.18,p = 0.006) involvement and Raynaud's (OR=2.94,p<0.001). SjS group: MAS patients had more frequently cryoglobulins (OR=2.96,p = 0.030), low complement (OR=2.43,p = 0.030) and Raynaud's (OR=4.38,p<0.001); monoautoimmune patients had more parotid enlargement (OR=0.12,p<0.001). APS group: MAS patients had more non-thrombotic manifestations (OR=4.69,p = 0.020) and Raynaud's (OR=9.12,p<0.001). Triple positive systemic MAS (SLE+SjS+APS) had more frequently severe kidney involvement (OR=11.67,p = 0.021) and CNS thrombosis (OR=4.44,p = 0.009). Anti-U1RNP increased frequency was transversally attributable to MAS. ConclusionsThe coexistence of AIDs contributes to a more severe disease course. We confirmed previously established genetic risk and protection factors and suggest a new protective one - HLA-DRB1*14. HLA-DRB1*07 and anti-U1RNP could be markers for mono and polyautoimmunity, respectively; HLA-DRB1*13 could be a predictor for vascular risk in patients with multiple AIDs. PTPN22(rs2476601) polymorphism could be associated with less severe disease.

Small vessel vasculitis: a rare case report

Small-vessel vasculitis is a rare immunological disease that affects arterioles, capillaries and venules. A 1-year-6-month-old male of non-consanguineous marriage came to the OPD with his mother with a complaint of swelling over bilateral legs for 3 days and rash over his body for 1 day. The swelling was increasing and gradually ascending upward. Systemic examination revealed S1, S2 +, and no murmur in CVS. Soft, NT, liver, spleen not palpable. The patient was admitted and routine investigations were sent. The case reported above had clinical spectrum with skin involvement as palpable purpura, nervous system involvement as peripheral neuropathy and proximal myopathy and hematological involvement, gastrointestinal involvement as vague abdominal pain.

Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus.

The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value.

Clinical and immune-related manifestations in patients with COVID-19

In late 2019 a previously unknown infection affected many people in China. The disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as coronavirus disease 2019 (COVID-19). In a very short period of time, the virus spread worldwide, so on March 11, 2020, the World Health Organization (WHO) declared a pandemic. Various studies have focused on the risk factors and pathogenesis of the virus and have distinguished different phases of the disease (viremic, hyperinflammatory phase and phase of complications) characterized by a wide range of clinical manifestations. Most patients experience mild flu-like symptoms, but severe disease and even death are possible. The main clinical manifestations are of the respiratory system with lung involvement. Damage caused by COVID-19 is observed in various organs and systems (nervous, endocrine, cardiovascular, excretory system, gastrointestinal tract, liver, immune system, eyes, etc.). In some patients, some of the symptoms may persist for weeks or months after the onset of infection (so-called "long COVID", "post-acute COVID-19" and "post-COVID syndrome (PCS)"). Antiphospholipid syndrome, systemic vasculitis, myositis, arthritis, systemic lupus, skin manifestations, hematological involvement, neurological involvement (Guillain-Barre syndrome, transverse myelitis, etc.), optic neuritis, cardiovascular involvement, acute pancreatitis, glomerulonephritis, thyroiditis, anterior uveitis, conjunctivitis, etc. stand out among them. Unfortunately, children are hit hard by COVID-19. In them, the viral load of SARS-CoV-2 is greater than in adults. More than 700 cases of a unique multisystem inflammatory syndrome in children (MIS-C) characterized by clinical and laboratory manifestations similar to Kawasaki disease and toxic shock syndrome have been described. The disease is severe - about 73% require intensive care, and the overall mortality is about 1.7%. Clinical criteria, laboratory parameters, analysis of blood oxygen saturation, imaging studies and RT-PCR (diagnostic gold standard) are used for the diagnosis of COVID-19. In patients with COVID-19, an individualized therapeutic approach is required. Since the beginning of the pandemic, affected countries have tried to flatten the epidemiological curve and avoid overloading health care systems by imposing specific hygiene measures, limiting social contact, wearing a mask, physical distance, travel restrictions, border closures, national lockdowns and mandatory quarantine for the infected and their contacts. In a short period of time, many highly effective vaccines have been developed, most with mild side effects after administration. Unfortunately, more severe reactions are possible after vaccination, but nevertheless the benefit outweighs the risk. This review aims to present the main clinical manifestations in patients with COVID-19 and the possible complications or post-covid syndromes.

