Prolactin's paradox: Friend, foe, or both in immune regulation?

Over 100 diseases have been recognized as autoimmune in nature, collectively affecting ∼20 % of the population in industrialized countries. These conditions are more prevalent among women of childbearing age, reflecting the potential association between alterations in the immune-neuroendocrine network, on the one hand, and autoimmune conditions, on the other. Prolactin (PRL), a polypeptide hormone that is primarily (but not only) secreted by the lactotrophic cells of the pituitary gland, is a critical element of the immune-neuroendocrine network. Although this hormone has several nonimmune functions, its role in regulating immune responses and affecting autoimmune inflammation is particularly enigmatic and controversial. Indeed, PRL interacts with various immune cells to bolster the body defenses, but also potentially to exacerbate autoimmune conditions. Understanding how and when PRL acts as a 'friend or foe' is crucial for unraveling its role as a potential therapeutic target in the management of autoimmune diseases (AIDs). This review therefore provides a critical overview of PRL's role in the immune system, and of the influence of this pleiotropic hormone in the development of autoimmunity.

Contribution of active surveillance cultures to the control of hospital-acquired carbapenem-resistant Acinetobacter baumannii in an endemic hospital setting.

BACKGROUND: Despite the increasing rates of carbapenem-resistant Acinetobacter baumannii (CRAB) carriage among hospitalized patients in endemic settings, the role of active surveillance cultures and cohorting is still debated. We sought to determine the long-term effect of a multifaceted infection-control intervention on the incidence of CRAB in an endemic setting. METHODS: A prospective, quasi-experimental study was performed at a 670-bed, acute-care hospital. The study consisted of 4 phases. In phase I, basic infection control measures were used. In phase II, CRAB carriers were cohorted in a single ward with dedicated nursing and enhanced environmental cleaning. In phase III large-scale screening in high-risk units was implemented. Phase IV comprised a 15-month follow-up period. RESULTS: During the baseline period, the mean incidence rate (IDR) of CRAB was 44 per 100,000 patient days (95% CI, 37.7-54.1). No significant decrease was observed during phase II (IDR, 40.8 per 100,000 patient days; 95% CI, 30.0-56.7; P = .97). During phase III, despite high compliance with control measures, ongoing transmission in several wards was observed and the mean IDR was 53.9 per 100,000 patient days (95% CI, 40.5-72.2; P = .55). In phase IV, following the implementation of large-scale screening, a significant decrease in the mean IDR was observed (25.8 per 100,000 patient days; 95% CI, 19.9-33.5; P = .03). An overall reduction of CRAB rate was observed between phase I and phase IV (rate ratio, 0.6; 95% CI, 0.4-0.9; P < .001). CONCLUSIONS: The comprehensive intervention that included intensified control measures with routine active screening cultures was effective in reducing the incidence of CRAB in an endemic hospital setting.

Outcomes of ICU patients treated with intravenous immunoglobulin for sepsis or autoimmune diseases.

OBJECTIVES: To evaluate the outcomes of hospitalized patients in two intensive care units (ICU) treated with intravenous immunoglobulin (IVIg) added to standard-of-care therapy. The indications for IVIg therapy were sepsis or autoimmune disease. METHODS: We conducted a retrospective study involving adult patients with sepsis and autoimmune diseases, who received IVIg in the ICU at Wolfson and Sheba Medical Centers. A predefined chart was compiled on Excel to include a complete demographic collection, patient comorbidities, chronic medication use, disease severity scores (Charlson Comorbidity Index; SOFA and APACHE II index scores), indication and dosage of IVIg administration, duration of hospitalization and mortality rates. RESULTS: Patients (n - 111) were divided into 2 groups: patients with sepsis only (n-67) and patients with autoimmune disease only (n-44). Septic patients had a shorter ICU stay, received IVIg early, and had reduced mortality if treated with high dose IVIg. Patients with autoimmune diseases did not have a favorable outcome despite IVIg treatment. In this group, IVIg was administered later than in the sepsis group. CONCLUSIONS: IVIg therapy improved the outcomes for ICU patients with sepsis.

Screening for Medication Errors and Adverse Events Using Outlier Detection Screening Algorithms in an Inpatient Setting.

