Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus1. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss1. Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial-neuronal interplay that defines a physiologic versus a maladaptive equilibrium.

Workplace- and Residence-Associated Leptospirosis: A Case Report and Review of Current Literature.

Leptospirosis is a zoonotic infection most commonly occurring in tropical regions through contact with water or soil contaminated with animal urine. In New York, approximately one to three cases occur annually, the majority occurring through workplace exposure to animal reservoirs. In cases of the more severe presentation of leptospirosis, Weil's disease, it is important to identify the infection promptly to allow for early antibiotic initiation as well as early initiation of daily dialysis in cases in which it is necessary. We present a case of Weil's disease in a 64-year-old male with presumed exposure through his combined workplace and residential environment. The resolution of symptoms occurred through a combination of hemodialysis, doxycycline, and meropenem antibiotic treatment. We also discuss the barriers to diagnosis, including the non-specific presentation of leptospirosis, the limitation of access to testing centers, and the limitations to antibody testing within the first week of symptom presentation due to low antibody levels.

Budd-Chiari syndrome in Behçet's disease: a retrospective multicenter study.

OBJECTIVE: To compare the clinical features, laboratory findings, and prognosis of Behçet's disease (BD) patients with and without Budd-Chiari syndrome (BCS). METHODS: This multicenter retrospective study investigated 61 (M/F: 41/20) patients with BD, having coexistent BCS, and 169 (M/F:100/69) BD patients as the control group without BCS from 22 different centers of Turkey diagnosed between 1990 and 2017. RESULTS: Of the total 61 BD patients with BCS, the onset of the first symptom and the median age of diagnosis were earlier in contrast to BD patients without BCS (p = 0.005 and p = 0.007). Lower extremity deep vein and inferior vena cava (IVC) thrombosis were more common in patients with BCS (all; p < 0.01) compared to the control group. Mortality was significantly higher in BD-BCS patients with IVC thrombosis than in the controls (p = 0.004). Since most of the cases in our cohort had chronic and silent form of BCS, mortality rate was 14.8%, which was on the lower range of mortality rate reported in literature (14-47%). While all BD-BCS patients received immunosuppressive (IS) agents, only half of them received additional anticoagulant treatments. Among IS agents, interferon treatment was more frequently used in this cohort (19%), compared to other series reported in literature (2.3%). CONCLUSION: To our knowledge, this is the largest series of BD patients with BCS. Our patients had earlier disease onset and diagnosis, higher frequency of IVC thrombosis, and higher mortality rate, compared to BD patients without BCS. Mortality was significantly higher in BD-BCS patients with IVC thrombosis compared to controls. Key Points • Mortality rate is higher in BD-associated BCS patients with IVC involvement. • Chronic and silent form of BD-associated BCS has a better prognosis. • The main treatment options are corticosteroids and immunosuppressive agents, whereas anticoagulant treatment remains controversial.

Tattoo-Associated Sarcoidosis With Severe Uveitis Successfully Treated With Mycophenolate Mofetil: A Report of Two Cases.

Tattooing is an increasing trend among Western countries, with about 18% of the population undergoing the procedure once in their lifetime. The process looks simple; introduce exogenous pigment into the dermis layer of the skin, altering the skin color permanently. However, this simple procedure leads to several health issues and medical complications, both acute and chronic, and some are difficult to cure. Sarcoidosis is high on the list of severity involving almost all body organs. Multiple organ involvement makes this condition more difficult to treat. Lungs and lymphatics are the leading sites of involvement, followed by an inflammatory disease of the eye called uveitis. An additional problem is the limited confirmatory diagnostic tests and treatment options for sarcoidosis. Each patient must be considered unique based on their age, clinical presentation, and severity of involvement. Proper treatment must be tailored for better outcomes with minimum side effects and rapid cure. Here we describe two case reports of tattoo-associated sarcoidosis with severe uveitis successfully treated with mycophenolate mofetil.