MACROPHAGIC ACTIVATION SYNDROME IN POST KIDNEY TRANSPLANTATION REVEALED BY PERITONITIS: CASE REPORT

Objective: Macrophage activation syndrome is a rare but potentially fatal condition. The diagnosis is often difficult, because the symptoms are not very specific and can mimic those of sepsis, however, its diagnosis is based on the association of clinical and biological, non-specific signs, coupled with cytological or histological research of hemophagocytosis and an exhaustive etiological investigation. Design and method: We report the case of a 40-year-old man with a history of chronic renal failure of undetermined origin, who received a kidney transplant in 2011 from a living related donor. The clinical objective shows signs of dehydration associated with non-fetid diarrhea with the presence of a tense and sensitive abdomen on palpation evoking a surgical abdomen, all evolving in a febrile context; Haematological involvement such as bicytopenia and a positive CMV PCR. Our patient was operated on urgently for peritonitis, after performing peritoneal cleansing, the surgeon took biopsy samples from the various mesenteric lymph nodes. Results: The diagnosis of Macrophage activation syndrome is made in the face of clinical and biological arguments in favor, the histological study of the mesenteric lymph nodes revealing non-Langerhancan lymph node histiocytosis CD 68 + CD 10 evoking a syndrome of macrophage activation and confirmed by the myelogram Conclusions: Much progress remains to be made in the field of SAM in adults, the severity of its prognosis, essentially in a kidney transplant patient, requires an aggressive diagnostic approach and multidisciplinary therapeutic management.

Neurological and endocrinological involvement in neonatal lupus erythematosus: a retrospective study at a tertiary hospital in Eastern China.

Neonatal lupus erythematosus (NLE) is a rare autoimmune disease that causes transient impairment of multi-organ functions and is mainly caused by maternally transmitted antibodies. This study aims to investigate the clinical features of infants with NLE, focusing on the presence of neurological and endocrinological involvement. The clinical data of infants diagnosed with NLE at the Children's Hospital of Soochow University from 2011 to 2022 were collected and retrospectively analyzed. In all, 39 patients with NLE were included, and the most common symptom was rash, followed by hematological, hepatic, cardiac, gastrointestinal, neurological, and endocrine symptoms. Among the 10 patients with neurological impairment, intracranial hemorrhage was the most common, followed by convulsions, hydrocephalus, extracerebral space enlargement, and aseptic meningitis. All patients with neurological impairment were positive for anti-SSA/Ro antibodies. Five of these patients were double positive for anti-SSA/Ro and anti-SSB/La antibodies. All 10 patients had multi-organ system involvement, with hematological involvement being the most common, and three patients had varying degrees of developmental delay at the post-discharge follow-up. Nine patients with endocrine impairment were positive for anti-SSA/Ro antibodies, with pancreatic impairment being the most common. There were four cases of hyperinsulinemia and hypoglycemia, one case of diabetes mellitus with ketoacidosis, two cases of hypothyroidism, one case of hypoadrenocorticism, and one case of lysinuric protein intolerance, all of which were normalized before discharge. All patients with endocrine impairment showed hematological involvement, and some showed feeding intolerance as their first symptom. One patient had abnormal liver function at post-discharge follow-up, and two patients had a rash caused by a severe allergy to milk protein. At our hospital, no significant gender differences were observed in the occurrence of NLE, and a predominance of skin, blood, liver, and heart involvement was observed. Patients with multiple central nervous system injuries and organ involvement are more likely to have growth retardation. Endocrine disorders are transient in NLE patients, and some showed feeding intolerance as the first manifestation. Key Points •A retrospective investigation of the clinical characteristics and prognosis of 39 NLE patients was performed, focusing on the clinical features of patients with neurological and endocrine system involvement to improve clinicians' understanding of this disease.

Study of 43 SLE patients with autoimmune liver cirrhosis: emphasis on clinical features and differences from lupus without cirrhosis.