OBJECTIVES: To evaluate the potential of a novel system using outlier detection screening algorithms and to identify medication related risks in an inpatient setting. METHODS: In the first phase of the study, we evaluated the transferability of models refined at another medical center using a different electronic medical record system (EMR) on 3 years of historical data (2017-2019), extracted from the local EMR system. Following the retrospective analysis, the system's models were fine-tuned to the specific local practice patterns. In the second, prospective phase of the study, the system was fully integrated in the local EMR and after a short run-in period was activated live. All alerts generated by the system, in both phases, were analyzed by a clinical team of physicians and pharmacists for accuracy and clinical relevance. RESULTS: In the retrospective phase of the study, 226,804 medical orders were analyzed, generating a total of 2731 alerts (1.2% of medical orders). Of the alerts analyzed, 69% were clinically relevant alerts and 31% were false alerts. In the prospective phase of the study, 399 alerts were generated by the system (1.6% of medical orders). The vast majority of the alerts (72%) were considered clinically relevant, and 41% of the alerts caused a change in prescriber behavior (i.e. cancel/modify the medical order). CONCLUSION: In an inpatient setting of a 600 bed computerized decision support system (CDSS) -naïve medical center, the system generated accurate and clinically valid alerts with low alert burden enabling physicians to improve daily medical practice.

[ABDOMINAL PAIN AND SEIZURES - A COLORFUL TURN OF EVENTS].

INTRODUCTION: The porphyria diseases are inherited and may be exacerbated by environmental triggers. The most common symptoms are abdominal pain, constitutional symptoms, and mental symptoms. The diagnosis of acute intermittent porphyria is usually made during an attack. The initial diagnosis of porphyria is made with the help of biochemical tests in the blood, urine and feces. The best diagnostic approach for carriers of the genes for porphyria, regardless of the manifestation of symptoms, is a molecular test of the genetic mutations, according to which the porphyria can be divided into different types.

Autoimmunity and COVID-19 - The microbiotal connection.

BACKGROUND AND AIMS: The novel SARS-CoV-2 has been rattling the world since its outbreak in December 2019, leading to the COVID-19 pandemic. The learning curve of this new virus has been steep, with a global scientific community desperate to learn how the virus is transmitted, how it replicates, why it causes such a wide spectrum of disease manifestations, resulting in none or few symptoms in some. Others are burdened by an intense immune response that resembles the cytokine storm syndrome (CSS), which leads to severe disease manifestations, often complicated by fatal acute respiratory distress syndrome and death. Research efforts have been focusing on finding effective cures and vaccinations for this virus. The presence of SARS-CoV-2 in the gastrointestinal (GI) tract, represented by several GI manifestations, has led to its investigation as a target for the virus and as an indicator of disease severity. The response of the microbiome (which is heavily linked to immunity) to the novel SARS-CoV-2 virus, and its role in igniting the exaggerated immune response has therefore become a focus of interest. The objective of our study was to gather the data connecting between the microbiome, the GI tract and COVID-19 and to investigate whether these reported alterations in the gut microbiome bear any resemblance to those seen in lupus, the prototypical autoimmune disease. Confirming such changes may become the steppingstone to potential therapies that may prevent transmission, progression and immune related manifestations of COVID-19, via manipulation of the gut microbiota. METHODS: We performed an extensive literature review, utilizing the Pubmed search engine and Google Scholar for studies evaluating the microbiome in COVID-19 patients and compared results with studies evaluating the microbiome in lupus. We searched for the terms: microbiome, dysbiosis, COVID-19, SARS-CoV-2, gastrointestinal as well as lupus and autoimmune. While there were hundreds of articles which referred to gastrointestinal manifestations in COVID-19, to date only 4 studies investigated the gastrointestinal microbiome in this setting. We compared the similarities between microbiome of COVID-19 patients and lupus patients. RESULTS: We found that there are several similar processes of immune dysregulation in patients with COVID-19 and in those with lupus, with several other alterations seen in other pathological states. Some of these similarities include loss of microbiota biodiversity, increased representation of pathobionts, which are microbes associated with inflammation and disease (i.e Proteobacteria) and a relative decrease of symbionts, which are protective microbes, associated with anti-inflammatory properties (i.e Lactobacillus). Compromise to the intestinal barrier has also been reported in both. CONCLUSIONS: We conclude that the gastrointestinal tract contributes to the disease manifestations in COVID-19. Whether gastrointestinal dysbiosis is the cause or effect of gastrointestinal manifestations and several severe systemic manifestations, which may be the response to an increased pro-inflammatory environment, is still debatable and warrants further investigation. Given the resemblance of the microbiome in COVID-19 patients to that seen in lupus patients, it becomes clearer why several therapies used in autoimmune conditions are currently under investigation for the treatment of COVID-19 patients. Moreover, these findings should promote further investigating the utility of manipulation of the microbiome, via nutritional supplementation or even fecal transplantations, interventions that may alter the course of the disease, and potentially prevent disease transmission at low cost and low risk.

The microbiome links between aging and lupus.

