Systemic Lupus Erythematosus (sle, Lupus) Vasculitis

Spinal Cord Image Denoising Using Dncnn Algorithm

Background: Spinal image denoising plays a vital role in the accurate diagnosis of disc herniation (DH).

Objective: Traditional denoising algorithms perform less due Limited Directional Selectivity problem and do not adequately capture directional information in pixels. Traditional algorithms' edge representation and texture details are insufficient for the earlier detection of DH. Limited Directional Selectivity leads to inaccurate diagnosis and classification of Disc Herniation (DH) stages. The DH stages are (i) Degeneration (ii) Prolapse (iii) Extrusion and (iv) Sequestration. Moreover, detection of DH size below 2mm using MR image is the major problem.

Methods: To solve the above problem, spinal cord MR images fed to the proposed Parrot optimization tuned Denoising Convolutional Neural Network (Po- DnCNN) algorithm for perspective enhancement of nucleus pulposus region in the spinal cord, vertebrae. The perspective enhancement of Spinal cord image led to the accurate classification of stages and earlier detection of DH by using the proposed Hippopotamus optimization- Fast Hybrid Vision Transformer (Ho–FastViT) algorithm. For this study, spinal cord MR images are obtained from the Grand Challenge website – SPIDER dataset.

Results: The proposed Po-DnCNN method and Ho-FastViT results are analysed quantitatively and qualitatively based on the edge, contrast, classification of the stage, and enhancement of the projected nucleus pulposus region in the spinal cord and vertebrae. The predicted DH results using the proposed method are compared with the manual Pfirrman Grade value of the spinal card method.

Conclusion: Proposed method is better than traditional methods for earlier detection of DH. Po-DnCNN and Ho-FastViat methods give high accuracy of about 98% and 97% compared to traditional methods.

Hydralazine Induced Vasculitis: A Case Report

Background: Hydralazine has been used in the treatment of hypertension and heart failure for a long time. It has been associated with the development of Vasculitis and Drug induced lupus. This is a male patient in his sixties who was admitted at the hospital and prescribed hydralazine. He developed Hydralazine-induced lupus with Pancytopenia and renal failure. This case report has been written to raise awareness about the hydralazine side effects.

Case Presentation: This case report describes a 68-year-old male, transferred to our hospital for rehabilitation. He was tracheostomized. He is hypertensive with a history of CVA. BP was elevated during the admission. He has no family history of immunological diseases or any allergies. 6 months after hydralazine, the patient started to have a purpuric rash over the lower limbs and an elevated renal profile. Only Direct Coomb’s test was positive. He had hematuria and pancytopenia also. He was started on steroids and he became edematous. On March 2021, the hydralazine was stopped and the patient's blood tests improved, the rash disappeared and hematuria stopped. Unfortunately, he got fungemia and septicemia with pneumonia. He became hypotensive and anuric. The patient kept deteriorating and passed away.

Discussion: Hydralazine is not a first line choice for the treatment of hypertension. Common side effects include tachycardia and headache. It can also cause drug-induced lupus.

Conclusion: Hydralazine has been used in the treatment of hypertension and heart failure for a long time. It has been associated with the development of Vasculitis and Drug induced lupus.

Rare and First Manifestation of Lupus Panniculitis as Lupus Mastitis: A Case Report and Literature Review

Introduction: This case report presents a rare occurrence of lupus mastitis affecting the breast.

Case Presentation: An induration with mild discomfort was detected in the upper inner quadrant of the right breast of a 27-year-old Chinese woman with regular menstrual cycles. The patient is currently unmarried and has no previous history of full-term pregnancies or lactation. An ill-defined, subcutaneous, hyperechoic lesion with no calcification was visualized on breast ultrasound. Peripheral and internal blood flow signals demonstrated high intensity. Pathological analysis of a breast needle biopsy revealed fat lobule necrosis accompanied by mixed lymphoplasmacytic and histiocytic aggregates.

Conclusion: The diagnosis of lupus mastitis necessitates a comprehensive evaluation of the patient's medical history, serological testing, imaging studies, and histopathological analysis.

Assessment of Interleukin 17 in Egyptian Systemic Lupus Erythematosus Patients as a Biomarker in Disease Activity

Introduction: Systemic lupus erythematosus (SLE) is a chronic idiopathic systemic autoimmune disorder with dysregulation of adaptive and innate immune systems. Interleukin (IL)-17 is the prototypical pro-inflammatory cytokine of T helper 17 (Th17) cells. Therefore, it contributes to the pathogenesis of human SLE.

Aim: The aim of the research paper was the evaluation of IL-17 level as a biomarker in the SLE cohort and its relation to disease activity and analysis of IL-17 concentration in patients with lupus nephritis and non-lupus nephritis.

Methods: The research enrolled 45 SLE patients according to Systemic Lupus International Collaborating Clinics Classification Criteria (SLICC), and age and sex-matched. The patients underwent full history, clinical examination, laboratory investigation, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) calculation.

Results: The mean age ± SD of the participants equaled 32 ± 11 years, and serum IL-17 in SLE cases was statistically significantly high (p < 0.001). No statistically significant correlations were reported between disease activity according to SLEDAI and IL-17. In addition, a statistically significant positive correlation was reported between IL-17 and ESR, and a high statistically significant negative correlation was reported between IL-17 and C3 and C4 (P < 0.001). A statistically significant positive correlation was reported between IL-17 and 24-hour urinary proteins with a Pvalue of 0.01.

Conclusion: SLE cases demonstrated higher levels of serum IL-17, contributing to SLE pathogenesis. However, no statistically significant difference was reported between IL-17 and Lupus nephritis. IL-17 and SLE activity (SLEDAI) did not correlate.

A statistically significant positive relation was reported between IL-17 and 24-hour urinary proteins. Additionally, a high statistically significant negative correlation was reported between IL-17 and C3 and C4.

Insight into the Epidemiology of the Adult-onset Systemic Autoimmune Rheumatic Diseases in Egypt: A Descriptive Study of 8690 Patients

Background/Objective: Although systemic autoimmune rheumatic diseases (SARDs) seem to be ubiquitous, Africa and the Middle East seem to be a remarkable exception with scarcity of data compared with the developed countries. Furthermore, most of the studies addressed a particular disease. This work aimed to shed light on the relative frequency and epidemiology of the different adult-onset SARDs in Egypt.

Methods: This is a retrospective hospital-based study including six university hospitals providing free health care services: Cairo, Alexandria, Tanta, Suez Canal, Beni-Suef and Assiut University Hospitals. All available files for patients attending the outpatient clinics or admitted to the inpatient departments between January 2000 and December 2021 were retrospectively reviewed. Data about the patient’s diagnosis, gender, age at disease onset, year of disease onset and residence were collected.

Results: The study included 8690 patients. Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Behçet’s disease (BD) and spondyloarthropathies (SPA) represented the main SARDs in Egypt. They mainly affect young patients below the age of 40 years. RA and SLE mainly affect females; males are mainly affected by axial SPA and BD. There is an increasing incidence of SARDs during the study period.

Conclusion: The study revealed the high burden of SARDs in Egypt, helping better allocation of economic resources for the management of diseases of the highest prevalence and those affecting the young reproductive age groups. Increased public and medical staff awareness about SARDs is recommended to help early referral of patients to rheumatologists and, hence, better estimation of their epidemiology.

“Scleroderma” and “Scleroderma-like” Capillaroscopic Pattern-Differences and Similarities

Introduction: The “scleroderma” type capillaroscopic pattern is a reference pattern in rheumatology that is a diagnostic sign for systemic sclerosis (SSc) in an appropriate clinical context and is observed in more than 90% of scleroderma patients. Similar microvascular changes, the so-called “scleroderma-like”, have been described albeit in a lower proportion of patients with other rheumatic diseases, such as dermatomyositis (DM), undifferentiated connective tissue diseases (UCTD), systemic lupus erythematosus (SLE), etc. Three distinct stages of “scleroderma” pattern have been suggested by Cutolo et al., i.e., “early”, “active”, and “late”. However, disease duration is just one of the factors that contributes to the progression of microvascular changes, and in this regard, “active” or even “late” pattern could be observed in patients with shorter disease duration. In addition, stable microvascular changes could be found for long periods in other cases.

Objective: The aim of the study was to assess the presence of differentiating features between “scleroderma” pattern in SSc and “scleroderma-like” pattern in other rheumatic diseases.

Methods: 684 capillaroscopic images demonstrating a “scleroderma” and “scleroderma-like” pattern have been analysed in the current retrospective cross-sectional study. 479 capillaroscopic pictures were obtained from 50 SSc patients, 105 from 7 DM patients, 38 from 10 rheumatoid arthritis (RA) patients, 36 images from 5 patients with SLE, and 26 images from 9 patients with UCTD. All capillaroscopic images used in the current analysis have fulfilled the criteria for “sclerderma/scleroderma-like” pattern, as the pathological changes in the capillaroscopic parameters have also been confirmed by quantitative measurement of capillary diameters, capillary density, and intercapillary distance. All the images have been categorized into one of the following groups, i.e., “early”, “active” and “late” phases (according to the definition of Cutolo et al.), or “other” findings, the latter being specifically described as they could not be attributed to one of the other three categories.

Results: 479 capillaroscopic pictures were obtained from 50 scleroderma patients. 31 of them showed an “early”, 391 an “active” phase, and 57 a “late” phase “scleroderma” type microangiopathy. In 69 images assessed as an “active” pattern, neoangiogenesis was found. In 43 out of 105 capillaroscopic pictures from DM patients, an “active” phase was detected; in 2 of the images, a “late” pattern was found, and in 60 capillaroscopic pictures, neoangiogenesis in combination with giant capillary loops was observed. Early microangiopathy was not found in this group. Among capillaroscopic images from SLE patients, “late” phase microangiopathy was not found. “Early” phase was present in 3 images, “active” phase in 29, neoangiogenesis in “active” phase in 4 pictures. Early microangiopathy was detected in 11 capillaroscopic pictures from RA patients (8 out of 9 patients), an “active” phase in 4 images (3 patients), and in 23 capillaroscopic images, neoangiogenesis with mild capillary derangement and capillary loss and single giant capillaries (“rheumatoid neoangiogenic pattern”) were observed. Classic “late” type microangiopathy was not found in RA patients as well as among patients with UCTD. The predominant capillaroscopic pattern in UCTD patients was early microangiopathy (n = 23). The rest images from UCTD exhibited features of the “active” phase.

Conclusion: In conclusion, early microangiopathy was observed in RA, SLE, and UCTD patients, but not in patients with DM. An “active” phase “scleroderma” type capillaroscopic pattern was detected in all patient groups other than SSc, i.e., DM, SLE, RA, and UCTD. “Late” phase “scleroderma” type microangiopathy was present in patients with scleroderma and DM and was not observed in SLE, RA, and UCTD. Despite the fact that in some cases, microangiopathy in scleroderma and other rheumatic diseases may be indistinguishable, the results of the current research have shown the presence of some differentiating features between “scleroderma” and ”scleroderma-like” microangiopathy that might be a morphological phenomenon associated with differences in the pathogenesis and the degree of microvascular pathology in various rheumatic diseases.