Current systematic reviews and meta-analyses of COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has left a significant impact on the world's health, economic and political systems; as of November 20, 2020, more than 57 million people have been infected worldwide, with over 1.3 million deaths. While the global spotlight is currently focused on combating this pandemic through means ranging from finding a treatment among existing therapeutic agents to inventing a vaccine that can aid in halting the further loss of life. AIM: To collect all systematic reviews and meta-analyses published related to COVID-19 to better identify available evidence, highlight gaps in knowledge, and elucidate further meta-analyses and umbrella reviews that are yet to be performed. METHODS: We explored studies based on systematic reviews and meta-analyses with the key-terms, including severe acute respiratory syndrome (SARS), SARS virus, coronavirus disease, COVID-19, and SARS coronavirus-2. The included studies were extracted from Embase, Medline, and Cochrane databases. The publication timeframe of included studies ranged between January 01, 2020, to October 30, 2020. Studies that were published in languages other than English were not considered for this systematic review. The finalized full-text articles are freely accessible in the public domain. RESULTS: Searching Embase, Medline, and Cochrane databases resulted in 1906, 669, and 19 results, respectively, that comprised 2594 studies. 515 duplicates were subsequently removed, leaving 2079 studies. The inclusion criteria were systematic reviews or meta-analyses. 860 results were excluded for being a review article, scope review, rapid review, panel review, or guideline that produced a total of 1219 studies. After screening articles were categorized, the included articles were put into main groups of clinical presentation, epidemiology, screening and diagnosis, severity assessment, special populations, and treatment. Subsequently, there was a second subclassification into the following groups: gastrointestinal, cardiovascular, neurological, stroke, thrombosis, anosmia and dysgeusia, ocular manifestations, nephrology, cutaneous manifestations, D-dimer, lymphocyte, anticoagulation, antivirals, convalescent plasma, immunosuppressants, corticosteroids, hydroxychloroquine, renin-angiotensin-aldosterone system, technology, diabetes mellitus, obesity, pregnancy, children, mental health, smoking, cancer, and transplant. CONCLUSION: Among the included articles, it is clear that further research is needed regarding treatment options and vaccines. With more studies, data will be less heterogeneous, and statistical analysis can be better applied to provide more robust clinical evidence. This study was not designed to give recommendations regarding the management of COVID-19.

Meant to B: B cells as a therapeutic target in systemic lupus erythematosus.

B cells have a prominent role in the pathogenesis of systemic lupus erythematosus (SLE). They are mediators of inflammation through the production of pathogenic antibodies that augment inflammation and cause direct tissue and cell damage. Multiple therapeutic agents targeting B cells have been successfully used in mouse models of SLE; however, these preclinical studies have led to approval of only one new agent to treat patients with SLE: belimumab, a monoclonal antibody targeting B cell-activating factor (BAFF). Integrating the experience acquired from previous clinical trials with the knowledge generated by new studies about mechanisms of B cell contributions to SLE in specific groups of patients is critical to the development of new treatment strategies that will help to improve outcomes in patients with SLE. In particular, a sharper focus on B cell differentiation to plasma cells is warranted.

Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with genetic, hormonal, and environmental influences. In Western Europe and North America, individuals of West African descent have a 3-4 fold greater incidence of SLE than Caucasians. Paradoxically, West Africans in sub-Saharan Africa appear to have a low incidence of SLE, and some studies suggest a milder disease with less nephritis. In this study, we analyzed sera from African American female SLE patients and four other cohorts, one with SLE and others with varying degrees of risk for SLE in order to identify serologic factors that might correlate with risk of or protection against SLE. METHODS: Our cohorts included West African women with previous malaria infection assumed to be protected from development of SLE, clinically unaffected sisters of SLE patients with high risk of developing SLE, healthy African American women with intermediate risk, healthy Caucasian women with low risk of developing SLE, and women with a diagnosis of SLE. We developed a lupus risk index (LRI) based on titers of IgM and IgG anti-double stranded DNA antibodies and levels of C1q. RESULTS: The risk index was highest in SLE patients; second highest in unaffected sisters of SLE patients; third highest in healthy African-American women and lowest in healthy Caucasian women and malaria-exposed West African women. CONCLUSION: This risk index may be useful in early interventions to prevent SLE. In addition, it suggests new therapeutic approaches for the treatment of SLE.

Multicentric reticulohistiocytosis: Rheumatology perspective.

