Short- and Long-Term Mortality of Hospitalized Patients With Autoimmune Rheumatic Diseases and Serious Infections: A National Cohort Study.

OBJECTIVE: Infectious conditions are a significant cause of mortality in autoimmune rheumatic diseases (ARD). Among patients hospitalized with an infection, we compared in-hospital and long-term (3-year) mortality between those with and without ARD. METHODS: This retrospective analysis included members of the largest health maintenance organization in Israel, aged > 18 years at the first episode of infection, who required hospitalization during 2003-2019. We compared in-hospital mortality and the results of a 3-year landmark analysis of those who survived the index hospitalization between patients with ARD, according to disease subgroups, and patients without ARD. Additionally, we compared mortality outcomes among patients with ARD, according to subgroup diagnosis, matched in a 1:3 ratio by age, sex, and ethnicity to patients without ARD. RESULTS: Included were 365,247 patients who were admitted for the first time with the diagnosis of a serious infection. Of these, we identified 9755 with rheumatoid arthritis (RA), 1351 with systemic lupus erythematosus, 2120 with spondyloarthritis (SpA), 584 with systemic sclerosis, and 3214 with vasculitis. In a matched multivariate analysis, the risk for in-hospital mortality was lower among patients with RA (odds ratio [OR] 0.89, 95% CI 0.81-0.97) and SpA (OR 0.77, 95% CI 0.63-0.94). In a similar analysis, the risk of 3-year mortality was lower among patients with RA (hazard ratio [HR] 0.82, 95% CI 0.78-0.86) and vasculitis (HR 0.86, 95% CI 0.80-0.93). CONCLUSION: Among patients hospitalized for an infection, the risk of in-hospital and 3-year mortality was not increased among those with ARD compared to those without ARD.

Fourth dose of BNT162b2 vaccine for patients with autoimmune rheumatic diseases in a nationwide setting.

OBJECTIVE: The effectiveness of COVID-19 vaccinations wanes due to immune evasion by the B.1.1.529 (Omicron) variant and diminished antibody titres over time. We aimed to evaluate the benefit of a fourth vaccination dose in patients with autoimmune rheumatic diseases (ARDs). METHODS: This retrospective analysis included ARD patients aged 18 years or older and members of Clalit Health Services in Israel (which at the time of the study insured 52% of the entire population), and covered the period from 16 January 2022 to 31 March 2022, when the predominant SARS-CoV-2 variant was Omicron. We compared patients without previous COVID-19 infection who had received three doses of the BNT162b2 vaccine (the control group) with those who had received the fourth dose. The primary outcome was COVID-19 infection, which was analysed using multivariate Cox regression in the entire cohort and within ARD subgroups. Secondary outcomes were COVID-19-related hospitalizations and COVID-19-related death. RESULTS: We included 43 748 ARD patients, of whom 27 766 and 15 982 were in the control and fourth vaccination groups, respectively. COVID-19 infection occurred in 6942 (25.0%) of the control group and 1754 (11.0%) of the fourth dose group (P < 0.001). Patients vaccinated with the fourth dose had a lower risk of COVID-19 infection than the entire cohort [Hazard Ratio (HR) 0.54, 95% CI 0.52, 0.58] and throughout every subgroup regardless of the baseline characteristic or medical treatment, except for rituximab. A similar association was observed for risk of COVID-19-related hospitalization (HR 0.36, 95% CI 0.22, 0.61) and of COVID-19-related death (HR 0.41, 95% CI 0.24, 0.71). CONCLUSION: A fourth BNT162b2 vaccination of ARD patients was associated with favourable outcomes compared with three doses among patients with no history of COVID-19 infection.

Obstacles in Early Diagnosis of Children With Juvenile Idiopathic Arthritis: A Nationwide Israeli Retrospective Study.

OBJECTIVE: Characterization of the stages that patients with juvenile idiopathic arthritis (JIA) pass until they are diagnosed, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel. METHODS: This is a retrospective cohort study conducted in 8 pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referring physicians were collected from hospital and community medical charts. RESULTS: Of 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients, on average, were evaluated during the diagnostic process by 3.1 different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.9%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and spondyloarthritis/enthesitis-related arthritis (SpA/ERA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis (P < 0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time (P < 0.05). CONCLUSION: This is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness about JIA, especially for patients with SpA/ERA, is crucial in order to avoid delays in diagnosis and treatment.