Insight of Engineered Nano-based Biologics Approaches used to Combat Autoimmune Disease using TNF-α & IL Inhibitors

Autoimmune disease is increasing widely, and the biologicals in autoimmune disease play a vital role in the cure. Biologicals have an affinity to bind the specific target molecule and suppress inflammation. The different biologicals are used to treat various autoimmune diseases by preventing the cytokines from unlocking cells and causing inflammation. Each biologic targets a different cytokine. The common classes of biologic that are used to treat autoimmune disease are i) Tumor Necrosis Factor-alpha (TNFα) inhibitors and ii) Interleukin Inhibitors (IL). Along with biologics, nanomedicine has shown to be a successful method for creating customized nanomaterials with the potential to deliver medicinal agents to particular organs or tissues drugs without causing immunosuppressive or immunostimulatory adverse effects. This article reviews biologics used in treating Autoimmune Disease (AD) and the mechanism involved. The examination of current developments that have been made to create innovative nanoparticle-based therapies for autoimmune illnesses and their inclusion in vaccines. Also, recent clinical trials display nanosystem strategies for treating AD.

Kikuchi-Fujimoto Disease: A Distinct Pathological Entity but also an "Overlap" Autoimmune Syndrome: A Systematic Review

Background: The association between KFD and autoimmune diseases, not only with systemic lupus erythematosus, has been repeatedly described.

Objective: The aim of this review is to evaluate whether an overlap syndrome is present between KFD and autoimmune diseases, whether there is a chronological and a casual relationship between the pathologies.

Methods: The databases used for the overlap case search were Medline and Embase from which we extrapolated the studies of interest. The search queries used were: Kikuchi-Fujimoto Syndrome and juvenile idiopathic arthritis or systemic lupus erythematosus or Systemic Sclerosis or Antiphospholipid Syndrome or Sjogren's Syndrome. All study types were considered (n = 103).

Results: Total number of included studies are 43. We have shown that there is an \"overlap\" syndrome between KFD and other autoimmune diseases. The chronology of disease onset was variable; autoimmune disease may be \"preceding\" (n = 11 cases) or \"simultaneous\" (n = 20 cases) or \"post\" (n = 8 cases). Kikuchi-Fujimoto Syndrome. Also, the autoimmune disease can present with a complete clinical picture or only with the presence of autoantibodies.

Conclusion: the different pathologies associated with KFD with different chronologies would suggest that there is an alteration of the immune system that allows the pathologies to occur in different temporal relationships.

An Approach to Psychiatric Illness in Rheumatology Clinics

Rheumatologists encounter patients with psychiatric illnesses daily in their practice; however, formal training in rheumatology does not sufficiently equip rheumatologists with guidance for managing common psychiatric illnesses. This study reviews common clinical situations involving psychiatric symptoms, their relationship with rheumatologic conditions, and their effects on clinical presentation and management. We illustrate key principles in a case-based format and reflect on the management of psychiatric components. Based on these discussions and a brief review of the epidemiology of psychiatric illnesses, we emphasize the prevalence and significance of these problems in daily practice.

Neurological Complications in Systemic Inflammatory Diseases

Systemic inflammatory diseases could produce neurologic complications, and they are frequently incorporated in the differential diagnosis of neurological symptoms. There are wellestablished criteria to meet the diagnosis of neurologic manifestations of these systemic diseases.

Methods: However, the range of clinical presentations varies in each condition, and the prevalence of these complications differs between studies. Hence, in many cases, an etiological relationship is not clearly defined.

Results and Conclusion: For these reasons, it is challenging to make an accurate diagnosis. We analyzed the spectrum of neurological manifestations in a cohort of patients with systemic lupus erythematosus, rheumatoid arthritis, Behçet disease and sarcoidosis in order to improve our current knowledge of these complications.

Interleukin-1 in Coronary Artery Disease

Cardiovascular disease is the leading cause of mortality worldwide. Inflammation has long been established as a key component in the pathophysiology of coronary artery disease. The interleukin-1 family consists of 11 members that regulate the inflammatory response through both pro- and anti-inflammatory properties with the Nod-like receptor (NLR) family pyrin domain containing 3 inflammasome having a pivotal role in the process of converting interleukin-1 beta and interleukin- 18, two key inflammatory mediators, into their mature forms. Interleukin-1 affects various cell types that participate in the pathogenesis of atherosclerosis as it enhances the expression of leukocyte adhesion molecules on the surface of endothelial cells and augments the permeability of the endothelial cell barrier, attracting monocytes and macrophages into the vessel wall and aids the migration of smooth muscle cells toward atheroma. It also enhances the aggregation of low-density lipoprotein particles in endothelium and smooth muscle cells and exhibits procoagulant activity by inducing synthesis, cell-surface expression and release of tissue factor in endothelial cells, promoting platelet adhesion. The value of interleukin-1 as a diagnostic biomarker is currently limited, but interleukin-1 beta, interleukin-18 and interleukin-37 have shown promising data regarding their prognostic value in coronary artery disease. Importantly, target anti-inflammatory treatments have shown promising results regarding atherosclerosis progression and cardiovascular events. In this review article, we focus on the immense role of interleukin-1 in atherosclerosis progression, inflammation cascade and in the clinical application of target anti-inflammatory treatments.

Association of Circulating Levels of Hypoxia-Inducible Factor-1α and miR-210 with Photosensitivity in Systemic Lupus Erythematosus Patients

Background: miR-210, a key hypoxamiR, regulates hypoxia and inflammation-linked hypoxia. Systemic lupus erythematosus (SLE), a chronic autoimmune disease, is responsible for many pathological disorders, including photosensitivity.

Objective: This study aimed to find the correlation between circulating miR-210/HIF-1α levels and photosensitivity in SLE patients and other SLE-associated pathological complications in a single-center case-control study.

Methods: The study population comprised 104 SLE Egyptian patients with photosensitivity, 32 SLE patients without photosensitivity, and 32 healthy subjects. SLE activity was assessed for all patients using the SLE Disease Activity Index (SLEDAI). Clinical complications/manifestations and hematological/serological analyses were recorded. HIF-α concentration was investigated by ELISA, and miR-210 expression was analyzed by qRT-PCR.

Results: The results revealed that circulating miR-210 was significantly increased in the SLE/photosensitivity group versus the SLE and control groups. The additional occurrence of malar rash, oral ulcers, renal disorders, or hypertension resulted in a higher expression of miR-210. SLEDAI activity status showed no effect on miR-210. Erythrocyte sedimentation rate, white blood cells, hemoglobin, platelets, patient age, and disease duration were positively correlated with circulatory miR-210. HIF-α concentration was significantly induced in the SLE/photosensitivity group versus the SLE and control groups. In SLE/photosensitivity, the presence of renal disorders and hypertension resulted in the highest HIF-α concentrations. A strong positive correlation was recorded between HIF-α concentration and circulatory miR-210 in SLE/photosensitivity patients (r = 0.886).

Conclusion: The dysregulation of circulating miR-210/HIF-1α levels in SLE/ photosensitivity patients is controlled by the presence of additional pathological complications, and results suggest that the hypoxia pathway might interact positively with the pathogenesis and disease progression of SLE.

Cyclosporine Ameliorates Silica-Induced Autoimmune Hepatitis in Rat Model by Altering the Expression of Toll-Like Receptor-4, Interleukin-2, and Tumor Necrosis Factor-α

Background: Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by the presence of autoantibodies. Toll-like receptor (TLR)-4 is a TLR family member that, upon activation in hepatocytes, initiates a cascade of events. Interleukin-2 (IL-2) and tumour necrosis factor α (TNF-α) are potent inflammatory cytokines secreted in AIH, playing an important role in the early development of inflammation and hepatocyte damage.

Objectives: This study examined the role of cyclosporine in AIH and illustrated its actions on altered hepatic function in the silica-induced AIH model.

Methods: AIH was induced in Wistar rats using sodium silicate. The rats were divided into four groups: the control group, silica-AIH group, cyclosporine-treated group, and prevention group. TLR-4 and IL-2 mRNA expressions in liver tissues were tested by RTPCR.

Results: AIH was associated with up-regulation of liver enzymes, IL-2 and TLR-4 gene expression, while cyclosporine significantly down-regulated the expression of both. The relative quantity of TLR-4 mRNA was 1±0, 13.57±1.91, 4±0.38, and 2±0 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Also, the relative quantity of IL-2 mRNA was 1±0, 14.79±1.42, 7.07±0.96, and 3.4±0.55 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Additionally, immunohistochemical staining for TNF-α in liver sections was increased in the silica-AIH group but was found to decrease in the cyclosporine-treated and prevention groups.

Conclusion: This study advocates the therapeutic role of cyclosporine in treating immune-mediated hepatic diseases. Cyclosporine improves histological alterations in the liver and inhibits the production of proinflammatory cytokines.

Cryofibrinogenemia: What Rheumatologists Should Know

Cryofibrinogenemia refers to the presence of cryofibrinogen in plasma. This protein has the property of precipitating at lower temperatures. Cryofibrinogenemia is a rare disorder, clinically characterized by skin lesions, such as ulcers, necrosis, livedo reticularis, arthralgia, thrombosis, and limb ischemia. These features are most often observed in rheumatological practice and consist of differential diagnoses of antiphospholipid syndrome, primary vasculitis, thrombotic thrombocytopenic purpura, and cryoglobulinemia. Classical histopathological findings include the presence of thrombi within the lumen of blood vessels of the skin without vasculitis. To date, there are no validated classification criteria. Management includes corticosteroids, immunosuppressive therapy, anticoagulants, and fibrinolytic agents. This narrative review aims to make physicians, particularly rheumatologists, aware of the existence of this underdiagnosed condition. There are no epidemiological studies evaluating the prevalence of cryofibrinogenemia in different rheumatological disorders. Studies are also required to investigate if certain features of rheumatological diseases are related to the presence of cryofibrinogenemia.

Prevalence of Anti-nuclear and Anti-phospholipid Antibodies in an Egyptian Cohort with Schizophrenia: A Case-control Study

Background: Psychiatric disorders, including schizophrenia, could herald other manifestation( s) of systemic lupus erythematosus (SLE) potentially hindering timely and optimal management. Moreover, schizophrenia is among the described ‘extra-criteria’ manifestations of anti-phospholipid syndrome (APS). Hence, screening schizophrenia patients for SLE and APS may pose diagnostic and therapeutic implications.

Objectives: Examine schizophrenia patients with no overt connective tissue disease(s) manifestation( s) for clinical and/or serologic evidence of SLE and/or APS.

Methods: The study included 92 schizophrenia patients (61 (66.3%) males) and 100 age- and gender- matched healthy controls. Both groups were tested for anti-nuclear antibodies (ANAs), antidouble stranded deoxyribonucleic acid (anti-dsDNA) antibodies, complement 3 (C3) and C4, and criteria anti-phospholipid antibodies (aPL) (anticardiolipin Immunoglobulin (Ig) G and IgM, antibeta- 2-glycoprotein I IgG and IgM, and lupus anticoagulant (LAC)).

Results: The patients’ mean age and disease duration were 28.8 ± 8.1 and 5.7 ± 2.2 years, respectively. The prevalence of ANA positivity, height of titre, and pattern was comparable between patients and controls (p = 0.9, p = 0.8 and p = 0.1, respectively). Anti-dsDNA antibodies and hypocomplementemia were absent in both groups. A significantly higher frequency of positive LAC was observed among patients compared with controls (7.6% vs. 1%, p = 0.02), whereas other aPL were comparable between both groups. None of the patients or controls demonstrated clinically meaningful (medium or high) aPL titres.

