Biologic therapy is associated with malignancies among Israeli patients with rheumatoid arthritis: A population-based study.

AIMS: To examine whether biologic disease-modifying anti-rheumatic drugs (bDMARDs) are associated with increased risk of malignancy among Israeli patients with rheumatoid arthritis (RA). METHODS: We identified RA patients meeting specified inclusion and exclusion criteria from the Leumit healthcare services database between the years 2000 and 2017. Data were collected regarding bDMARD and conventional DMARD consumption, types of malignancies, and their temporal relation to RA diagnosis. The association between baseline variables and occurrence of malignancies was examined by Cox regression. RESULTS: Among 4268 eligible RA patients, 688 (16.12%) were diagnosed with any malignancy. Melanoma skin cancer (MSC) was the most prevalent malignancy (148/688, 21.5%). The proportions out of all malignancies of MSC and non-melanoma skin cancer (NMSC) were higher after than before RA diagnosis (24.7% vs 19.1%, p = .025 and 24.7% vs 13.0%, p = .021, respectively). A higher proportion of RA patients diagnosed with malignancy used bDMARDs in comparison with RA patients who were malignancy-free (40.2% vs 17.5%, p < .001). After adjusting for demographic and clinical variables, bDMARDs were associated with an increased risk of malignancy (hazard ratio 1.42, 95% confidence interval 1.10-1.78). CONCLUSIONS: Biologic DMARDs are associated with increased risk of malignancy among Israeli RA patients, presumably contributed by MSC and NMSC. MSC was the most prevalent type of malignancy in this cohort and may indicate a predisposition state among Israeli RA patients.

Vitamin D Insufficiency is Associated with Higher Incidence of Dementia, a Large Community-Based Retrospective Cohort Study.

INTRODUCTION: Active metabolite of vitamin D has neuro-immunomodulatory and neuroprotective properties. However, there is still a debate about the potential association between low serum levels of hydroxy-vitamin D and increased risk for dementia. OBJECTIVES: To determine an association between hypovitaminosis D and dementia for different 25-hydroxyvitamin-D (25(OH)D) serum level cutoffs. METHODS: Patients were identified utilizing the database of Clalit Health Services (CHS), the largest healthcare provider in Israel. For each subject, all available values of 25(OH)D during the study period, which lasted from 2002 to 2019, were obtained. Rates of dementia were compared across different cutoffs of 25(OH)D levels. RESULTS: Cohort included 4278 patients, of whom 2454 (57%) were women. The mean age at the beginning of follow-up was 53 (±17). During the 17-year study period, a total of 133 patients (3%) were diagnosed with dementia. In a fully adjusted multivariate analysis, the risk for dementia was almost 2-fold higher in patients with an average of vitamin D insufficiency (<75 nmol/l) measurements (OR = 1.8, 95% C.I. = 1.0-3.2) compared to reference values (≥75 nmol/l). Patients with vitamin D deficiency (<50 nmol/l) demonstrated higher rates of dementia (OR = 2.6, 95% C.I. = 1.4-4.8). In our cohort, patients were diagnosed with dementia at a younger age in the deficiency (77 vs. 81 P-value = 0.05) and the insufficiency groups (77 vs. 81 P-value = 0.05) compared to the reference values (≥75 nmol/l). CONCLUSION: Insufficient levels of vitamin D are associated with dementia. Dementia is diagnosed at a younger age in patients with insufficient and deficient vitamin D levels.