Risk factors for haemodynamic compromise in multisystem inflammatory syndrome in children: a multicentre retrospective study.

OBJECTIVES: To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. METHODS: This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. RESULTS: Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. CONCLUSION: Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

Case Series of Myocarditis Following mRNA COVID Vaccine Compared to Pediatric Multisystem Inflammatory Syndrome: Multicenter Retrospective Study.

INTRODUCTION: Since the development of COVID-19 vaccines, more than 4.8 billion people have been immunized worldwide. Soon after vaccinations were initiated, reports on cases of myocarditis following the second vaccine dose emerged. This study aimed to report our experience with adolescent and young adults who developed post-COVID-19 vaccine myocarditis and to compare these patients to a cohort of patients who acquired pediatric inflammatory multisystem syndrome (PIMS/PIMS-TS) post-COVID-19 infection. METHODS: We collected reported cases of patients who developed myocarditis following COVID-19 vaccination (Pfizer mRNA BNT162b2) from all pediatric rheumatology centers in Israel and compared them to a cohort of patients with PIMS. RESULTS: Nine patients with post-vaccination myocarditis were identified and compared to 78 patients diagnosed with PIMS. All patients with post-vaccination myocarditis were males who developed symptoms following their second dose of the vaccine. Patients with post-vaccination myocarditis had a shorter duration of stay in the hospital (mean 4.4 ± 1.9 vs. 8.7 ± 4.7 days) and less myocardial dysfunction (11.1% vs. 61.5%), and all had excellent outcomes as compared to the chronic changes among 9.2% of the patients with PIMS. CONCLUSION: The clinical course of vaccine-associated myocarditis appears favorable, with resolution of the symptoms in all the patients in our cohort.

A novel zeta-associated protein 70 homozygous mutation causing combined immunodeficiency presenting as neonatal autoimmune hemolytic anemia.

Biallelic mutations in the zeta-associated protein 70 (ZAP70) gene cause combined immunodeficiency (CID). Neonatal screening for severe CID in Israel is implemented since 2015. We report on clinical, flow cytometry, and genetic data of an unusual ZAP70 deficiency patient. A 10-week-old Bedouin female presented with severe autoimmune hemolytic anemia. Cytomegalovirus (CMV) negative packed cell therapy was given without improvement; indexes of hemolysis worsened. At this time, thrombocytopenia was noted. The patient was treated with single dose of 1 g/kg intravenous immunoglobulin with rapid resolution of hemolysis. Serum immunoglobulin concentrations were normal; flow cytometry revealed severe CD8 lymphocytopenia. Lymphocyte proliferation test demonstrated reduced response to concanavalin A and phytohemagglutinin. Gated T cells were negative for intracellular ZAP70. A genetic analysis revealed a missense homozygous c.1388C > T (p.A463V) mutation, confirming the diagnosis of ZAP70 deficiency. She later on developed urinary tract infection due to ESBL producing E. coli treated with amikacin and severe CMV infection that partially responded to ganciclovir therapy and at 7 months of age, she successfully underwent allogeneic hematopoietic stem cell transplantation. Neonatal screening by T cell receptor excision circles (TRECs) for SCID was normal, yet very low TRECs were recorded at the time of CID diagnosis. Normal neonatal screening for SCID does not rule out the diagnosis of CID due to ZAP70 deficiency. This type of CID can present with autoimmunity as the sole initial manifestation of the disease.

Purpuric rash and fever among hospitalized children aged 0-18 years: Comparison between clinical, laboratory, therapeutic and outcome features of patients with bacterial versus viral etiology.