Conclusion: In our study, schizophrenia was solely associated with LAC. Thus, in the absence of findings suggestive of SLE or APS, routine screening for both diseases is questionable.

Neuropsychiatric Systemic Lupus Erythematosus: A Remaining Challenge

Systemic Lupus Erythematosus (SLE) is an autoimmune disease, which affects a wide range of organs with variable clinical features. Involvement of the nervous system is a challenging and multifaceted manifestation of the disease, presenting with a broad range of symptoms. Neuropsychiatric lupus (NPSLE) encompasses seven syndromes of the peripheral and 12 of the central nervous system, associated with a high disease burden. Despite advances in the management of SLE, NP manifestations still pose a challenge to clinicians. First, diagnosis and attribution of SLE are difficult due to the lack of specific biomarkers or imaging modalities. Second, therapeutic options are limited, and evidence is mainly based on case reports and expert consensus, as clinical trials are sparse. Moreover, no validated outcome measure on disease activity exists. Current recommendations for treatment include supportive as well as immunosuppressive medication, depending on the type and severity of manifestations. As NPSLE manifestations are increasingly recognized, a broader spectrum of therapeutic options can be expected.

Rheumatologic Aspects of the COVID-19 Pandemic: A Practical Resource for Physicians in Kuwait and the Gulf region as Recommended by the Kuwait Association of Rheumatology

The Kuwait Association of Rheumatology members met thrice in April 2020 to quickly address and support local practitioners treating rheumatic disease in Kuwait and the Gulf region during the coronavirus disease 2019 (COVID-19) pandemic. Because patients with rheumatic and musculoskeletal disease (RMD) may need treatment modifications during the COVID-19 pandemic, we voted online for the general guidance needed by local practitioners. In this review, we have addressed patients' vulnerability with rheumatic disease and issues associated with their optimum management. Our recommendations were based on the formulation of national/international guidelines and expert consensus among KAR members in the context of the Kuwaiti healthcare system for patients with RMD. The most recent reports from the World Health Organization, the Center for Disease Control, the National Institutes of Health-National Medical Library, and the COVID-19 educational website of the United Kingdom National Health Service have been incorporated. We discuss the management of RMD in various clinical scenarios: screening protocols in an infusion clinic, medication protocols for stable patients, and care for patients with suspected or confirmed COVID infection and whether they are stable, in a disease flare or newly diagnosed. Further, we outline the conditions for the hospital admission. This guidance is for the specialist and non-specialist readership and should be considered interim as the virus is relatively new, and we rely on the experience and necessity more than evidence collection. The guidance presented should be supplemented with recent scientific evidence wherever applicable.

Predictors of Avascular Necrosis in a Cohort of Egyptian Systemic Lupus Erythematosus Patients: Retrospective Two Centers Study

Background: Avascular necrosis is a common complication in patients with SLE.

Objective: This study aimed to investigate the risk factors for the occurrence of avascular necrosis among SLE patients receiving steroid therapy at various doses in combination with immunosuppressants.

Methods: In this retrospective study, the medical records of all SLE patients under follow-up at the outpatient clinics of Cairo and Kafr Elsheikh University hospitals through the period from November 2014 to August 2019 were included. Avascular necrosis was diagnosed by the findings of different imaging modalities.

Results: We retrieved the medical records of 770 SLE patients during the study period; of them, 55 patients (7.1%) had avascular necrosis. There was significant higher usage of cyclophosphamide (p = 0.003), total cumulative dose of steroids 15-35g plus immunosuppressants (p < 0.001), and steroids >35g plus immunosuppressants (p = 0.016) in the avascular necrosis cohort. Based on the univariate analysis, disease duration of more than five years and cumulative use of steroids were statistically significant predictors for the evolvement of avascular necrosis. Multivariate logistic regression analysis revealed that a disease duration of more than five years was associated independently with avascular necrosis.

Conclusion: Our data seem to show a role of the association of immunosuppressants plus steroids in the risk of developing avascular necrosis.

Immunopathology of Type 1 Diabetes and Immunomodulatory Effects of Stem Cells: A Narrative Review of the Literature

Type 1 Diabetes (T1D) is a complex autoimmune disorder which occurs as a result of an intricate series of pathologic interactions between pancreatic β-cells and a wide range of components of both the innate and the adaptive immune systems. Stem-cell therapy, a recently-emerged potentially therapeutic option for curative treatment of diabetes, is demonstrated to cause significant alternations to both different immune cells such as macrophages, natural killer (NK) cells, dendritic cells, T cells, and B cells and non-cellular elements, including serum cytokines and different components of the complement system. Although there exists overwhelming evidence indicating that the documented therapeutic effects of stem cells on patients with T1D are primarily due to their potential for immune regulation rather than pancreatic tissue regeneration, to date, the precise underlying mechanisms remain obscure. On the other hand, immune-mediated rejection of stem cells remains one of the main obstacles to regenerative medicine. Moreover, the consequences of efferocytosis of stem-cells by the recipients’ lung-resident macrophages have recently emerged as a mechanism responsible for some immune-mediated therapeutic effects of stem-cells. This review focuses on the nature of the interactions amongst different compartments of the immune systems which are involved in the pathogenesis of T1D and provides an explanation as to how stem cell- based interventions can influence immune system and maintain the physiologic equilibrium.

TNF-induced Lupus. A Case-Based Review

Nowadays, tumor necrosis factor-alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, including drug-induced lupus (DIL).

Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti- Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued, and she was treated successfully with prednisone plus local calcineurin inhibitors.

Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

The Potential Role of Pro-Inflammatory and Anti-Inflammatory Cytokines in Epilepsy Pathogenesis

Within the pathophysiology of epilepsy, as a chronic brain disorder, the involvement of neuroinflammation has been extensively implied. Recurrent seizures of epilepsy have been associated with elevated levels of immune mediators that seem to play a pivotal role in triggering them. Neurons, glia, and endothelial cells of the blood-brain barrier (BBB) take part in such inflammatory processes by expressing receptors of associated mediators through autocrine and paracrine stimulation of intracellular signaling pathways. In this milieu, elevated cytokine levels in serum and brain tissue have been reported in patients with an epileptic profile. Noteworthy, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) are the proinflammatory cytokines mostly associated, in literature, with the pathogenesis of epilepsies. In this review, we examine the function of these cytokines in connection with transforming growth factor-beta (TGF-β), IL-8, IL-12, IL-18, and macrophage inflammatory protein (MIP) as potential proinflammatory mediators in the neuropathology of epilepsy.

Distribution Characteristics of ANA and ANCA in Patients with Hyperthyroidism

Background: Antinuclear antibody (ANA) and Antineutrophil autoantibodies (ANCA) are often used as markers for the diagnosis of autoimmune diseases. In clinical practice, we have found that ANA and ANCA often occur in sera of patients with hyperthyroidism.

Objective: The study aimed to discover the positive features of anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) in hyperthyroidism.

Materials and Methods: In sera samples from 171 patients with hyperthyroidism and 50 healthy controls, ANA and ANCA were detected with indirect immunofluorescence (IIF) method.

Results: ANA and ANCA positive rates were higher in hyperthyroidism (33.9% and 29.2%, respectively) than those in control (4.0% and 2.0%, respectively); the low titer (≤1:320)of ANA was dominated (86.2%) in 58 hyperthyroidism patients with positive ANA, the major pattern involved homogeneous (48.3%) and speckled patterns (48.3%). The low titer (≤1:32) of ANCA was dominated( 64.6%) in 50ANCA positive samples and the major pattern was perinuclear (p) ANCA (96%).

Conclusion: The positive rates of ANA and ANCA were increased and mainly appeared of low titer in hyperthyroidism, which supplement the laboratory characteristics of hyperthyroidism.

Adverse Reactions Induced by Minocycline: A Review of Literature

Background: Minocycline is a tetracycline antibiotic that is widely used to treat infections and is a first-line oral antibiotic in the treatment of moderate to severe inflammatory acne. Although it has high efficacy, several adverse reactions, including life-threatening ones, have been reported in association with its use.

Objective: To identify all the potential adverse reactions due to minocycline and analyze them in terms of the number of cases reported so far, salient features, severity and clinical outcome.

Methods: Comprehensive PubMed search of English and non-English literature for case reports of adverse reactions to minocycline was conducted.

Results: A total of 550 cases were identified from over 200 publications. The major reported adverse events caused by minocycline are drug reaction with eosinophilia and systemic symptoms syndrome, autoimmune syndromes like hepatitis, lupus and vasculitis, acute eosinophilic pneumonia, pseudotumor cerebri, hyperpigmentation, serum sickness-like reaction, Sweet’s syndrome and drug fever. Several other reactions involving multiple organ systems have also been reported. These show an overlap of clinical features and may be associated with multiple events causing considerable morbidity. Eight of these cases resulted in the death of the patients.

Conclusion: In view of the evident potential of minocycline to cause long-lasting and severe adverse effects, significant morbidity and even mortality, it should be prescribed with caution in the first-line treatment for moderate to severe acne.

Myocardial Infarction in Systemic Lupus Erythematosus – the Sex-Specific Risk Profile

Background: Accelerated atherosclerosis is widely present in patients with systemic lupus erythematosus.

Objective: The aim of this review was to analyze the relationship between systemic lupus erythematosus and cardiovascular diseases, with the emphasis on acute myocardial infarction.

Methods: We conducted a literature review through PubMed and Cochrane, using keywords: SLE, atherosclerosis, atherothrombosis, coronary artery disease, myocardial infarction, prognosis, sex specifics.

Results: Various molecular mechanisms triggered by infection/inflammation are responsible for endothelial dysfunction and the development of atherosclerosis at an earlier age. A contributing factor is the cumulative effect of traditional cardiovascular risk factors interaction with disease-related characteristics. Myocardial infarction rates are 2- to 10-fold higher compared to the general population. Young women have the highest relative risk, however, men carry at least 3-fold higher risk than women. Coronary involvement varies from normal coronary artery with thrombosis, coronary microartery vasculitis, coronary arteritis, and coronary atherosclerosis. Typical clinical presentation is observed in men and older women, while atypical is more frequent in young women. Treatment is guided by the underlying mechanism, engaging invasive procedures alone, or accompanied with immunosuppressive and/or anti-inflammatory therapy. There are significant gender differences in pathophysiology and clinical presentation. However, they receive the same therapeutic treatments.

Conclusion: Systemic lupus erythematosus is a major contributor to atherosclerotic and non-atherosclerotic mechanisms involved in the development of myocardial infarction, which should be taken into account during therapeutic treatment. Although systemic lupus erythematosus per se is a “female” disease, males are at increased cardiovascular risk and worse outcomes.

Novel Biomarkers for Lupus Nephritis in the “OMICS” Era

Lupus nephritis (LN) is severe renal comorbidity associated with systemic lupus erythematosus (SLE), a complex autoimmune disorder with high morbidity and mortality. Diagnosis and monitoring of LN patients still rely on renal biopsy, a procedure that exposes patients to a variety of risks and is not capable of providing longitudinally information about disease prognosis. In this review, we summarized current data of recent promising biomarkers developed in the precision medicine era, particularly under genomic, transcriptomic, proteomic, and metabolomic techniques. Genome-wide association studies have been evaluating the role of endogenous elements beyond the autoimmunity in LN. Transcriptomic methods, including single-cell sequencing, are potential tools in identifying inflammatory signatures, miRNAs, and gene expression. Proteomic measures, including anti-C1q antibodies, cytokines, TLRs, VCAM-1, NGAL osteopontin, angiostatin, have been considered helpful to provide a more profound comprehension of the disease pathogenic processes. Metabolomic approaches may identify several abnormal metabolite profiles related to the impairment of cellular functions. Together, these accurate, non-invasive, and moderate-cost propedeutic resources may be the novel tools for recognizing, distinguishing, and predicting LN progression and prognosis. Furthermore, omics evaluation may also predict responsiveness to treatment and, consequently, change the way we manage LN cases in the near future.