Long-term outcomes after pre-emptive liver transplantation in primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by the liver defect of oxalate metabolism, which leads to kidney failure and systemic manifestations. Until recently, liver transplantation was the only definitive treatment. The timing of liver transplantation can be early, while kidney function is still normal (pre-emptive liver transplantation-PLT), or when the patient reaches stage 5 chronic kidney disease (CKD) and needs combined liver-kidney transplantation. We aimed to determine the long-term kidney outcomes of PLT in PH1 patients. METHODS: A retrospective single-center study of PH1 patients who were followed in our center between 1997 and 2017. We compared the kidney outcomes of patients who underwent PLT to those who presented with preserved kidney function and did not undergo PLT. RESULTS: Out of 36 PH1 patients, 18 patients were eligible for PLT (eGFR > 40 mL/min/1.73 m2 at the time of diagnosis). Seven patients underwent PLT (PLT group), while 11 continued conservative treatments (PLTn group). In the PLT group, the median eGFR at the time of PLT and at the end of the follow-up period (14-20 years) was 72 (range 50-89) and 104 (range 86-108) mL/min/1.73 m2, respectively, and no patient died or reached stage 5 CKD. In the PLTn group, eight patients (72.7%) reached stage 5 CKD (median time to kidney replacement therapy was 11 years), and two patients died from disease complications (18.2%). CONCLUSIONS: Pre-emptive liver transplantation preserved kidney function in patients with PH1 in our cohort. Early intervention can prevent kidney failure and systemic oxalosis in PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

The profile of the causative organisms which lead to septic arthritis of native joints over the last two decades in a single tertiary medical center in the east coast of the United States.

BACKGROUND: Septic arthritis (SA) is associated with significant morbidity and mortality. Delayed or inadequate treatment may result in joint destruction, osteomyelitis and sepsis. Like other types of infection, the causative agents of SA may have changed over time. Early targeted intervention is important in cases of SA and can be achieved only by understanding the current trends in the microbiology of SA. OBJECTIVES: To determine the trends in the microbiology of SA over the last two decades. METHODS: We conducted a retrospective study including all patients 18 and older with culture positive, surgically treated, native joint septic arthritis (NJSA), admitted to a single tertiary medical centre in Boston between the years of 1997 and 2015. We excluded cases of osteomyelitis and septic bursitis. We focused our analysis on the microbiology data which included synovial fluid gram stain and culture, blood cultures and synovial biopsy cultures. RESULTS: Among 260 cases, the most common bacteria isolated were Methicillin Sensitive Staphylococcus aureus (MSSA, 36%), Methicillin Resistant Staphylococcus aureus (MRSA, 17.6%), Coagulase Negative Staphylococci (CoNS, 13%) and Group B Streptococcus (GBS, 7.3%). Trends in the rates of these bacteria demonstrated no significant variation. The knee was the most common joint affected, followed by the shoulder and hip. Shoulder SA was most commonly caused by MRSA while MSSA was the leading causative organism in other joints. GBS was a causative bacterium in shoulder SA significantly more often than in knee or hip infections. CONCLUSIONS: Although no significant trends were noted in the microbiology of SA over nearly 2 decades, we observed meaningful findings regarding shoulder SA as MRSA was the most common bacterial because of SA in this joint. Prompt joint aspiration, microbiologic testing of synovial fluid and empiric antibiotic therapy that covers MRSA may improve outcomes in SA.

Factors associated with drug survival on first biologic therapy in patients with rheumatoid arthritis: a population-based cohort study.

Lack of sufficient head-to-head trials comparing biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA), makes the choice of the first bDMARD a matter of rheumatologist's preference. Longer drug survival on the first bDMARD usually correlates with early remission. We aimed to identify factors associated with longer drug survival. We conducted a population-based retrospective longitudinal cohort study. We identified RA patients using the relevant International Classification of Disease 9th codes. "True" RA patients were defined as patients fulfilling, additionally, at least one of the following: receiving conventional DMARDs (cDMARDs), being positive for rheumatoid factor or anti-cyclic citrullinated peptide, or being diagnosed by a rheumatologist. We compared drug survival times and identified factors associated with longer drug survival. We identified 4268 true RA patients between the years of 2000-2017. 820 patients (19.2%) received at least one bDMARD. The most commonly prescribed bDMARDs were etanercept (352, 42.9%), adalimumab (143, 17.4%), infliximab (142, 17.3%) and tocilizumab (58, 7.1%). Infliximab was associated with the longest drug survival (47.1 months ± 46.3) while golimumab was associated with the shortest drug survival (14.9 months ± 15.1). Male gender [hazard ratio (HR) = 0.76, 95% confidence interval (CI), 0.63-0.86, p = 0.001], concurrent conventional DMARDs use (HR = 0.79, 95% CI 0.68 - 0.98, p = .031) and initiating bDMARD therapy in earlier calendric years (HR = 1.12, 95% CI 1.10 -1.18, p = 0.0001) were associated with longer drug survival. Male gender, concomitant cDMARDs and initiating biologic therapy at earlier calendric years are associated with longer drug survival.