To investigate the clinical characteristics of systemic lupus erythematosus accompanied by autoimmune liver cirrhosis (SLE-ALC) patients and differences from the non-cirrhosis group. Forty-three patients with SLE-ALC were enrolled in this study from 2653 patients with SLE in Peking University People's Hospital. A descriptive case-control study was performed between SLE-ALC patients and the entry time-matched non-cirrhosis group. Among the 43 SLE-ALC patients, 41 (95.3%) were female. Eight patients (18.6%) were first found to have cirrhosis and then diagnosed with SLE. Eighteen patients (41.9%) had jaundice and 27 (62.8%) had esophageal and gastric varices. The age of SLE-ALC patients was 51.1 ± 17.2 years, which was significantly older than the non-cirrhosis group (P < 0.001). Lung involvement was more common as initial manifestations in SLE-ALC patients during the SLE course (P=0.027). Compared with the non-cirrhosis group, SLE-ALC patients had worse liver function. A significantly higher rate of hematological system involvement (anemia, leucopenia, and thrombocytopenia) and a higher level of immunoglobulins were observed in SLE-ALC patients (P<0.05). Moreover, SLE-ALC patients displayed a lower positive rate of anti-double-stranded DNA and anti-ribosomal P protein (P<0.05). The most common radiologic manifestations are ascitic fluid (72.1%) and splenomegaly (71.4%) in SLE-ALC patients. Six SLE-ALC patients underwent liver biopsy, and interface hepatitis was present in all patients. Cirrhosis is rare in SLE patients but is manifested as a unique pattern of clinical features characterized by late-onset age, lung involvement, high immunoglobulins, and impaired liver function.

Systematic search for the UBA1 mutation in men after a first venous thrombotic episode

VEXAS syndrome (acronym for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an autoinflammatory disease, described in adults in 2020, caused by a somatic mutation of the Ubiquitin like modifier activating enzyme 1 (UBA1) gene located on the X chromosome. VEXAS syndrome is mainly described in men after 50 years of age with a systemic inflammatory disease associated with febrile episodes, but also hematological, pulmonary, cutaneous, vascular, cartilaginous and articular involvement. Thrombotic complications have been reported in approximately 40% of VEXAS patients, with a predominance of venous thromboembolic events (VTE) rather than arterial thromboembolic events. Among the VTEs, deep vein thrombosis (DVT) was more frequent than pulmonary embolism (PE). The pathophysiology of VTE in VEXAS remains unknown. The objective of the study was to determine the frequency of UBA1 mutations in a cohort of men over 50 years of age with a first VTE. Our study included male patients aged > 50 years included in our center between January 2003 and January 2009, as part of the multicenter FARIVE study. The FARIVE case-control study included consecutive patients treated as inpatients or outpatients for a first episode of proximal DVT and/or PE. All patients were sampled for genetic study. In this study, exon 3 of UBA1 was sequenced. A total of 97 patients were included with a median age of 65 years and a median body mass index of 25.5. Of the patient cohort, 49 (50.5%) presented with an unprovoked VTE. Thrombophilia testing was available for 56 (57.7%) of the 97 patients and no severe thrombophilia was diagnosed among the patients tested. In the end, no UBA1 mutations were detected among the 97 patients (Table 1). VEXAS syndrome is associated with a high incidence of VTE but our study does not encourage its investigation in all men over 50 years of age with a first VTE without considering other clinical symptoms related to VEXAS. Routine screening for UBA1 exon 3 mutations should not be recommended after a first VTE.

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.

Expanding the phenotypic landscape of Gaucher disease type 3c with a novel entity - Transient neonatal cholestasis

Gaucher disease (GD) is the most frequent lysosomal storage disorder due to biallelic pathogenic variants in GBA gene. Only homozygous D409H variant has been associated with the cardiovascular phenotype which is also known as Gaucher disease type 3c. In this descriptive study, we presented phenotypic heterogeneity and a novel clinical finding among 13 patients with GD type 3c. Patients presented with varying degrees of cardiac valve and/or aortic calcifications (84,6%) and corneal opacities (76,9%) in addition to visceral (100%), hematological (92,3%), neurological (92,3%), and skeletal (30%) manifestations. Also, cervical dystonia (38,4%) and psychiatric disorders (46,1%) were not infrequent entities with respect to neurological involvement in GD type 3c. In this report, we highlight transient neonatal cholestasis (38,4%) as a novel finding in GD type 3c. Neonatal cholestasis is a finding associated with Gaucher type 2, but transient neonatal cholestasis has not been reported in GD patients, so far. The clinical features of GD type 3c are highly heterogeneous, from disease severity or age of onset to disease progression. Also, we concluded that phenotypic spectrum may be associated with age at onset of clinical symptoms. As, patients presenting in infancy or childhood had mainly visceral and hematological involvement and patients presenting in adolescence and adulthood had mainly cardiac, neurological involvement, and psychiatric behavioral disorders. Identifying the heterogeneous clinical course of these patients in this fatal disease, may lead a sufficient understanding of the pathophysiology which will enable targeted therapeutic interventions.