BACKGROUND AND AIMS: Many forms of immune dysregulation, which lead to inflammaging and senescence, have been demonstrated in patients with systemic lupus erythematosus (SLE; lupus) and in the aging population. The discovery of the microbiome and its association with human health and pathology has led it to be the center of investigation as a major contributor to the pathogenesis of immunosenescence in both populations. Similar alterations to the microbiome in the form of dysbiosis, that are demonstrated in both aging and in lupus patients, may help explain the significant overlap in clinical manifestations seen in these groups. METHODS: We performed an extensive literature review, utilizing the Pubmed search engine and Google Scholar for studies evaluating the microbiome in two groups, elderly populations and lupus patients (both murine and human models), between the years 2000-2019. We searched for the terms: microbiome, dysbiosis, lupus, elderly, aging and inflammaging, which yielded hundreds of articles, of which 114 were used for preparation of this paper. We compared the similarities between the populations. RESULTS: We found that the similar processes of immune dysregulation, in both aging populations and lupus patients, extend to the microbiome, in the form of dysbiosis. Some of these similarities include loss of microbiota biodiversity, increased representation of microbes that are associated with inflammation and disease (i.e Proteobacteria, Bacteroidetes), a relative decrease in protective microbes with "anti-inflammatory" properties (i.e Firmicutes) and a subsequent compromise to the intestinal barrier, leading to leakage of proinflammatory microbial components in both groups. CONCLUSIONS: We conclude that there are several similar alterations in the composition and function of the microbiome of lupus patients and aging individuals, leading to immunosenescence, which may also be a contributing mechanism in lupus. It seems in fact that the microbiome of SLE may actually be analogous to immunosenescence. This knowledge may help the continuous efforts in finding a solution for both conditions.

[AN UNUSUAL DIAGNOSIS OF CHRONIC URTICARIA].

INTRODUCTION: Cutaneous lupus is an autoimmune disease that can be represented individually or as part of the systemic disease, systemic lupus erythematosus (SLE). Initial presentation of skin manifestations, such as chronic urticatia, should raise the possibility that it might be the first manifestation of an active disease, for example SLE. Despite the broad differential diagnosis of chronic urticaria, other plausible diagnosis should be ruled out with complete anamnesis that includes family background, substance exposure, new and chronic drug therapy, serological and immunological blood tests, diagnostic biopsy of the skin and imaging as needed to rule out malignancy. We present a case of a patient with a family history of various autoimmune diseases, who presented with chronic urticatia and joint pain with partial response to steroid therapy over a period of several months.

Histiocytic Sarcoma

BACKGROUND: Histiocytic sarcoma (HS) is a rare hematopoietic malignancy originating from the monocyte/macrophage bone marrow lineage. HS can occur in isolation or in association with other hematological neoplasms such as non-Hodgkin lymphoma (NHL), myelodysplasia, or acute leukemia. Clinically, HS can affect lymph nodes, gastrointestinal tract, skin, bone marrow, and spleen as well as the central nervous system. Most cases of HS follow an aggressive clinical course, with most patients dying of progressive disease within one year of diagnosis.

Systemic lupus erythematosus: an expert insight into emerging therapy agents in preclinical and early clinical development.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic disease that is potentially fatal. There is no cure for SLE and the medications used are associated with toxic side effects. In the era of revolutionary emerging novel biologic agents, the design and investigation of targeted therapy for these patients is necessary. Novel therapies under investigation in phase II-III clinical trials showed promising results. Therapies can target various pathways involved in SLE including cytokines, signal transduction inhibitors, B-cell depletion and interference with co-stimulation. Of interest is the proof of concept of sequential therapy. AREAS COVERED: We performed an extensive literature search via PubMed, Medline, Elsevier Science and Springer Link databases between the years 2014-2020 using the following terms: SLE, novel treatments. We have reviewed 232 articles and selected those articles that (i) focus on phase II-III emerging therapies and (ii) offer new findings from existing therapies, which reveal breakthrough concepts in SLE treatment. EXPERT OPINION: It is still difficult to crack the puzzle of a successful SLE treatment approach. New strategies with potential may encompass the targeting of more than one protein. Another way forward is to identify each SLE patient and personalize therapy by clinical manifestations, disease activity, serology and activated protein.

Prolactin and autoimmunity: The hormone as an inflammatory cytokine.

Nowadays, more than 80 autoimmune disorders are recognized, in which an aberrant immune response against different organs and tissues plays a crucial role. Hormonal homeostasis has great influence in achieving competent and healthy immune system function. Prolactin has a bioactive function acting as a hormone and a cytokine. It influences the immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Hyperprolactinemia has been detected in many patients with different autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, multiple sclerosis, autoimmune thyroid disease, systemic sclerosis, among others, and its believed to play a crucial role in disease pathogenesis. A direct correlation between prolactin levels and disease activity was not clear. Genetic factors may have a role in humans as in animal models. Dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, the authors attempt to provide a critical overview on the role of prolactin in the immune system, exploring its contribution to the development of autoimmune diseases.