The Therapeutic use of the Zonulin Inhibitor AT-1001 (Larazotide) for a Variety of Acute and Chronic Inflammatory Diseases

Background: The involvement of intercellular tight junctions and, in particular, the modulation of their competency by the zonulin pathway with a subsequent increase in epithelial and endothelial permeability, has been described in several chronic and acute inflammatory diseases. In this scenario, Larazotide, a zonulin antagonist, could be employed as a viable therapeutic strategy.

Objective: The present review aims to describe recent research and current observations about zonulin involvement in several diseases and the use of its inhibitor Larazotide for their treatment.

Methods: A systematic search was conducted on PubMed and Google Scholar, resulting in 209 publications obtained with the following search query: “Larazotide,” “Larazotide acetate,” “AT-1001,” “FZI/0” and “INN-202.” After careful examination, some publications were removed from consideration because they were either not in English or were not directly related to Larazotide.

Results: The obtained publications were subdivided according to Larazotide’s mechanism of action and different diseases: celiac disease, type 1 diabetes, other autoimmune diseases, inflammatory bowel disease, Kawasaki disease, respiratory (infective and/or non-infective) diseases, and other.

Conclusion: A substantial role of zonulin in many chronic and acute inflammatory diseases has been demonstrated in both in vivo and in vitro, indicating the possible efficacy of a Larazotide treatment. Moreover, new possible molecular targets for this molecule have also been demonstrated.

Antineutrophil Cytoplasmic Antibody in Lupus Nephritis: Correlation with Clinicopathological Characteristics and Disease Activity

Background: Lupus nephritis (LN) represents 40%-50% of all systemic lupus erythematosus (SLE) patients, and rapidly progressive glomerulonephritis is associated with significant morbidity and mortality. Antineutrophil cytoplasmic antibody (ANCA) might be involved in the pathogenesis of LN.

Objective: We evaluated the role of myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA, and anti-glomerular basement membrane autoantibodies (anti-GBM autoAb) for the diagnosis of LN.

Methods: In this cross-sectional study, 95 SLE patients were divided into 2 subgroups: LN group (n = 60) and non-LN group (n = 35). For further analysis, we subclassified the LN group into ANCA- positive (n = 16) and ANCA-negative (n = 44) LN patients. The entire Non-LN group was ANCA- negative. The SLE disease activity index (SLEDAI) was reported for each patient. Determination of MPO-ANCA, PR3-ANCA, and anti-GBM autoAb was performed using a novel multiplex bead-based technology in all patients. Data analyses were done using SPSS, version 20. Approval was obtained from the institutional review board of Zagazig University (ZU-IRB#6000).

Results: Of 95 patients with SLE, 16 patients (16.84%) had ANCA-positive LN, all of which were MPO-ANCA. There was a positive correlation between MPO-ANCA and SLEDAI, as well as with class IV LN. Receiver operating characteristic analyses revealed that the sensitivity and specificity of MPO-ANCA were 81.3% and 99.8%, respectively, in discriminating LN from systemic lupus without nephritis.

Conclusion: MPO-ANCA level was significantly correlated with SLEDAI, inflammatory markers, kidney function tests, and LN class IV.

Clinical Features and Disease Damage Risk Factors in an Egyptian SLE Cohort: A Multicenter Study

Background: Systemic lupus erythematosus (SLE) has a variable natural history and clinical characteristics. Objectives: This study aims to evaluate the clinical and immunological characteristics, and assess the disease accrual of an Egyptian SLE cohort.

Methods: The study included 569 SLE patients who were collected from three different centers; demographic, laboratory data, cumulative manifestations, and comorbidities were assessed (characteristics at the time of diagnosis were recorded retrospectively, while current clinical data were recorded cross-sectionally). Evaluation of disease activity was done using Systemic Lupus Erythematosus Disease Activity Index score (SLEDAI) and damage by Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SDI).

Results: The median age of patients at disease onset was 25.0±10.5 years, the median disease duration was 4.0 (6.5) years, the female to male ratio was (12.5:1), and the median SLEDAI was 12.0±14.0. Family history of SLE was noticed in 4%. Antinuclear antibody was positive in all patients and 86% had positive anti-double-stranded DNA. Arthritis/arthralgia was the most frequent presenting symptom (44%) followed by fever (39%). Along the disease course; alopecia was the most common clinical manifestation (76.1%), followed by constitutional symptoms (75.9%), and nephritis (65.7%). Three hundred and five patients encountered organ damage (SDI >1); kidney damage was the most frequent (32%), followed by cardiovascular damage (24.3%). Neutropenia, hypocomplementemia, arthritis, hypertension, longer disease duration, and higher disease activity were found to be independent risk factors for disease damage.

Conclusions: There are some diversities and similarities in our findings compared to the previously reported data. Arthritis is the most common presenting symptom, while alopecia is the most frequent clinical finding, and a higher prevalence of nephritis was reported. Renal damage is the most frequent outcome.

Cytotoxic T Lymphocyte Antigen 4 Gene +49 A/G (rs231775) Polymorphism and Susceptibility to Systemic Lupus Erythematosus

Aim: To assess the probable role of +49AG polymorphism in susceptibility to SLE in an Egyptian population.

Background: Systemic lupus erythematosus (SLE) is a compound inflammatory chronic disease distinguished through the release of autoantibodies. Cytotoxic T lymphocyte associated antigen-4 is a main down controller of T-cell response; its dysregulation could affect SLE pathogenesis by altered T cells activation to self-antigens.

Objectives: To evaluate the CTLA-4 +49AG allelic and genotype frequency in a sample of the Egyptian population and correlate them with disease susceptibility and clinical severity.

Materials and methods: Including 100 patients with SLE and 100 healthy controls (age and gender matched), CTLA-4 exon 1 49 A>G Genotyping was done using Real-Time PCR.

Results: No difference was noticed in genotype or allele distributions of the studied polymorphism between both groups. Similar genotypes and allele frequencies were established for the 2 groups after their stratification by the age of disease onset, clinical course, or severity.

Conclusion: CTLA-4 +49AG gene polymorphism is not linked with the liability to develop SLE in the studied Egyptian population. Yet it is significantly related to disease severity.

The Perfect Storm: A Rheumatologist's Point of View on COVID-19 Infection

The new coronavirus infection (Covid-19) is a pandemic that has affected the whole world and progresses with high morbidity and mortality. It has a high contagion rate and a course capable of rapid lung involvement with severe acute respiratory distress syndrome (ARDS) and pulmonary insufficiency. A severe clinical picture develops as a result of a “perfect cytokine storm” which results from possible immunological mechanisms triggered by the viral infection. Immune system dysregulation and possible autoinflammatory and autoimmune mechanisms are responsible for a higher amount of cytokines release from immune cells. Although no clear treatment of Covid-19 infection has emerged yet, it is argued that some disease-modifying anti-rheumatic drugs (DMARDs) may be effective in addition to anti-viral treatments. These drugs (anti-malarial drugs, colchicum dispert, biologics) have been well known to rheumatologists for years because they are used in the treatment of many inflammatory rheumatologic diseases. Another important issue is whether DMARDs, which can cause severe immunosuppression, pose a risk for Covid-19 infection and whether they have been discontinued beforehand. Although there are insufficient data on this subject, considering the risk of disease reactivation, patients may continue their DMARDs treatment under the supervision of a rheumatologist.

In this article, the possible immunological mechanisms in the pathogenesis of Covid-19 infection and the efficacy and safety of various DMARDs used in the treatment are discussed from a rheumatologist’s perspective in the light of recent literature data.

Autoantibodies Among HIV-1 Infected Individuals and the Effect of Anti-Retroviral Therapy (ART) on It

Background: Antiretroviral therapy (ART) has led to a decline in autoimmune diseases but lacks studies on its effect on autoantibodies.

Methods: It is a cross-sectional study with archived samples from 100 paired HIV-1 infected ART naïve and experienced individuals and 100 prospectively collected matched blood-donor controls. Antinuclear antibody, IgG anticardiolipin antibody, IgM and IgG β2 glycoprotein-1 antibodies, and total IgG levels were detected. Results are expressed as mean with standard deviation (SD), median, percentage positivity, and a p<0.05 is considered significant. The study was approved by the Institutional Review Board.

Results: The median viral load of the treatment naïve samples was 4.34 Log copies/mL, while all were virally suppressed post ART with a median duration of treatment for 12 months (range: 3-36 months). The percentage of antinuclear antibody positivity was 5% among ART naïve and controls, with a decrease of 2% post ART (p= 0.441). The positivity for anti-cardiolipin antibody was 15% among ART naïve while none of the ART experienced or controls were positive (p<0.05). IgM β2 glycoprotein-1 were 4%, 1% and 3% among ART naïve, treated and controls, respectively (p<0.05). IgG β2 glycoprotein-1 was 2% among ART naïve while none of the treated and controls were positive (p<0.05). The mean total IgG level among ART naïve, experienced, and controls were 21.82 (SD 6.67), 16.91 (SD 3.38), 13.70 (SD 2.24) grams/Litre, respectively (p<0.05).

Conclusion: ART has a significant effect on IgG anti-cardiolipin antibody and total IgG but only a marginal effect on ANA, IgM, and IgG β2 glycoprotein-1 antibodies.

Therapeutic Applications of Mesenchymal Stem Cells: A Comprehensive Review

Mesenchymal Stem Cells (MSCs) are one of the most promising tools for cell therapy, that are isolated from bone marrow and many other adult tissues such as liver, cord blood, placenta, dental pulp and adipose tissue. Due to the lack of MHC class II expression on the surface of MSCs, they can also be used as a potent cell source for tissue regeneration in non-autologous cell therapy applications. Many advantages of MSCs such as their self-renewal, in vitro proliferation, rapid cell doubling capacity, anti-fibrotic, anti-apoptotic, anti-inflammatory, immunomodulatory and immunosuppressive effects, and also paracrine nature have been demonstrated in various pre-- clinical studies and clinical evidence. The ability of MSCs to differentiate into multiple cell lineages, as well as the lack of ethical issues in comparison with embryonic and induced Pluripotent Stem Cells (iPSCs), has introduced them as a suitable candidate for cell therapy. This review provides a comprehensive overview of various clinical trials based on MSCs for the treatment of a variety of diseases, demonstrating their capability in the treatment of dermatological, musculoskeletal, neurological, cardiovascular, respiratory, renal, gastroenterological and urological conditions, etc.

Atherogenic Index of Plasma in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus: A 10-Year Potential Predictor of Cardiovascular Disease

Background: Women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are at high risk of cardiovascular diseases (CVD). The atherogenic index of plasma (AIP) is a new marker for the assessment of CVD.

Objective: This study aimed to determine the predictive value of AIP with long-term CVD risk among women with RA and SLE.

Methods: This is a cross-sectional study of 99 RA and 59 SLE women. Demographic, clinical, and biochemical data were obtained, and disease activities were calculated. For each patient, the longterm risk of CVD was calculated using the Framingham risk score (FRS); AIP was derived according to the logarithmic (triglycerides/high-density lipoproteins cholesterol).