Presentation and Outcomes of Peri-Prosthetic Joint Infection: A Comparison of Culture-Positive and Culture-Negative Disease.

Background: Peri-prosthetic joint infection (PJI) is a debilitating and costly complication of joint replacement. Synovial fluid cultures are negative in up to 25% of PJI cases. The purpose of this study was to compare the clinical characteristics and outcomes of culture negative and culture positive PJI. Patients and Methods: We conducted a retrospective study including all patients aged 18 and older admitted to a single tertiary-care hospital between 1998 and 2015 diagnosed with PJI and treated with antibiotic agents and surgery. Results: One hundred ninety-six patients with PJI were identified; 48 (24.5%) were culture-negative (CN) and 148 (75.5%) were culture-positive (CP). The groups were similar in age and presence of associated comorbidities. Fever was more common among the CP patients (CN, 23.8%; CP, 38.4%; p = 0.03) as was sepsis defined by Sepsis-2 criteria (CN, 12.8%; CP, 28.7%; p = 0.03). Patients who were CP had higher synovial white blood cell (WBC) count (CN, 30,500 per milliliter; CP, 95,400 per milliliter; p < 0.01), a longer length of stay (CN, 3.8%; CP,7.9%; p = 0.02), and fewer alternative diagnoses established within one year (CN, 25.0%; CP, 2.7%; p < 0.01). Our logistic regression models also found that CP patients had an adjusted odds ratio (OR) of 2.59 for rehabilitation placement with 95% confidence interval (CI) of 1.15-5.83 and adjusted OR of 0.04 for an alternative diagnosis within one year with 95% CI, 0.009-0.22 compared with their CN counterparts. Conclusions: This study suggests that patients with CN PJI have less severe disease, better outcomes, and higher rates of alternative diagnoses within one year.

The impact of gender on the clinical presentation, management, and surgical outcomes of patients with native-joint septic arthritis.

RATIONALE, AIMS AND OBJECTIVES: Approximately 20 000 cases of septic arthritis (SA) occur in the U.S. yearly. We examined whether gender-related differences exist in the presentation, management, and outcomes of patients with native joint septic arthritis (NJSA). METHODS: This was a retrospective study of medical files of patients aged 18 years and older admitted between 1998 and 2015 to a single tertiary care hospital and diagnosed with NJSA. All study subjects had positive synovial fluid or blood cultures and each was managed surgically. Patients' charts were reviewed for demographics, comorbidities, clinical presentations, microbiology profiles, management, and outcomes. Cases of osteomyelitis, septic bursitis, prosthetic joint, and culture-negative SA were excluded. RESULTS: Of 324 NJSA patients, those who were female (n = 130; 40.1%) were significantly older at presentation than males (mean age: 63.6 vs 58.3; P = .006). Prior joint pathology was more common amongst females, including osteoarthritis (20.8% vs 12.9%; P = .04) and rheumatoid arthritis (10% vs 3.6%; P = .03). Female patients had a higher frequency of hip involvement (17.7% vs 10.8%; P = .05). No differences were observed in clinical presentations, culture results, medical management, or outcomes between genders. CONCLUSIONS: Compared to men, women with NJSA presented at an older age and had more prior joint pathology and a higher frequency of hip involvement. These differences, however, had no significant impact on the clinical presentation, medical management, or outcomes of NJSA.

Patients with surgically treated culture-negative native joint septic arthritis have less severe disease and better outcomes.