Pediatric mixed connective tissue disease versus other overlap syndromes: a retrospective multicenter cohort study.

Pediatric mixed connective tissue disease (MCTD) is a subgroup of overlap syndromes. We aimed to compare the characteristics and outcomes in children with MCTD and other overlap syndromes. All MCTD patients met either Kasukawa or Alarcon-Segovia and Villareal criteria. The patients with other overlap syndromes had the features of ≥ 2 autoimmune rheumatic diseases but did not meet MCTD diagnostic criteria. Thirty MCTD (F/M = 28/2) and thirty (F/M = 29/1) overlap patients were included (disease onset < 18years). The most prominent phenotype at disease onset and the last visit was systemic lupus erythematosus (SLE) in the MCTD group; juvenile idiopathic arthritis and dermatomyositis/polymyositis, respectively, in the overlap group. At the last visit, systemic sclerosis (SSc) phenotype was more frequent among MCTD than overlap patients (60% vs. 33.3%; p = 0.038). The frequency of the predominant SLE phenotype had decreased (60% to 36.7%), while predominant SSc phenotype had increased (13.3% to 33.3%) during follow-up in MCTD patients. Weight loss (36.7% vs. 13.3%), digital ulcers (20% vs. 0), swollen hands (60% vs. 20%), Raynaud phenomenon (86.7% vs. 46.7%), hematologic involvement (70% vs. 26.7%), and anti-Sm positivity (29% vs. 3.3%) were more common, while Gottron papules (16.7% vs. 40%) were less frequent among MCTD than overlap patients (p < 0.05). A higher percentage of overlap patients achieved complete remission than MCTD patients (51.7% vs. 24.1%; p = 0.047). The disease phenotype and outcome differ between pediatric MCTD and other overlap syndromes where MCTD may be regarded as a more severe disease. Analyzing these patients could pave the way for early and effective treatment.

Active congenital toxoplasmosis, an underestimated threat: case report

Congenital toxoplasmosis (CT) is a consequence of vertical transmission of the toxoplasma gondii parasite during gestation. We present a case of premature CT, adolescent mother diagnosed in the second trimester of pregnancy with gestational toxoplasmosis, without treatment. After birth, the patient was admitted to the neonatal intermediate unit, with normal vital signs, on physical examination with mild signs of shortness of breath, splenomegaly approximately 7cm, hepatomegaly 3 cm, generalized micropapular lesions, chest X-ray without alteration and positive IgG and IgM serologies, confirming a severe CT diagnosis due to ocular, cerebral, hematologic and skin involvement; she received pyrimethamine, sulfadiazine, folinic acid and prednisolone. The appearance of these cases of severe component sets off alarms in prioritizing maternal and family education and also human talent at the time of approaching and monitoring the pregnant woman, contributing substantially to the decrease in vertical transmission, and in turn the long-term impact on the newborn and her family.

Patient with Systemic Lupus Erythematodes, high pANCA antibodies and end-stage renal failure

A 47-year-old female patient with active Systemic lupus erythematosus (SLE) - skin, joint, hematological, and renal involvement was admitted for rapidly progressive renal failure at the background of very high anti-dsDNA and pANCA antibodies. Active pathogenetic treatment was started pulse therapy with methylprednisolone, intravenous immunoglobulins (IVIG) and cyclophosphamide, blood transfusions were performed, symptomatic treatment with infusions ad diuretic was initiated. Due to progression of renal failure with volume overload and increase in urea and creatinine levels renal-replacement therapy was initiated. The patient developed E. faecalis and E. durans sepsis with disseminated intravascular coagulation and ground-glass-type lung changes and the condition further deteriorated to fatal multiorgan failure. The authors discuss the role of pANCA antibodies in SLE with renal and lung involvement.