Results: The mean age of the RA and SLE patients was 47.97 ± 8.78 and 36.75 ± 9.09 years, respectively. The median (interquartile range) of AIP values in RA and SLE patients were 0.34 (-0.15, 1.02) and 0.33 (-0.53, 0.96), respectively, while FRS values of RA patients and SLE patients were 6.38 ± 5.58 and 4.86 ± 4.5, respectively (p >0.05). There was a moderate correlation between AIP and FRS in RA and SLE patients (r=0.42, p=0.002 and r=0.33, p=0.007, respectively). According to the multivariate regression analyses, we found that AIP value is an independent factor for FRS in RA (β: 4.13, 95% confidence interval; 1.71, 6.18; p=0.008) and in SLE patients (β: 6.19, 95% confidence interval; 2.58, 9.81; p<0.001).

Conclusions: We reported that AIP can be used as an independent indicator for long-term CVD risk in RA and SLE patients.

COVID-19: A Great Mime or a Trigger Event of Autoimmune Manifestations?

Viruses can induce autoimmune diseases, in addition to genetic predisposition and environmental factors. Particularly, coronaviruses are mentioned among the viruses implicated in autoimmunity. Today, the world's greatest threat derives from the pandemic of a new human coronavirus, called “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the responsible agent of coronavirus disease 2019 (COVID-19). First case of COVID-19 was identified in Wuhan, the capital of Hubei, China, in December 2019 and quickly spread around the world. This review focuses on autoimmune manifestations described during COVID-19, including pro-thrombotic state associated with antiphospholipid antibodies (aPL), acute interstitial pneumonia, macrophage activation syndrome, lymphocytopenia, systemic vasculitis, and autoimmune skin lesions. This offers the opportunity to highlight the pathogenetic mechanisms common to COVID-19 and several autoimmune diseases in order to identify new therapeutic targets. In a supposed preliminary pathogenetic model, SARS-CoV-2 plays a direct role in triggering widespread microthrombosis and microvascular inflammation, because it is able to induce transient aPL, endothelial damage and complement activation at the same time. Hence, endothelium might represent the common pathway in which autoimmunity and infection converge. In addition, autoimmune phenomena in COVID-19 can be explained by regulatory T cells impairment and cytokines cascade.

Advances in Drug Therapy for Systemic Lupus Erythematosus

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a local or systemic inflammatory response. At present, the increasing research results show that the pathogenesis of the disease is complex, and the methods of clinical treatment also show diversity. This review analyzes and summarizes the existing mechanism research and drug treatment methods in order to provide a reference value for further drug research and development.

Method: We carried out a thorough literature search using databases. According to the main purpose of the article, irrelevant articles were excluded after further examination and directly relevant articles were included. Finally, the information related to the article was summarized.

Result: In this article, seventy-four articles are included. According to related articles, there are mainly four kinds of drugs, namely antimalarial drugs, glucocorticoids, immunosuppressive agents and biological agents. About fifty-five articles summarized the drugs for the treatment of systemic lupus erythematosus. The rest of the articles were related to the research progress of the mechanism of systemic lupus erythematosus.

Conclusion: This article describes the pathogenesis of systemic lupus erythematosus, and summarizes the traditional and new therapeutic drugs, which is not only beneficial to the treatment of lupus erythematosus patients, but also plays a vital reference significance for the future development of new systemic lupus erythematosus drugs.

Drug Induced Cutaneous Manifestations due to Treatment of Gastrointestinal Disorders

Cutaneous manifestations due to drugs used in the treatment of gastrointestinal disorders are multiple and common. Adequate diagnosis is of great importance, bearing in mind that the therapeutic regimen depends on its diagnosis. In this review, we provided an overview of the most common drug-induced skin lesions with a detailed explanation of the disease course, presentation and treatment, having in mind that in recent years, novel therapeutic modalities have been introduced in the treatment of various gastrointestinal disorders, and that incidence of cutaneous adverse reactions has been on the rise.

Characterization of the Clinical and Laboratory Features of Primary and Secondary Antiphospholipid Syndrome in a Cohort of Egyptian Patients

Objective: To study the clinical and laboratory features of Antiphospholipid Syndrome (APS) in a cohort of Egyptian patients and compare between primary and secondary type on the basis of clinical and immunological pattern.

Patients and Methods: We reviewed the medical records of 148 antiphospholipid syndrome patients following in Rheumatology and Rehabilitation department, Cairo University. Clinical and immunological data were recorded; subsequently, our patients were compared based on the type of APS, patient’s age and sex.

Results: The cohort consisted of 148 patients, 135 females (91.2%) and 13 males (8.8%). The mean age at onset was 23.6 ±7.66 years. 28.4% of patients had primary while, 71.6% of patients had secondary APS.

Patients with secondary APS presented more frequently with the following manifestations compared to patients with primary APS: systemic manifestations (56.6% versus 4.8%, P-value: 0.00), venous thrombosis (41.5% versus 19%, P-value: 0.009), cutaneous vasculitis (19.8% versus 4.8%, P-value: 0.023), thrombocytopenia (37.7% versus 11.9%, P-value: 0.002) and hemolytic anemia (28.3% versus 4.8%, P-value: 0.002). On the other hand, total obstetric manifestations were more common in primary APS (92.5% versus 75%, P-value: 0.007).

Juvenile onset APS presented more frequently with systemic (68.8%, p-value: 0.02), neurological (62.5%, p-value: 0.01) and renal manifestations (31.3%, p-value: 0.005). No statistically significant difference was found between males and females in our cohort.

Conclusion: APS has broad spectrum manifestations, which may vary according to the patient’s age at disease onset and association with other diseases. Further more, different ethnicities may show different presentations.

Radix Paeoniae Rubra Ameliorates Lupus Nephritis in Lupus-Like Symptoms of Mrl Mice by Reducing Intercellular Cell Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, and Platelet Endothelial Cell Adhesion Molecule-1 Expression

Objective: Vasculitis is the basic pathological change of systemic lupus erythematosus (SLE). Radix Paeoniae Rubra (RPR), a traditional Chinese herb with the function of reducing blood stasis, has anti-inflammatory and immunoregulatory properties. This study explored the effects of RPR on the kidneys of lupus-like symptoms of mrl (MRL/lpr) mice from the perspective of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1).

Methods: Eighteen MRL/lpr lupus model mice were randomly divided into three groups, the model control group, prednisone-treated group, and RPR-treated group, and 6 C57BL/ 6 mice were classified as a control group. After the mice had been treated for 12 weeks, the expression of ICAM-1, VCAM-1 and PECAM-1in the kidney was determined by immunohistochemistry and Reverse Transcription-Polymerase Chain Reaction (RT-PCR).

Results: After 12 weeks, there were significant differences in body weight in the model, prednisone and RPR groups compared with the normal group (P <0.05). Pathological observation: Compared with the model group, the proliferation of inflammatory cells infiltrated glomeruli and interstitial cells in prednisone and RPR groups were reduced, and renal pathological damage was reduced. Compared with the model group, urine protein level of prednisone and RPR groups were reduced with no significance (P> 0.05). The mRNA expression levels of ICAM-1 and VCAM-1 were significantly reduced in the prednisone group and RPR group compared with the model group (P <0.05 or P <0.01). Meanwhile, the immunohistochemistry expressions of ICAM-1 and VCAM- 1 expressed in the kidney were significantly reduced in the prednisone group and RPR group (P <0.01 or P <0.05). However, The mRNA expression level and the immunohistochemistry expressions of PECAM-1 expressed in the kidney were reduced in each treatment group (prednisone group and RPR group), but these differences were not significant (P>0.05).

Conclusions: ICAM-1, VCAM-1 and PECAM-1 expression in the model group was found to be significantly increased. In addition, RPR could reduce the expression of ICAM-1, VCAM-1 and PECAM-1 in MRL/lpr lupus mice as effectively as prednisone, which may result in the dosage reduction of prednisone, thus decreasing the toxicity and improving the efficacy of prednisone - based treatment of SLE.

Cardio-Rheumatology: Two Collaborating Disciplines to Deal with the Enhanced Cardiovascular Risk in Autoimmune Rheumatic Diseases

In Part 1 of this Thematic Issue entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, a panel of specialists and experts in cardiology, rheumatology, immunology and related fields discussed the cardiovascular complications of spondyloarthritides, rheumatoid arthritis, Sjogren’s syndrome and vasculitides, as well as relevant cardiovascular issues related to non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), and provided their recommendations for prevention and management of these complications. In part 2 of this Thematic Issue, experts discuss the enhanced cardiovascular risk conferred by additional autoimmune rheumatic diseases (ARDs), including systemic lupus erythematosus, the antiphospholipid syndrome, psoriasis and psoriatic arthritis and juvenile idiopathic arthritis. These, and the previous articles, place inflammation as the key common link to explain the enhanced risk of cardiovascular complications in patients with ARDs. It follows that treatment should probably target inflammation. From all these contemporary reviews, the conclusion that is derived further supports the notion of the emerging field of Cardio- Rheumatology where physicians and experts from these two disciplines collaborate in risk stratification and optimization of preventive strategies and drug therapies in patients with ARDs.

Cardiovascular Disease in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous, arterial or microvascular thrombosis or obstetric events in the presence of persistently positive antiphospholipid antibodies and constitutes a major cause of cardiovascular events in young people. Τhis review highlights the pathophysiology of cardiovascular complications in patients with APS and possible treatment options.

Patients with APS have endothelial dysfunction, accelerated endothelial proliferation and intimal hyperplasia, atherogenesis, platelet activation, inflammatory products secretion and coagulation-fibrinolytic dysregulation. Cardiovascular complications include accelerated atherosclerosis, acute coronary syndrome, Libman-Sacks endocarditis, cardiomyopathy and venous, arterial or intracardiac thrombi. Moreover, pulmonary hypertension and peripheral microvascular dysfunction are common findings.

Management of these patients is not well documented. The role of primary thrombosis prevention remains controversial in individuals with positive antiphospholipid antibodies. Treatment of traditional cardiovascular risk factors according to current guidelines for the prevention of cardiovascular disease in the general population is recommended for primary prevention of APS. Anticoagulation therapy with unfractionated or low-molecular-weight heparin overlapped with a vitamin K antagonist remains the mainstay of the treatment for APS patients with venous thrombosis, whereas direct oral anticoagulants are not yet recommended. Data are scarce regarding the secondary arterial thrombosis prevention and it is not clear whether dual or triple antithrombotic therapy is necessary. To date, it is recommended to follow current guidelines for the management of acute coronary syndrome in the general population. New treatment targets are promising options for patients with catastrophic APS.

Combined Brain/Heart Magnetic Resonance Imaging in Systemic Lupus Erythematosus

Cardiovascular Disease (CVD) in Systemic Lupus Erythematosus (SLE) and Neuropsychiatric SLE (NPSLE) has an estimated prevalence of 50% and 40%, respectively and both constitute major causes of death among SLE patients. In this review, a combined brain/heart Magnetic Resonance Imaging (MRI) for SLE risk stratification has been proposed.