Background: Patients with culture-negative septic arthritis patients are often treated surgically but might be successfully managed medically. We compared clinical characteristics and outcomes in patients with culture negative and culture positive native joint monoarticular septic arthritis.Methods: This retrospective study included all patients age ≥18 years admitted to a single, tertiary-care hospital between 1998 and 2015 with native joint monoarticular SA and treated with antibiotics and surgery.Results: Of 306 patients, 85 had negative and 221 had positive cultures. Mean C-reactive protein (p < .01) and mean percentage of peripheral polymorphonuclear cells (p = .01) were higher in culture-positive patients who had higher intensive care unit admission rates (16.7% vs. 4.7%, respectively, [p < .01]), longer length of hospital stay (11.4 vs. 7.1 days, respectively, [p < .01]) and higher mortality rates within 30 days (0% vs. 5.5%, respectively,[p = .02]). Of culture-negative patients, 28.6% received an alternative diagnosis within one year. Logistic regression models showed that culture positive patients had an adjusted odds ratio for length of stay of 4.5 (2.69, 7.51), intensive care unit admission of 5.76 (1.31, 25.22), discharge to rehabilitation of 4.7 (2.28, 9.71) and an alternative diagnosis within one year of 0.05 (0.02, 0.15) compared to culture negative patients.Conclusion: Patients with culture-negative native joint septic arthritis had less severe disease, better outcomes and higher rates of alternative diagnosis within one year than patients with positive cultures.

Clinical characteristics and outcomes of patients with septic arthritis treated without surgery.

Septic arthritis (SA) is typically managed with antibiotic therapy with or without surgery. Little is known about how patients without surgery differ from their operatively managed counterparts. We compared SA patients who received antibiotic treatment with and without surgery. We conducted a retrospective study of patients with monoarticular septic arthritis admitted to a single tertiary care centre between 1998 and 2015. All 441 monoarticular septic arthritis patients received antibiotics; 382 were also managed operatively and 59 nonoperatively. Nonoperative patients were older (64.4 vs 58.3 years old; p = 0.02) and less likely to have prior joint pathology (44.1% vs 67.5%; p < 0.001). Nonoperative patients presented more often with sepsis (37.3% vs 31.9; p = 0.02) and were more frequently admitted to the intensive care unit (23.7% vs 16.5%; p = 0.04). Nonoperative patients were less often discharged to a rehabilitation facility (37.9% vs 55.8%; p = 0.002) and less frequently readmitted to hospital within 60 days of initial discharge (15.3% vs 18.6%; p = 0.05). However, nonoperative patients were more likely to expire within 30 days after hospital discharge (11.9% vs 3.9%; p = 0.009). Nonoperative patients were sicker at presentation; despite deferral of surgery, they had a relatively high survival rate (88%). Among survivors whose data was available, there were no significant sequelae in post-discharge imaging. These findings support the nonsurgical approach as effective for patients with septic arthritis who are not critically ill at time of presentation.

Clinical features of patients with septic arthritis and echocardiographic findings of infective endocarditis.

PURPOSE: Patients with septic arthritis (SA) often undergo echocardiographic evaluation to identify concomitant infective endocarditis (IE). The purpose of this study is to identify distinguishing features of patients with SA and IE by comparing them to patients with SA alone. METHODS: We conducted a retrospective study of all patients 18 and older admitted to a single tertiary hospital between 1998 and 2015 with culture-positive SA. Patients were stratified by echocardiogram status and the presence of vegetations: those who had echocardiographic evaluation with no evidence of infective endocarditis (ECHO + IE-) or with a vegetation present (ECHO + IE+) and those who had no echocardiographic evaluation (ECHO-). Demographic data, clinical characteristics, microbiology data, treatment strategies, and patient outcomes were recorded and compared. RESULTS: We identified 513 patients with SA. Transthoracic echocardiogram and/or transesophageal echocardiogram were performed in 263 patients (51.2%) and demonstrated evidence for IE in 19 patients (3.7%). While most demographic features, comorbidities, and clinical characteristics did not differ significantly between those with and without IE, those with IE had higher rates of sepsis and septic shock. In addition, patients with SA and IE had higher rates of positive blood cultures and Methicillin-sensitive staphylococcus aureus (MSSA) infection when compared to those with SA without IE. Patients with IE had higher rates of intensive care unit admission and increased 30-day mortality. CONCLUSIONS: IE is uncommon among patients with SA. Echocardiography may be overutilized and may be more useful among patients presenting with sepsis, shock, or positive blood cultures, especially when MSSA is isolated.