BACKGROUND: The evaluation of children with purpuric rash and fever (PRF) is controversial. Although many of them have viral infections, on occasion such patients may be infected with Neisseria meningitidis. We described all children aged 0-18 years with PRF in southern Israel during the period 2005 ̶ 2016 and compared their microbiologic, laboratory, clinical and outcome characteristics in relation to various etiologies of this syndrome. METHODS: Data were summarized from electronic patient and microbiology files. Viral diagnoses were made by serology and/or PCR. RESULTS: Sixty-nine children with PRF were admitted; 30 (43.48%), 9 (13.04%) and 30 (43.48%) had a syndrome of bacterial, viral or non-established etiology, respectively. N. meningitidis infection was diagnosed in 16/69 (23.19%) patients and in 16/30 (53.33%) patients with bacterial etiology; 14/30 (46.67%) patients suffered from a non-invasive bacterial disease (9 with Rickettsial disease). Adenovirus and Influenza B (3 and 2 cases, respectively) represented the most frequent etiologic agents among patients with viral etiology. More patients with PRF of bacterial etiology were older, of Bedouin ethnicity, looked ill on admission, had higher rates of meningitis and were treated more frequently with antibiotics compared with patients with non-bacterial PRF. Fatality rates among patients with bacterial, viral and non-established etiology were 5/30 (16.7%), 0% and 2/39 (5.1%). CONCLUSIONS: Although PFR was uncommon, high rates of meningococcal infections were recorded in children with PRF, which was associated with high fatality rates. Rickettsial infections were frequent, emphasizing the need for a high index of suspicion for this disease in endemic geographic areas.

Mycophenolate Mofetil Alone and in Combination with Tacrolimus Inhibits the Proliferation of HT-29 Human Colonic Adenocarcinoma Cell Line and Might Interfere with Colonic Tumorigenesis.

BACKGROUND/AIM: Familial adenomatous polyposis (FAP) was found to be completely reversed in a patient treated with mycophenolate mofetil (MMF) and tacrolimus following kidney transplantation. In this preliminary study, we assessed whether MMF and tacrolimus alone or in combination interfere with the cell cycle and proliferation in a human colonic adenocarcinoma cell line and in the colonic polyps of the patient with FAP. MATERIALS AND METHODS: Human colonic adenocarcinoma HT-29 cells were treated with tacrolimus and MMF alone and in combination at different concentrations. Cell viability and proliferation were assessed using the MTT assay. Cell-cycle distribution was analyzed by flow cytometry. Expression of Ki-67, a marker of mitotic activity, was evaluated in the patient's colonic polyps before and under drug treatment. RESULTS: MMF in combination with tacrolimus induced S-phase cell-cycle arrest and markedly inhibited HT-29 cell proliferation. Ki-67 expression in the patient's colonic polyps was significantly reduced following combined tacrolimus and MMF treatment. CONCLUSION: MMF and tacrolimus synergistically inhibited proliferation of a human colonic adenocarcinoma cell line and interfered with the expansion of colonic crypt proliferation in the polyp from a patient with FAP. The results confirm our clinical observation and indicate the possibility of novel approach to therapy of colorectal neoplasia.

Teaming Up for Trouble: Cancer Cells, Transforming Growth Factor-ß1 Signaling and the Epigenetic Corruption of Stromal Naïve Fibroblasts.

It is well recognized that cancer cells subvert the phenotype of stromal naïve fibroblasts and instruct the neighboring cells to sustain their growth agenda. The mechanisms underpinning the switch of fibroblasts to cancer-associated fibroblasts (CAFs) are the focus of intense investigation. One of the most significant hallmarks of the biological identity of CAFs is that their tumor-promoting phenotype is stably maintained during in vitro and ex vivo propagation without the continual interaction with the adjacent cancer cells. In this review, we discuss robust evidence showing that the master cytokine Transforming Growth Factor-ß1 (TGFß-1) is a prime mover in reshaping, via epigenetic switches, the phenotype of stromal fibroblasts to a durable state. We also examine, in detail, the pervasive involvement of TGFß-1 signaling from both cancer cells and CAFs in fostering cancer development, taking colorectal cancer (CRC) as a paradigm of human neoplasia. Finally, we review the stroma-centric anticancer therapeutic approach focused on CAFs-the most abundant cell population of the tumor microenvironment (TME)-as target cells.

Performance of risk stratification criteria in the management of febrile young infants younger than three months of age.

AIM: We evaluated the diagnosis, risk stratification and management of febrile infants under three months of age who presented to an Israeli paediatric emergency room (ER). METHODS: This retrospective study enrolled all febrile infants examined in the paediatric ER of Soroka Medical Center during 2010-2013. The patients were classified into low-risk and high-risk subgroups and compared by age and ethnicity. RESULTS: Overall, 2251 febrile infants (60.5% of Bedouin and 34.4% of Jewish ethnicity) were enrolled. Hospitalisation rates were higher among Bedouin vs. Jewish infants (55 vs. 39.8%, p < 0.001). Fever without localising signs was diagnosed in 1028 (45.6%) infants and 499 (48.5%) were hospitalised; 26% were stratified as high-risk and 74% as low-risk. Bedouin infants rates were more likely to be at high-risk (p = 0.001) and hospitalised (p < 0.001) than Jewish infants. With regard to low-risk infants, the incidence rates were higher before two months than two to three months of age (73.3 vs. 59%, p < 0.001), as were the hospitalisation rates (46.3 vs. 20.1%, p < 0.001). No differences were recorded for the hospitalisation rates of Bedouin and Jewish infants between the three daily shifts. CONCLUSION: Major differences were recorded in hospitalisation rates, risk stratification and management of Bedouin and Jewish infants with fever without localising signs.