The pathophysiologic background of NPSLE includes microangiopathy, macroscopic infarcts and accelerated atherosclerosis. Classic brain MRI findings demonstrate lesions suggestive of NPSLE in 50% of the NPSLE cases, while advanced MRI indices can detect pre-clinical lesions in the majority of them, but their clinical impact still remains unknown. Cardiac involvement in SLE includes myo-pericarditis, valvular disease/endocarditis, Heart Failure (HF), coronary macro-microvascular disease, vasculitis and pulmonary hypertension. Classic and advanced Cardiovascular Magnetic Resonance (CMR) indices allow function and tissue characterization for early diagnosis and treatment follow-up of CVD in SLE.

Although currently, there are no clinical data supporting the combined use of brain/heart MRI in asymptomatic SLE, it may have a place in cases with clinical suspicion of brain/heart involvement, especially in patients at high risk for CVD/stroke such as SLE with antiphospholipid syndrome (SLE/APS), in whom concurrent cardiac and brain lesions have been identified. Furthermore, it may be of value in SLE with multi-organ involvement, NPSLE with concurrent cardiac involvement, and recent onset of arrhythmia and/or heart failure.

Cardio-Rheumatology: Cardiovascular Complications in Systemic Autoimmune Rheumatic Diseases / Is Inflammation the Common Link and Target?

In the current Thematic Issue of Current Vascular Pharmacology (CVP), entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, presented in two parts, Part 1 and Part 2, review articles are included from specialists in cardiology, rheumatology, immunology and related fields. These reviews discuss the cardiovascular complications of the main systemic Autoimmune Rheumatic Diseases (ARDs). For example, the underlying pathogenetic mechanisms, the role of cardiovascular imaging and recommendations for prevention and management. These articles place inflammation as the key process, linking cardiovascular complications with ARDs. From all these reviews, the conclusion is the need for collaboration between the disciplines of Rheumatology and Cardiology to establish the emerging field of Cardio- Rheumatology. This will aid to fine-tune risk stratification and optimize preventive strategies and pharmacological therapies for patients with ARDs.

Primary Sjögren’s Syndrome and Cardiovascular Disease

Sjögren’s syndrome is a rheumatic autoimmune disease that primarily affects middle-aged women and runs a slowly progressing course with sicca symptoms being the prevalent manifestation. Premature atherosclerosis and increased cardiovascular (CV) morbidity and mortality are frequently encountered in rheumatic diseases characterized by significant systemic inflammation, such as the inflammatory arthritides, systemic vasculitides and systemic lupus erythematosus. In the same context, chronic inflammation and immune aberrations underlying Sjögren’s syndrome are also reported to be associated with augmented risk of atherosclerosis. Increased CV disease (CVD) frequency has been found in recent meta-analyses. The involvement of the CV system is not a common feature of Sjögren’s syndrome; however, specific manifestations, such as autoantibody-mediated heart block, pericarditis, pulmonary arterial hypertension and dysautonomia, have been described. This review focuses on studies addressing CV morbidity in Sjögren’s syndrome and presents current data regarding distinct CV features of the disease.

Mannitol Reduces Spinal Cord Edema in Rats with Acute Traumatic Spinal Cord Injury

Background: The research about anti-edema effects of mannitol on acute traumatic spinal cord injury (SCI) in rats is rare.

Objective: This study aimed to explore the effect of mannitol on spinal cord edema after SCI in rats.

Methods: Seventy-eight adult female rats were assigned to three groups randomly: a sham control group (n = 18), a contusion and normal saline contrast group (n=30), and a contusion and mannitol treatment group (n=30). We used the open-field test to estimate the functional recovery of rats weekly. Spinal cord water content was measured to determine the spinal cord edema. The ultrastructure features of the injured dorsolateral spinal cord were determined on the 7th day after SCI by HE staining.

Results: The mannitol group had greatly improved Basso-Beattie-Bresnahan (BBB) scores when compared with the saline contrast group. The spinal cord water content was increased significantly after SCI, and there was no significant difference in the water content between the NaCl and mannitol groups 1 day after SCI. The water content at 3 and 7 days after SCI was significantly lower in the mannitol group than in the NaCl group (p < 0.05). Mannitol can reduce spinal cord edema by increasing the number of red blood cells in the injured spinal cord and decrease the ratio (dorsoventral diameter/ mediolateral diameter) of spinal cord 7 days post-SCI.

Conclusion: Mannitol increases recovery of motor function in rats, reduces spinal cord edema and increases the number of red blood cells in the injured spinal cord, decreasing the ratio of spinal cord to reduce pressure.

TREX1 As a Potential Therapeutic Target for Autoimmune and Inflammatory Diseases

Background and Objectives: The 3’ repair exonuclease 1 (TREX1) gene is the major DNA-specific 3’–5 ’exonuclease of mammalian cells which reduces single- and double-stranded DNA (ssDNA and dsDNA) to prevent undue immune activation mediated by the nucleic acid. TREX1 is also a crucial suppressor of selfrecognition that protects the host from inappropriate autoimmune activations. It has been revealed that TREX1 function is necessary to prevent host DNA accumulating after cell death which could actuate an autoimmune response. In the manuscript, we will discuss in detail the latest advancement to study the role of TREX1 in autoimmune disease.

Methods: As a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as an antiinflammatory molecule, the functional mechanisms of TREX1 were multifactorial. In this review, we will briefly summarize the latest advancement in studying the role of TREX1 in autoimmune disease, and discuss its potential as a therapeutic target for these diseases.

Results: Deficiency of TREX1 in human patients and murine models is characterized by systemic inflammation and the disorder of TREX1 functions drives inflammatory responses leading to autoimmune disease. Moreover, much more studies revealed that mutations in TREX1 have been associated with a range of autoimmune disorders. But it is also unclear whether the mutations of TREX1 play a causal role in the disease progression, and whether manipulation of TREX1 has a beneficial effect in the treatment of autoimmune diseases.

Conclusion: Integration of functional TREX1 biology into autoimmune diseases may further deepen our understanding of the development and pathogenesis of autoimmune diseases and provide new clues and evidence for the treatment of autoimmune diseases.

The Application of Neural Stem/Progenitor Cells for Regenerative Therapy of Spinal Cord Injury

Spinal cord injury (SCI) is a devastating event, and there are still no effective therapies currently available. Neural stem cells (NSCs) have gained increasing attention as promising regenerative therapy of SCI. NSCs based therapies of various neural diseases in animal models and clinical trials have been widely investigated. In this review we aim to summarize the development and recent progress in the application of NSCs in cell transplantation therapy for SCI. After brief introduction on sequential genetic steps regulating spinal cord development in vivo, we describe current experimental approaches for neural induction of NSCs in vitro. In particular, we focus on NSCs induced from pluripotent stem cells (PSCs). Finally, we highlight recent progress on the NSCs, which show great promise in the application to regeneration therapy for SCI.

Genetic Alleles Associated with SLE Susceptibility and Clinical Manifestations in Hispanic Patients from the Dominican Republic

Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with marked disparities in prevalence and disease severity among different ethnic groups. The purpose of this study is to characterize a Latin American cohort and identify genetic risk factors for developing SLE and its end-organ manifestations in this Latin Hispanic cohort.

Methods: A total of 201 SLE cases and 205 non-diseased controls were recruited in the Dominican Republic (DR). Cases were defined according to the 1997 revised American College of Rheumatology criteria for the classification of SLE. Genomic DNA was prepared from whole blood and applied to genotyping analyses for 42 single nucleotide polymorphisms (SNPs) that have been implicated in autoimmune diseases, including SLE, in other ethnic populations. Data were analyzed by Fisher’s Exact Probability Test.

Results: In this cohort, SNP rs9271366 (tag SNP for HLA-DRB1*15:01) confers the highest risk for SLE among the 13 MHC gene alleles that display association with SLE (p = 8.748E-10; OR = 3.5). Among the 26 non-MHC gene alleles analyzed, SNP rs2476601 in PTPN22 gene confers the highest risk for SLE (p = 0.0001; OR = 5.6). ITGAM, TNFSF4, TNIP1, STAT4, CARD11, BLK, and TNXB gene alleles were confirmed as SLE-susceptible alleles in the DR cohort. However, IRF5 and TNFAIP3 gene alleles, established risk factors for SLE in populations of European and Asian ancestry, are not significantly associated with SLE in this cohort. We also defined a novel HLA-DRA haplotype that confers an increased risk for lupus nephritis (LN) and alleles in HLA-DRA2 and TNFSF4 genes as genetic risk factors for developing neuropsychiatric (NP) SLE.

Conclusion: Our data suggest that the Latin American population shares some common genetic risk factors for SLE as other populations, but also has distinct risk gene alleles that contribute to SLE susceptibility and development of LN and NPSLE. This is the first study focusing on genetic risk factors for SLE in the DR, a Latin American population that has never been characterized before.

Selenium and Autoimmune Diseases: A Review Article

Background: Selenium is an essential trace element with fundamental effects on human biology. Trace elements deficiency is not an uncommon finding in autoimmune diseases. This deficiency may be a consequence of autoimmune diseases or may contribute to their etiology. With regard to evidence showing the association between selenium deficiency and generation of reactive oxygen species and subsequent inflammation, reviewing the role of selenium in collagen vascular diseases could help researchers to devise strategies for managing these diseases.

Objective: The present study aimed to evaluate the role of selenium and autoimmune rheumatic diseases.

Data Sources: PubMed, Scopus, Science Direct, and Google Scholar.

Study Eligibility Criteria: All the studies on the use of selenium without any limitations in terms of the preparation method, administration route, or formulation process were included in the study. The exclusion criteria were: 1) Articles published in languages other than English, 2) Administration of chemical and hormonal drugs rather than selenium, 3) Investigation of the effects of selenium on the autoimmune problems in animal models, and 4) Insufficiency of the presented data or poor description of the applied methods. Furthermore, review articles, meta-analyses, expert opinions, editorial letters, case reports, consensus statements, and qualitative studies were excluded from the study.

Data Extraction: In this systematic review, articles were evaluated through searching following keywords in combination with selenium: "autoimmune rheumatic diseases "or "scleroderma" or "systemic sclerosis" or "Behcet's disease" or "Sjögren syndrome" or "systemic lupus erythematosus" or "musculoskeletal diseases" or "rheumatoid arthritis" or "vasculitis" or "seronegative arthritis" or "antiphospholipid antibody syndrome".

Results: Of 312 articles, 280 were excluded and 32 articles were entered in this study. Based on the majority of studies assessing selenium level in patients with collagen vascular diseases, lower selenium levels were observed in these patients. Moreover, the majority of articles showed an improvement in clinical symptoms of collagen vascular diseases compared to controls after the treatment of patients with different dosages of L-selenomethionine.

Conclusion: A decrease in the serum level of selenium was noted in patients with autoimmune diseases, which may be a risk factor for inflammation and initiation of autoimmunity in these patients. A sufficient quantity of selenium has been shown to contribute to the management of complications of autoimmune diseases and even improved survival in patients with autoimmune diseases, which may be due to the anti-inflammatory effects of selenium. Since this issue is of clinical importance, it can be considered in potential nutrition interventions and have beneficial effects on some autoimmune diseases.