Multicentric reticulohistiocytosis (MRH) is a rare, multisystemic non-Langerhans cell histiocytosis characterized by skin and articular involvement, and rarely involves various other organs. There are no specific laboratory findings for MRH. Diagnosis is based on clinical findings and skin or synovial biopsy results. There is currently no consensus for the treatment of MRH. Here, we review the differential diagnosis and treatment options of MRH from the rheumatologist's perspective. We also report an index case of MRH associated with Sjögren's syndrome and pulmonary embolism.

Microscopic colitis in patients with Takayasu's arteritis: a potential association between the two disease entities.

The association of Takayasu's arteritis (TAK) and inflammatory bowel disease (IBD) has previously been reported in case series. Microscopic colitis (MC) has IBD-like symptoms with regard to clinical and histopathological feature. We aim to assess the presence of MC in TAK patients in this study. We cross-sectionally assessed TAK patients, between the ages of 18-65 years, who were diagnosed according to the American College of Rheumatology (ACR) criteria. Disease activity was evaluated by Kerr's criteria. Age- and sex-matched irritable bowel syndrome (IBS) patients were selected as control group. All patients and controls have been interviewed for IBD and IBS symptoms using the questionnaires of WHO guideline and Rome III criteria, respectively. Lower endoscopic procedure was performed with at least five random biopsies taken from different colonic segments and the terminal ileum. A blinded expert pathologist evaluated the specimens for the features of MC. Thirty TAK patients (29 females and 1 male) with the mean age of 35 ± 11 years (range, 20-59 years) and 15 IBS controls with the mean age of 38 ± 13 years were included in the study. TAK patients all fulfilled the MC criteria (three "complete" and six "incomplete" cases). MC was found to be significantly higher in active TAK patients in comparison to inactive group (67 vs 14 %, p = 0.03, OR = 7.9). Our results show that there is an increased frequency of MC in TAK patients, and this is the first report on the association of TAK and MC.

Factors affecting progression-free survival in non-HIV-related Kaposi sarcoma.

BACKGROUND: Non-HIV related Kaposi sarcoma (NHKS) is a rare indolent neoplasm which is more common around Mediterranean origin. Data concerning factors that influence progression-free survival (PFS) for NHKS are insufficient. The purpose of present retrospective analysis was to distinguish the factors affecting PFS in patients with NHKS. METHODS: A hundred and twenty-eight consecutive patients with NHKS who were treated or observed between 1997 and 2014 at Istanbul University Institute of Oncology were included into the study. Treatment response and progression definitions were determined according to different treatment modalities administered at first line. RESULTS: Majority of patients were male (n = 97, 75.8%). Median age of the whole group was 66 years (28-85). Of the patients, 15 patients were immunosuppressant, whereas 113 patients had no disease that caused immunosuppression. Patients were treated with local excision (n = 57, 44.5%), chemotherapy (n = 32, 25.0%) and/or radiotherapy (n = 13, 10.2%) or observed without treatment (n = 26, 20.3%). At a median follow-up of 28 months, 71 (55.5%) patients had progression, while 3 patients (2.3%) died of NHKS. On univariate analysis, patients who had hypertension (HT) had poorer PFS compared with others (19 ± 12 versus 41 ± 22 months; p = 0.03), whereas plaque formation was associated with better outcome (25 ± 9 versus 54 ± 12 months; p = 0.03). In addition, heavy smoking (≥40 pack-years) had a borderline significance regarding better PFS time (23 ± 24 versus 45 ± 38 months, p = 0.06). On multivariate analysis, none of factors evaluated had any impact on PFS. CONCLUSIONS: HT was correlated with poorer outcome among NHKS patients. Patients with plaque formation and ≥40 pack-years of smoking had better PFS than others.

Cystatin C is better than albuminuria as a predictor of pulse wave velocity in hypertensive patients.