Exacerbations of autoimmune diseases during pregnancy and postpartum.

Autoimmune diseases represent a complex heterogeneous group of disorders that occur as a results of immune homeostasis dysregulation and loss of self-tolerance. Interestingly, more than 80% of the cases are found among women at reproductive age. Normal pregnancy is associated with remarkable changes in the immune and endocrine signaling required to tolerate and support the development and survival of the placenta and the semi-allogenic fetus in the hostile maternal immune system environment. Gravidity and postpartum represent an extremely challenge period, and likewise the general population, women suffering from autoimmune disorders attempt pregnancy. Effective preconception counseling and subsequent gestation and postpartum follow-up are crucial for improving mother and child outcomes. This comprehensive review provides information about the different pathways modulating autoimmune diseases activity and severity, such as the influence hormones, microbiome, infections, vaccines, among others, as well as updated recommendations were needed, in order to offer those women better medical care and life quality.

Cardiac Manifestations of Antiphospholipid Syndrome With Focus on Its Primary Form.

Antiphospholipid syndrome (APS) is a multisystem autoimmune disease most commonly associated with recurrent arterial and venous thromboembolism and recurrent fetal loss. Other possible antiphospholipid antibody (aPL)-related clinical manifestations include cardiac involvement. The heart can be involved through immune mediated and /or thrombotic mechanisms. Mortality due to cardiovascular problems is elevated in APS. However, the cardiovascular risk in patients with primary APS (PAPS) compared with lupus-related APS is yet to be established. Cardiac symptoms of APS include valve abnormalities (thickening and vegetations), coronary artery disease (CAD), myocardial dysfunction, pulmonary hypertension, and intracardiac thrombi. Heart valve lesions are the most common cardiac manifestation, observed in approximately one third of PAPS patients and usually do not cause hemodynamic significance. Deposits of immunoglobulins including anticardiolipin (aCL), and of complement components, are commonly observed in affected heart valves from these patients. This suggests that an inflammatory process is initiated by aPL deposition, eventually resulting in the formation of valvular lesion. aPL may have a direct role in the atherosclerotic process via induction of endothelial activation. Multiple traditional and autoimmune-inflammatory risk factors are involved in triggering an expedited atherosclerotic arterial disease evident in APS. It is imperative to increase the efforts in early diagnosis, control of risk factors and close follow-up, in the attempt to minimize cardiovascular risk in APS. Clinicians should bear in mind that a multidisciplinary therapeutic approach is of paramount importance in these patients. This article reviews the cardiac detriments of APS, including treatment recommendations for each cardiac complication.

The complexity of an overlap type resistant cryoglobulinemia: a case report and review of the literature.

Type I cryoglobulinemia is associated with B cell proliferative diseases, whereas essential mixed cryoglobulinemia is classically associated with infections, malignancy, and autoimmune diseases, but may be idiopathic. Prognosis in patients with grave manifestations and renal involvement is often poor. We report a case of a 40-year-old woman, 2 weeks post-partum for pre-eclampsia who was hospitalized with nephritic syndrome and acute renal failure. The patient harbored type I and type II cryoglobulinemia. Renal and cutaneous biopsies confirmed the diagnosis; however, an underlying etiology was not established. A bone marrow biopsy suggested monoclonal gammopathy of undetermined source (MGUS). Despite therapy with intravenous cyclophosphamide, rituximab, plasmapheresis, dialysis, and bortezomib, the patient succumbed after 8 months of hospitalization. We suggest that an overlap entity of types I and II cryoglobulinemia with severe multi-organ involvement not only is rare but also may be resistant to conventional therapy and fatal.

Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors.

The discovery and approved treatment with immune checkpoint inhibitors (ICIs) for a variety of cancers has changed dramatically the morbidity and mortality rates for these patients. Despite the obvious benefits, their use is associated with unique immune-related adverse effects (irAEs), including autoimmune conditions such as: inflammatory arthritis, myositis, vasculitis and Sicca syndrome. The appearance of ICIs-induced autoimmune irAE requires from oncologists and rheumatologists a different approach to the identification and treatment of these conditions, which may differ from the classic and traditional approach to rheumatologic diseases. It should be taken into consideration that ICIs therapy in patients with preexisting autoimmunity could be possible, but with a cost of causing disease exacerbation. In this extensive review, we present the autoimmune irAEs, mostly as phenomena, but also as classic autoimmune diseases as well as therapeutic options for the side effects.

Prolactin and Autoimmunity.

The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.