Clinical characteristics of patients with polymicrobial septic arthritis.

Little is known about the incidence, risk factors, clinical characteristics, and outcomes of patients with polymicrobial SA (PMSA). We aimed to determine the unique characteristics of patients with PMSA by comparing them to patients with monomicrobial SA (MMSA). We conducted a retrospective cohort study of patients 18 years and older admitted to a single tertiary care medical center, between 1998 and 2015, with surgically treated culture-positive SA affecting one or more joints. Patients were separated into two groups by the presence of one (MMSA) or more organisms (PMSA). A total of 441 patients with MMSA and 47 with PMSA were identified. Prior history of SA was more common among the PMSA group (31.9% vs. 18.6%; p = 0.03) as well as higher rates of prosthetic joint involvement (48.9% vs. 36.1%; p = 0.06). Patients with PMSA were sicker with higher rates of shock at presentation (14.9% vs. 5.5%; p = 0.02), intensive care unit admissions (39.1% vs. 18%; p < 0.001), and longer mean length of stay (16.1 vs. 10.9 days; p < 0.001). The most prevalent pathogens in the PMSA group were coagulase-negative Staphylococcus (31%), followed by methicillin-sensitive Staphylococcus aureus (29%), and Enterococcus (24%). To our knowledge, this is the first study to determine the clinical and microbiologic profiles of patients with PMSA. Important differences were noted such as more frequent involvement of atypical and prosthetic joints in PMSA. PMSA should be suspected in patients with these clinical features, and broad-spectrum antibiotics should be considered as these patients appear to be sicker and have worse outcomes.

Clinical characteristics and outcomes in polyarticular septic arthritis.

OBJECTIVES: Septic polyarthritis is rarer than septic monoarthritis, but associated with higher mortality. Septic polyarthritis may be difficult to distinguish clinically from noninfectious inflammatory arthritis. We describe one of the largest samples of septic polyarthritis with the aim of distinguishing septic monoarthritis from polyarthritis. METHODS: We conducted a retrospective study of adults admitted to tertiary care with septic monoarthritis and polyarthritis. Baseline characteristics, microbial profiles, joint involvement, length of stay, and 60-day readmission rates were determined. RESULTS: We identified 464 and 42 cases of septic monoarthritis and polyarthritis, respectively, including 7 cases of septic polyarthritis with comorbid rheumatoid arthritis. Compared to those with septic monoarthritis, patients with septic polyarthritis were more likely to have rheumatoid arthritis (P<0.01), sepsis (P<0.01), and higher peripheral (P<0.001) and synovial (P<0.001) white blood cell counts. Operative intervention rates were similar, but mean length of stay was longer in polyarticular septic arthritis (P<0.001). Patients with septic polyarthritis with/without underlying rheumatoid arthritis were similar in terms of presenting features and outcomes, except for more frequent immunosuppressive therapy in rheumatoid arthritis (P<0.01). CONCLUSIONS: In this sample of patients with septic arthritis, patients with septic polyarthritis were more likely to have systemic infection at presentation than those with septic monoarthritis. Despite this difference, patients with septic monoarthritis and polyarthritis tended to have similar outcomes. While rheumatoid arthritis was observed more frequently among patients with septic polyarthritis, those with/without underlying rheumatoid arthritis had similar presenting features and outcomes.

Pathogen or contaminant? Distinguishing true infection from synovial fluid culture contamination in patients with suspected septic arthritis.