Endothelial Progenitor Cells as Mediators of the Crosstalk between Vascular Repair and Immunity: Lessons from Systemic Autoimmune Diseases

From the discovery of Endothelial Progenitor Cells (EPC), these bone marrowderived precursors have been placed as crucial mediators of the endothelial repair. Accordingly, altered levels and function of EPC have been found in different scenarios of CV risk. Despite the fact that EPC exhibit important characteristics which support a link of this cell subset with a number of inflammatory and immune networks, little is known on the actual mediators involved and the clinical relevance of these features. Systemic diseases are generally hallmarked by a vascular repair failure and increased cardiovascular disease occurrence, EPC impairment having a pivotal role. Because of their immunemediated etiology, this group of conditions represents an invaluable scenario to unravel the connections between immune dysregulation and EPC dysfunction. In the present review, we summarize the current knowledge regarding the cutting-edge area of the modulation of EPC levels and function by inflammatory cytokines in systemic diseases. We also address the possibility of the available immunomodulatory drugs to counteract this situation. Finally, due to the emerging role of the vitamin D as a common mediator in the immune system and the cardiovascular axis, we cover the topic of the role of vitamin D as a potential player in the inflammatory-mediated EPC dysfunction in systemic diseases.

Role of Positron Emission Tomography for Central Nervous System Involvement in Systemic Autoimmune Diseases: Status and Perspectives

In the last years, an increasing interest in molecular imaging has been raised by the extending potential of positron emission tomography [PET]. The role of PET imaging, originally confined to the oncology setting, is continuously extending thanks to the development of novel radiopharmaceutical and to the implementation of hybrid imaging techniques, where PET scans are combined with computed tomography [CT] or magnetic resonance imaging[MRI] in order to improve spatial resolution.

Early preclinical studies suggested that 18F–FDG PET can detect neuroinflammation; new developing radiopharmaceuticals targeting more specifically inflammation-related molecules are moving in this direction. Neurological involvement is a distinct feature of various systemic autoimmune diseases, i.e. Systemic Lupus Erythematosus [SLE] or Behcet’s disease [BD]. Although MRI is largely considered the gold-standard imaging technique for the detection of Central Nervous System [CNS] involvement in these disorders. Several patients complain of neuropsychiatric symptoms [headache, epilepsy, anxiety or depression] in the absence of any significant MRI finding; in such patients the diagnosis relies mainly on clinical examination and often the role of the disease process versus iatrogenic or reactive forms is doubtful.

The aim of this review is to explore the state-of-the-art for the role of PET imaging in CNS involvement in systemic rheumatic diseases. In addition, we explore the potential role of emerging radiopharmaceutical and their possible application in aiding the diagnosis of CNS involvement in systemic autoimmune diseases.

The Role of Autophagy in Rheumatic Disease

Autophagy is an evolutionarily conserved degradation process in triggered by metabolic stress or environmental changes. Autophagy involves formation of autophagosomes, which fuse with lysosomes and degrade encapsulated intracellular components, such as long-lived and misfolded proteins, as well as intracellular organelles. Autophagy has been implicated in a wide variety of physiological and pathological conditions, and was recently implicated in the regulation of immunity and inflammation. Rheumatic diseases are a group of disorders characterized by immune system malfunctions in which the body attacks its own tissues. These diseases can seriously threaten human health if untreated. Although the underlying pathophysiology of autoimmune diseases has not yet been fully elucidated, autophagy has been implicated in their progression. In this article, we review the basics of autophagy, and the functional role of autophagy in the pathogenesis of rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Crohn's disease and ankylosing spondylitis (AS). Moreover, we reviewed the role of autophagy and autophagy-related genes (Atgs) in innate and adaptive immunity, as well as the pathogenic crosstalk between autophagy and apoptosis. Our findings should provide valuable insights into the role of autophagy in the pathogenesis of rheumatic diseases. In addition, identification of novel autophagy-associated target proteins may offer a promising target for drugs treating human rheumatic disorders.

Lupus Nephritis: Current Treatment Paradigm and Unmet Needs

Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation, which can result in a multitude of systemic or organ-limited manifestations, including the skin, lungs, heart, and kidney. SLE nephritis is present in an average of 38% of patients at the time of diagnosis, and may occur as the initial presentation of disease with progression to End-Stage Renal Disease (ESRD) in roughly 10-20% of patients.

Methods: A review of the current literature was undertaken to investigate the evolution of treatment of SLE nephritis based on randomized trials and robust observational studies. We aimed to provide a timeline of the development of current induction and maintenance therapy, as well as the development of novel targeted therapies, all leading to current guidelines.

Results: Based on all available current data on standard of care therapies for SLE nephritis, there is at best a complete remission rate of 50-60%, and roughly 13-25% of patients experience periods of relapse during maintenance therapy for SLE nephritis. Therefore, the need for newer, targeted therapies has been the focus of many current, ongoing clinical trials.

Conclusion: Standard induction and maintenance therapies at present are anti-proliferative and nonspecific, that is, interfering with the process of autoantigen presentation and activation of autoreactive leukocytes. However, newer agents with specific T-cell, B-cell, or proteasome targets are currently being investigated.

Lipid Profile of Children Suffering from Pediatric Rheumatic Diseases (pRDS)

Background: Aim of this study was to assess the lipid status of the patients of pediatric rheumatologic diseases (pRDS).

Methods: This observational study was carried out in the department of pediatrics, Khulna medical college hospital, Bangladesh for a period of one year. Total 23 patients were included in this study. These new cases were diagnosed according to the ILAR, ACR, and EULAR criteria. Early morning blood samples were sent to the laboratory for the assessment of lipid status (TC, TG, HDL, and LDL). These values were collected and statistically recorded.

Results: Total new cases of pRDS were 23. Among them JIA was 15, SLE 4, and Vasculitis 4 in number. HSP was in 3 and KD in 1 cases of vasculitis group. Male/ Female ratio is 1.6:1. Mean age of the diseases were 8.54 years. TC, and TG was found in significant level in 4(17.4%), and 12(52.8%) pRDS cases respectively. HDL was observed of risk level in 4(17.3%) patients. LDL was observed normal in all the patients. TG was found of significant level in 7(46.7%) JIA, 3(75%) SLE and 2 (50%) vasculitis patients.

Conclusion: TG was the lipid observed in significant level in majority of the new pRDS cases. Elevated TG might be considered as an index of disease activity in all cases of pRDS. Measures could be adopted in all pRDS to control the lipid status from the beginning of illness to reduce the complications from dyslipidemia like atherosclerosis and cardiovascular morbidity and mortality in future.

Torsades de Pointes in Patients with Polymyalgia Rheumatica

Polymyalgia rheumatica (PMR) represents the most common inflammatory rheumatic disease of the elderly. It is characterized by synovitis of proximal joints and extra-articular synovial structures, along with chronic high-grade systemic inflammation. PMR is closely related to giant cell arteritis (GCA), a large–vessel vasculitis that involves the major branches of the aorta, particularly the extracranial branches of carotid artery including temporal arteries. It is currently believed that PMR and GCA may represent different manifestations of the same disease process.

Chronic systemic inflammation is presently recognized as one of the key pathogenic mechanisms underlying cardiovascular disease and associated complications, including cardiac arrhythmias and sudden death. In this regard, several studies demonstrated that besides promoting structural heart disease, inflammatory activation may also be per se arrhythmogenic, via cytokine-mediated effects on cardiac electrophysiology. In particular, increasing evidence points to inflammation as a novel risk factor for QTc prolongation and related life-threatening arrhythmias, specifically Torsade de Pointes (TdP).

Starting from the report of two cases of TdP occurring in PMR patients with active disease and elevated circulating IL-6 levels, we here reviewed literature data regarding heart involvement and arrhythmic events in PMR/GCA, as well as TdP risk in inflammatory diseases. Potential underlying mechanisms were dissected, by focusing on the driving role of inflammatory activation.

Biologics in Inflammatory Immune-mediated Systemic Diseases

Background: The use of biologic agents in systemic immune-mediated diseases has dramatically increased in recent years, replacing conventional immunosuppressive strategies that are characterized by unspecific mechanisms of action and burdened with serious adverse effects. Biologic drugs have selective action towards specific targets, with considerable steroid-sparing effect. They are used nowadays to induce remission or treat specific organ involvements in systemic autoimmune diseases.

Conclusion: In this review, we will discuss the scientific evidence supporting the use of biologics in these diseases, with a particular emphasis on their efficacy and safety profile compared to the conventional drugs.

Structure-function Evaluation of Stem Cell Therapies for Spinal Cord Injury

Background: Spinal cord injuries (SCI) are prevalent, devastating for quality and expectancy of life, and cause heavy economic burdens. Stem cell therapies hold promise in complete structural and functional restoration of SCI.

Objective: This review focuses on the methods currently used to evaluate the stem cell therapies for SCI.

Results: Various kinds of stem cells involving embryonic stem cells (ESCs), bone marrow stromal cells (BMSCs), neural stem cells (NSCs) and induced pluripotent stem cells (iPSCs) are extensively used in regenerative research of SCI. For evaluation, the survival and integration of transplanted cells, spinal cord reconstruction and functional recovery all should be considered. Histological and histochemistrical, microscopic, and colorimetric assays, and real-time RT-PCR techniques are applied to determine the outcome. From the three main aspects-transplanted cells, spinal cord structure, and functional recovery-we summarize and discuss these methods with certain instances of applications in SCI models. Importantly, for the evaluations of function, neuronal transmitting, electrophysiological analysis and behavioral score are included.

Conclusion: Wider conjunction of established technologies, as well as the further development of nondestructive methods might make a big difference in testing stem cell therapies.

Vasculitis Following Influenza Vaccination: A Review of the Literature

Background: Influenza vaccine is safe and effective for the general population as well as for patients with autoimmune diseases. However, although rare, vasculitis has been reported as an adverse event following influenza vaccination.

Object: The aims of this literature review were to identify patients who developed vasculitis following influenza vaccination and to clarify the clinical manifestations of vasculitis in these patients.

Methods: Using the PubMed database and search engine, we performed a search of the Englishlanguage literature by combining the term influenza vaccination with each term for a specific form of vasculitis from January 1966 through April 2016.

Results: A total of 65 patients who developed vasculitis after influenza vaccination were identified from 45 published reports. The majority of patients were elderly, and the patients were predominantly female. The vasculitides included large vessel vasculitis (13 patients), medium vessel vasculitis (2), small vessel vasculitis (42), single organ vasculitis (5), vasculitis associated with systemic disease (1), and vasculitis associated with probable etiology (1). Although the majority of patients achieved complete recovery or remission, there were 3 deaths in patients with ANCA-associated vasculitis and severe long-term sequelae developed in 3 patients (1 with granulomatosis with polyangiitis, 1 with IgA vasculitis and 1 with unclassified small vessel vasculitis).

Conclusion: Since vasculitis following influenza vaccination has been only rarely reported, routine influenza vaccination should not be restricted. However, caution should be required when patients with small vessel vasculitis, especially with ANCA-associated vasculitis following influenza vaccination or with post-influenza vaccination-reactivated IgA vasculitis, receive influenza vaccination again.