INTRODUCTION: Arterial stiffness is important in the evaluation of the cardiovascular risk in both general population and hypertensive patients. In this study, we aimed to investigate the associations of both serum cystatin C levels and albuminuria with arterial stiffness in healthy controls and hypertensive patients. PATIENTS AND METHODS: Seventy-six healthy controls (male/female = 44/32) and 76 hypertensive patients (male/female = 43/33) were enrolled. Arterial stiffness parameters such as augmentation index (AIx) and pulse wave velocity (PWV) were non-invasively measured with the Arteriograph (Tensiomed Ltd., Budapest, Hungary). RESULTS: AIx (31.92 ± 14.31 vs. 27.95 ± 11.03, p = 0.03) and PWV (9.84 ± 1.62 vs. 8.87 ± 2.04, p < 0.001) were significantly higher in hypertensive patients compared to healthy controls. Patients with microalbuminuria had significantly higher AIx (43.47 ± 9.91 vs. 30.37 ± 14.13, p = 0.002) and higher serum cystatin C levels [0.76 (0.67-0.95) vs. 0.68 (0.62-0.78) mg/L, p = 0.03]. In the hypertensive group, AIx was significantly correlated with PWV (r = 0.519, p < 0.001), glomerular filtration rate (cystatin C) (r = -0.438, p = 0.003), mean arterial pressure (MAP) (r = 0.288, p = 0.015) and urinary albumin-creatinine ratio (ACR) (r = 0.386, p = 0.004). PWV was associated with serum cystatin C (r = 0.442, p = 0.003) and MAP (r = 0.377, p = 0.001). In the linear regression analysis (model r = 0.577, p = 0.006) for the prediction of PWV in hypertensive patients, MAP, urinary ACR, age and serum cystatin C levels were included as independent variables. Cystatin C was found to be the significant determinant of PWV in hypertensive patients. CONCLUSION: Multivariate analysis revealed that serum cystatin C but not albuminuria was significantly associated with PWV in hypertensive patients. Serum cystatin C may be better than albuminuria as a predictor of arterial stiffness in hypertensive patients.

There is an increased risk of atherosclerosis in hereditary angioedema.

BACKGROUND: Hereditary angioedema is associated either with a deficiency in the amount or in the function of the C1 inhibitor (C1 INH). OBJECTIVE: In this study the endothelial function of HAE patients was investigated to evaluate the impact of hereditary C1-INH deficiency on atherosclerosis, which has not yet been established before. METHODS: A total of 26 patients (14 female, 12 male. Mean age: 38±13) diagnosed with HAE and 30 healthy controls were enrolled in the study. Measurement of coronary flow reserve (CFR) in the left anterior descending coronary artery was performed using transthoracic doppler harmonic echocardiography at baseline and following dipyridamol infusion. The intima-media thickness (IMT) in the carotid artery was measured using an echocardiographic system equipped with 10 MHz linear transducer (Vingmed System Five). RESULTS: The mean CFR value for the HAE patient group was significantly lower than that of the control group (p<0.001). The mean IMT was not found to be significantly different between the two groups, although it was slightly higher in the HAE patient group. No correlation was found between the CFR and the disease severity scores, nor was it shown between the CFR values and the duration of danazol treatment. CONCLUSION: Our results indicate that there is a microvascular endothelial dysfunction in HAE patients. Although carotid intima media thickness of these patients was not significantly increased, the presence of microvascular endothelial dysfunction might be regarded as an early indicator of a premature atherosclerosis.

Primary Burkitt's Lymphoma Presenting as a Rapidly Growing Thyroid Mass.

A 31-year-old male patient presented with a rapidly growing neck mass with normal thyroid function tests. Ultrasonography showed thyroidal expansion, a hypoechoic nodule that completely filled the right lobe, and 2 hypoechoic lymphadenopathies in the right jugulodigastric chain. The patient underwent right total and left subtotal thyroidectomy, following the diagnosis of nodular goiter; however, postoperative histopathological evaluation demonstrated primary Burkitt's lymphoma of the thyroid gland. The tumor was staged as stage 1, and R-hyper-CVAD protocol (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) was administered. The protocol was changed to R-CHOP after 4 cycles due to recurrent grade III/IV cytopenias and febrile neutropenia. The PET-CT scans performed after chemotherapy and at the 6-month follow-up were normal. In summary, we reported a case with a diagnosis of Burkitt's lymphoma, which is a rare type of primary thyroid lymphoma.