BACKGROUND: Isolation of bacteria from synovial fluid (SF) is the gold standard for diagnosis of septic arthritis (SA). Contamination results in misdiagnosis and mismanagement. This study identifies clinical characteristics, microbiology, and outcomes of patients with contaminated SF and compares them with patients with true SA. METHODS: We conducted a retrospective study including all patients aged 18 and older admitted to a single, tertiary-care hospital between 1998 and 2015 with suspected SA and positive SF cultures. Contamination cases were determined by infectious disease specialists involved in the patients' care and a clinical course inconsistent with SA. RESULTS: 398 patients with true SA and 22 with contaminated SF were identified. The SA group was younger (60.9 vs. 75.6 years; p < 0.01), had higher peripheral polymorphonuclear lymphocytes (78.0 vs. 69.4%; p < 0.01) and SF white blood cell count (91.7 vs. 25.6K/mL; p = 0.02), and longer mean length of stay (10.9 vs. 6.7 days; p = 0.02). The average time to positive culture was longer in the contaminated group (3.62 vs. 1.4 days; p < 0.01). The SA group was less likely to receive a new rheumatologic diagnosis within 1 year (3.0 vs. 36.4%; p < 0.01). CONCLUSION: This is the first study of its kind looking at clinical features and outcomes of patients with contaminated SF. These patients present with less severe disease, have better outcomes, and receive new rheumatologic diagnoses in more than a third of cases within 1 year. We recommend a conservative approach for patients with suspected contaminated SF, mild symptoms, and no bacterial growth within the first 48 h.

Clinical characteristics and outcomes of septic bursitis.

PURPOSE: Limited data guide practice in evaluation and treatment of septic bursitis. We aimed to characterize clinical characteristics, microbiology, and outcomes of patients with septic bursitis stratified by bursal involvement, presence of trauma, and management type. METHODS: We conducted a retrospective cohort study of adult patients admitted to a single center from 1998 to 2015 with culture-proven olecranon and patellar septic bursitis. Baseline characteristics, clinical features, microbial profiles, operative interventions, hospitalization lengths, and 60-day readmission rates were determined. Patients were stratified by bursitis site, presence or absence of trauma, and operative or non-operative management. RESULTS: Of 44 cases of septic bursitis, patients with olecranon and patellar bursitis were similar with respect to age, male predominance, and frequency of bursal trauma; patients managed operatively were younger (p = 0.05). Clinical features at presentation and comorbidities were similar despite bursitis site, history of trauma, or management. The most common organism isolated from bursal fluid was Staphylococcus aureus. Patients managed operatively were discharged to rehabilitation less frequently (p = 0.04). CONCLUSIONS: This study of septic bursitis is among the largest reported. We were unable to identify presenting clinical features that differentiated patients treated surgically from those treated conservatively. There was no clear relationship between preceding trauma or bursitis site and clinical course, management, or outcomes. Patients with bursitis treated surgically were younger. Additional study is needed to identify patients who would benefit from early surgical intervention for septic bursitis.

Update on the role of Interleukin 17 in rheumatologic autoimmune diseases.

Interleukin 17 is a proinflammatory cytokine produced by CD4+ T cells when in the presence of a distinct set of cytokines and other cells. Preclinical and clinical studies have assigned a role to IL-17 in tissue inflammation and damage in patients with rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus. Antibodies blocking the action of IL-17 have already been approved to treat patients with psoriasis and it is expected that they may also benefit patients with other rheumatic diseases.

The role of T cells in systemic lupus erythematosus: an update.

PURPOSE OF REVIEW: To describe our current understanding of the role of T cells in the pathophysiology of systemic lupus erythematosus (SLE). RECENT FINDINGS: Over the last few years, the dominant role of T cells in autoimmunity and SLE was established. Genome-wide-association studies led to the discovery of multiple single-nucleotide polymorphisms associated with SLE. Most of these single-nucleotide polymorphisms fall within the noncoding DNA regions of immune response-related genes and few seem to contribute to the observed abnormal T cell function. The field of epigenetics research developed rapidly and provided us with new insights into the observed generalized hypomethylation in SLE T cells, the abnormal histone modifications and the role of RNA interference. Old observations, such as the decreased interleukin-2 production, are better understood with our evolved knowledge of many signal transduction pathways and the way they converge and regulate the transcription of different genes in T cells. Finally, we are now able to identify subpopulations of T cells, such as Th17 and T regulatory cells, and to define their role in SLE. SUMMARY: T cells are key players in SLE, and over the last few years our understanding of their activation, signal transduction and gene regulation has evolved significantly.

C4d deposits on the surface of RBCs in trauma patients and interferes with their function.