Complete Reversion of Familial Adenomatous Polyposis Phenotype Associated with Tacrolimus and Mycophenolate Mofetil Treatment Following Kidney Transplantation.

Numerous germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene are responsible for development of multiple adenomatous colorectal polyps with their inevitable progression to cancer. Multiple attempts at dietary and pharmacological prevention of colorectal carcinoma development in patients with familial adenomatous polyposis (FAP) have provided conflicting results. Immunosuppressive treatment with tacrolimus is known to be associated with an increased risk of malignancy and should be avoided in patients with high propensity for development of neoplasia. We observed a complete reversion of FAP phenotype in a male teenager carrying a germline mutation in APC gene who underwent a kidney transplant due to end-stage kidney disease secondary to congenital dysplastic kidneys. The patient was treated with tacrolimus and mycophenolate mofetil after transplantation. The possible chemopreventative role of these agents should be evaluated and confirmed in a larger cohort. The elucidation of molecular mechanisms underpinning the observed chemopreventative effect of tacrolimus and mycophenolate mofetil might lead to the development of a novel colorectal cancer therapy.

Human Colorectal Cancer Stage-dependent Global DNA Hypomethylation of Cancer-associated Fibroblasts.

BACKGROUND/AIM: Cancer-associated fibroblasts (CAFs) play an important role in tumor development and progression. The prevailing consensus favors the view that a specific epigenetic signature underpins the stable CAF phenotype. The aim of the present study was to assess global DNA methylation in CAFs during the adenoma-carcinoma sequence in non-familial sporadic human colorectal cancer (CRC). PATIENTS AND METHODS: Immunohistochemical staining of nuclear 5-methylcytosine (5'-meCyt) was performed in matched samples of colonic tumor tissue and normal colonic mucosa excised from six patients with adenomas and four with adenocarcinomas. The staining intensity was expressed semi-quantitatively as the immunohistochemical staining score (ISS). RESULTS: ISS values of human colonic CAFs and adenomatous samples were 14.00±2.2 and 14.08±1.8, respectively, showing no statistically significant difference. In contrast, a marked trend was found towards global DNA hypomethylation in CAFs from adenocarcinomatous specimens compared to matched normal mucosa: ISS: 9.25±2.44 (range=6-11) vs. 16.17±0.75, respectively, p<0.03. CONCLUSION: Final stages of cancer development in CRC are associated with global DNA hypomethylation in stromal CAFs.

Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice.

Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co-cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA­pulsed APCs. The levels of the Th1-type cytokines, interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17-type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA­immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1 involvement. In addition, rabbit and mouse anti-rFBA antisera significantly protected the mice against a lethal S. pneumoniae challenge in comparison with preimmune sera. Our results emphasize the mixed involvement of the Th1, Th2 and Th17 arms of the immune system in response to immunization with pneumococcal rFBA, a potential vaccine candidate.

IL-12 receptor 1ß deficiency with features of autoimmunity and photosensitivity.

Primary immunodeficiences are often accompanied by autoimmune phenomena. IL-12 receptor deficiency is a well characterized primary immunodeficiency that leads to propensity to intracellular infections mainly with mycobacteria and Salmonella. We report on two patients with IL-12 receptor ß1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena.

Acute Liver Failure in a Pediatric Patient with Congenital Dysery-Thropoietic Anemia Type I Treated with Deferasirox.

Congenital dyserythropoietic anemias (CDA) represent a heterogeneous group of disorders characterized by morphological abnormalities of erythroid precursor cells and various degrees of hemolysis. Iron overload is a result of continuous hemolysis and recurrent transfusions. It is treated with iron chelators, including deferasirox. We present here a case of acute liver failure in a 12 years old girl with CDA type I treated with deferasirox and discuss the approach to treatment.