OBJECTIVE: Complement system is activated in patients with trauma. Although complement activation is presumed to contribute to organ damage and constitutional symptoms, little is known about the involved mechanisms. Because complement components may deposit on RBCs, we asked whether complement deposits on the surface of RBC in trauma and whether such deposition alters RBC function. DESIGN: A prospective experimental study. SETTING: Research laboratory. SUBJECTS: Blood samples collected from 42 trauma patients and 21 healthy donors. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: RBC and sera were collected from trauma patients and control donors. RBCs from trauma patients (n = 40) were found to display significantly higher amounts of C4d on their surface by flow cytometry compared with RBCs from control (n = 17) (p < 0.01). Increased amounts of iC3b were found in trauma sera (n = 27) (vs 12 controls, p < 0.01) by enzyme-linked immunosorbent assay. Incubation of RBC from universal donors (type O, Rh negative) with trauma sera (n = 10) promoted C4d deposition on their surface (vs six controls, p< 0.05). Complement-decorated RBC (n = 6) displayed limited their deformability (vs six controls, p < 0.05) in two-dimensional microchannel arrays. Incubation of RBC with trauma sera (n = 10) promoted the phosphorylation of band 3, a cytoskeletal protein important for the function of the RBC membrane (vs eight controls, p < 0.05), and also accelerated calcium influx (n = 9) and enhanced nitric oxide production (n = 12) (vs four and eight controls respectively, p < 0.05) in flow cytometry. CONCLUSIONS: Our study found the presence of extensive complement activation in trauma patients and presents new evidence in support of the hypothesis that complement activation products deposit on the surface of RBC. Such deposition could limit RBC deformability and promote the production of nitric oxide. Our findings suggest that RBC in trauma patients malfunctions, which may explain organ damage and constitutional symptoms that is not accounted for otherwise by previously known pathophysiologic mechanisms.

New therapeutics in systemic lupus erythematosus.

PURPOSE OF REVIEW: The purpose of this review is to discuss new therapeutics in systemic lupus erythematosus (SLE). We will concentrate on both approved and unapproved treatments that were published during the last year. RECENT FINDINGS: Efforts have focused on the optimization of the use of Belimumab and Rituximab using information generated previously in clinical trials and the development of small new drugs inhibitors of the proteasome and immune cell signaling molecules such as Btk, ROCK and CaMK4. We cannot predict which biologics are going to be effective in humans, as many of the biologics that provide significant benefit in preclinical trials and lupus-prone mice have often proved noneffective in clinical trials. We now realize that lupus-prone mice do not represent human SLE. Yet, genetic or treatments studies in mice are valuable and help us to understand the role of immune or biochemical abnormalities identified in patients in a whole organism. SUMMARY: 2012 was an exciting year for the field of novel therapeutics in SLE and was signified by the effort to target specific signaling pathways with small molecules and biological agents.

The genetics of benign neutropenia.

In Israel, Yemenite Jews and other populations including Ethiopian Jews and Bedouins have a low neutrophil count. This phenomenon has been called "benign neutropenia" since it has not been associated with any increased risk of infection and has also been described in other populations around the world including Africans, African Americans and Afro-Carribeans. Here we describe the recent success in mapping the gene that underlies benign neutropenia in African American populations. We discuss the known function of the gene and consider potential mechanisms for the effect on neutropenia. We also consider the possibility that this gene underlies the same effect observed in Yemenite Jews, Ethiopian Jews and Bedouins in Israel.

Antifibrosis: to reverse the irreversible.

Fibrosis is a pathological process that includes scar formation and overproduction of extracellular matrix by the connective tissue as a response to tissue damage. The fibrotic process involves multiple organs and results in progressive life-threatening diseases. Today, we know more about the molecular mechanism that leads to fibrosis involving different type of cells, cytokines, chemokines, and tissue enzymes. Fibrosis was considered an irreversible process, at least clinically, and is still usually treated by anti-inflammatory and immunosuppressive agents. No proven antifibrotic therapy has shown efficacy in ameliorating the clinical course of fibrotic diseases, but our current understanding led to the development of different drugs with promising results, like: mycophenolate mofetil, interferon, relaxin, and intravenous immunoglobulin. This review will provide a glance to this heavily investigated subject.