Congenital Malformations Attributed to Prenatal Exposure to Cyclophosphamide

Cyclophosphamide (CPA) remains one of the most widely prescribed anticancer drugs. It is also used in the treatment of rheumatoid arthritis, childhood nephrotic syndrome and systemic lupus erythematosus. It is a potent immunosuppressive agent. It is commonly used in blood and bone marrow transplantation. With the growing trend among women postponing childbearing, the number of women who are diagnosed with breast cancer is also increasing thus escalating the chances of exposure of the unborn child to antineoplastic drugs. A review of the literature provides strong evidence for the teratogenic effects on infants prenatally exposed to CPA. Both sporadic case reports and larger case series have demonstrated that babies with cyclophosphamide embryopathy are afflicted with intrauterine growth restriction, small for gestational age, and craniofacial malformations including eye anomalies, cleft/arched palate, hydrocephaly, micrognathia, low set microtia, hearing defects, craniosynostosis, and facial asymmetry. Also observed in these cases are limb defects such as radial, ulnar and tibial hypoplasia, club foot, digital defects of the hand and feet as well as vertebral fusion, brevicolis, and occasional Sprengel’s deformity. These anomalies vary in consistency of occurrence and severity of the phenotype across cases and lack the specificity of thalidomide embryopathy or rubella embryopathy. However, they do occur is no longer in doubt. First trimester of pregnancy seems to be particularly susceptible to fetal malformations, although CPA effects on fetuses of later stages of gestation (hearing defects, growth restriction for example) are also reported occasionally. One of the major concerns from a mechanistic point of view is our inability to dissect the teratogenic effects of CPA from those of other drugs administered together with CPA as combination therapy. Animal experiments have been of particular value in that they are able to circumvent the numerous extraneous variables inherent to human case reports. They have also revealed the detrimental effects of CPA on gametes, preimplantation embryos, organogenesis as well as their potential teratogenic mechanisms. Of particular importance are the role of genetic polymorphisms, male mediated teratogenesis, ovarian failure, preimplantation embryo loss, epigenetic modifications, proxidant-antioxidant imbalance, autophagy, apoptosis, microRNAs and postclosure neural tube defects induced by CPA -all of which are areas for further research in CPA teratogenesis.

Crosstalk between Oxidative and Nitrosative Stress and Arterial Stiffness

Background: Arterial stiffness, the expression of reduced arterial elasticity, is an effective predictor of cardiovascular disorders. Oxidative stress is an imbalance between exposure to toxic reactive oxygen species (ROS) and antioxidant systems. The increase in reactive nitrogen species (RNS) is termed nitrosative stress.

Methodology: We review the main mechanisms and products linking arterial stiffness with oxidative and nitrosative stress in several disorders, focusing on recent experimental and clinical data, and the mechanisms explaining benefits of antioxidant therapy. Oxidative and nitrosative stress play important roles in arterial stiffness elevation in several disorders, including diabetes mellitus, hypertension, metabolic syndrome, obesity, peripheral arterial disease, chronic obstructive pulmonary disease, systemic lupus erythematosus, thalassemia, Kawasaki disease and malignant disorders. Oxidative and nitrosative stress are responsible for endothelial dysfunction due to uncoupling of the nitric oxide synthase, oxidative damage to lipids, proteins and DNA in vascular endothelial cells, associated with inflammation, arteriosclerosis and atherosclerosis.

Conclusion: Regular physical exercise, caloric restriction, red wine, statins, sartans, metformin, oestradiol, curcumin and combinations of antioxidant vitamins are therapeutic strategies that may decrease arterial stiffness and oxidative stress thus reducing the risk of cardiovascular events. ROS and RNS represent potential therapeutic targets for preventing progression of arterial stiffness.

Prognostic Parameters for Symptomatic Intracranial Hemorrhage after Intravenous Thrombolysis in Acute Ischemic Stroke in an Asian Population

Background: Symptomatic intracranial hemorrhage (sICH) is a major complication after intravenous thrombolysis leading to severe disability and death. The incidence was higher in Asian than in western countries. Prognostic factors across ethnicities are presumably different. Studies in Asian populations are limited.

Method: Clinical data from January 2008 to September 2016 in one provincial and four regional hospitals in the northern part of Thailand were retrospectively reviewed. Patients were those with acute ischemic stroke, to whom recombinant tissue plasminogen activator (rt-PA) had been prescribed. They were classified into 3 groups; no intracranial hemorrhage (no ICH), asymptomatic intracranial hemorrhage (asICH) and symptomatic intracranial hemorrhage (sICH), based on clinical and brain imaging (computed tomography or CT). Prognostic parameters were investigated using a multi-level, multivariable ordinal logistic model.

Results: After exclusion of ineligible patients, the remaining 1,172 patients were classified into no ICH (n=923, 78.8%), asICH (n=154, 13.1%) and sICH (n=95, 8.1%). Independent prognostic parameters for intracranial hemorrhage were the National Institutes of Health Stroke Scale (NIHSS) >20 (OR, 3.51; 95% CI, 2.18-5.65; p<0.001), NIHSS >10 (OR, 2.02; 95% CI, 1.42-2.87; p<0.001), use of nicardipine during rt-PA (OR, 1.61; 95% CI, 1.09-2.40; p=0.018), systolic blood pressure (SBP) prior to thrombolysis ≥ 140 mmHg (OR, 1.47; 95% CI, 1.06-2.04; p=0.021), and platelet count <250,000 cell/mm3 (OR, 1.45; 95% CI, 1.04-2.01; p=0.029).

Conclusion: Patients with these parameters should be closely monitored. Information should be provided to the patients and their relatives.

A Review of Clinical Trials of Belimumab in the Management of Systemic Lupus Erythematosus

There have been few changes over the last 50 years in the treatment of Systemic lupus erythematosus (SLE), using non-specific anti-inflammatory agents such as: nonsteroidal anti-inflammatory drugs along with the immune cell modulating agent hydroxychloroquine for mild disease, and broad spectrum immunosuppressants plus antiinflammatories such as corticosteroids, azathioprine, cyclophosphamide, or mycophenolate during flares or severe disease with organ involvement. In some patients, the response is inadequate and side effects appear from mild unpleasant up to severe toxicity. Drug metabolism and clearance may be severely compromised. Therefore, it is a priority to develop better treatments with fewer adverse events that can be used at different stages of disease activity.

In recent years, a member of the tumor necrosis factor (TNF) family, soluble human B Lymphocyte Stimulator protein (BLyS), also referred to as B-cell activating factor (BAFF) and TNFSF13B has been studied extensively. This protein is synthesized by myeloid cell lines, specifically interacts with B lymphocytes and increases their life-span. BlyS plays a key role in the selection, maturation and survival of B cells and it has a significant role in the pathogenesis of SLE.

In this review, we analyzed the role of BLyS as a diagnostic/prognostic marker and/or therapeutic target for lupus patients, and the different clinical studies published using belimumab.

Circulating Advanced Oxidation Protein Products as Oxidative Stress Biomarkers and Progression Mediators in Pathological Conditions Related to Inflammation and Immune Dysregulation

Evidence came out showing that oxidative stress has a pivotal role in development and maintenance of inflammation and aberrant immune responses. Biomarkers of oxidative stress may define the proportion of oxidative damage underlying pathological conditions, and also foresee and monitor the possible efficacy of therapeutic strategies designed to control these pathologies. New compounds, which can be used as biomarkers, have been identified, and among them advanced oxidation protein products (AOPPs), formed mainly by chlorinated oxidants resulting from activity of myeloperoxidase. Our paper is aimed to review clinical evidences concerning the valuable potential of AOPPs as biomarkers of oxidative injury in development and progression of diseases and chronic conditions related to inflammatory status and immune dysregulation. These pathologies include metabolic syndrome, obesity, immune-mediated inflammatory diseases, neurodegenerative diseases, and cancer. Due to the heterogeneity of pathologies reported to be characterized by AOPP accumulation, it is evident that AOPPs are not merely a marker of neutrophil activation, but at the same time AOPPs cannot always be disease determinants. The data reported in this review corroborate the opinion that AOPPs can be successfully used to in vitro confirm the diagnosis of inflammatory and immune-mediated diseases, but at the same time evidence is that, very likely due to the way through which AOPPs are formed as well as the effect they can contribute to induce, AOPP values cannot be clearly reflective of their involvement in the pathogenesis and in the evolution of a specific disease.

Spinal Cord Injury Changes Cytokine Transport

Here we summarize three aspects of our understanding of the interactions of cytokines and neurotrophic peptides/proteins with the blood-brain and bloodspinal cord barriers (BBB): (a) pharmacokinetic analysis that has been reported for native cytokines and neurotrophic peptides/proteins; (b) landmark work on conjugated proteins to enhance their delivery across the normal BBB; and (c) regulatory changes under pathophysiological conditions in rodents, particularly after spinal cord injury (SCI). First, though the BBB restricts the permeation of large proteins, some cytokines and neurotrophic peptides/proteins in the periphery can reach the central nervous system (CNS) by specific transport systems. Moreover, SCI and some other disease processes may regulate these transport systems. The significance of studies of the transport systems is obvious because of the biological impact of these molecules on the CNS in health and disease. We have characterized the pharmacokinetic characteristics of some stable cytokines and neurotrophic peptides/proteins in mice after intravenous administration and also in the setting of in situ brain perfusion. In the particular case of SCI, there are time- and regionspecific changes of BBB permeability and transport systems. Tumor necrosis factor-α, a cytokine with dual actions in regeneration of the spinal cord, has a slow basal influx into the brain and spinal cord. After SCI, the increase in the entry of tumor necrosis factor-α to the CNS differs from leakage after BBB disruption and is related to upregulation of the transport system in a unique temporal and regional pattern. Overall, the permeation of cytokines across the BBB can be mediated by specific transport systems. The regulation of transport in pathophysiological conditions affects the extent of neuroinflammation and is implicated in neuroregeneration.

Imaging Patterns of Cardiovascular Involvement in Mixed Connective Tissue Disease Evaluated by Cardiovascular Magnetic Resonance

Background: To clarify the imaging patterns of cardiovascular lesions in patients with mixed connective tissue disease (MCTD) and cardiovascular symptoms with or/ without abnormal routine non-invasive evaluation.

Patients-Methods: Twenty-two MCTD patients (19F/3M), aged 38±4 yrs with cardiovascular symptoms were evaluated using a 1.5 T scanner. Of them, 8/22 had systemic lupus erythematosus (SLE), 5/22 rheumatoid arthritis (RA), 5/22 scleroderma (SSc) and 4/22 myositis (MY) overlap syndromes; 10/22 patients with MCTD presented with Raynaud phenomenon (RP) and all were positive for Anti-RNP antibodies. The cardiovascular magnetic resonance study (CMR) included evaluation of function, inflammation and fibrosis. Myocardial stress perfusion-fibrosis evaluation was performed only in MCTD patients with RP.

Results: A positive CMR study was identified in 4/8 with SLE, 1/5 with RA, 4/5 with SSc and in 1/4 with MY like MCTD. The CMR lesions were subendocardial or transmural LGE following the distribution of coronary arteries, intramyocardial LGE and diffuse subendocardial LGE in SLE-RA, MY and SSc like MCTD, respectively. Although no evidence of fibrosis was identified in patients with RP, adenosine stress myocardial perfusion revealed diffuse subendocardial perfusion defects. No correlation between disease duration and/or inflammatory indices and cardiac lesions was identified.

Conclusion: CMR can reveal myocardial lesions in MCTD patients with cardiac symptoms including myocardial infarction, inflammation, diffuse subendocardial fibrosis and diffuse perfusion defects, necessitating further cardiac investigation and/or treatment.

Mechanisms of Inflammatory Atherosclerosis in Rheumatoid Arthritis

Cardiovascular disease dependent on inflammatory accelerated atherosclerosis leads to increased mortality in rheumatoid arthritis (RA). In addition to traditional, Framingham risk factors, several immuno-inflammatory cells, mediators and molecules may link atherosclerosis to arthritis. Among immune cells, primarily TH1 cells, as well as endothelial cells play a crucial role in synovial and vascular inflammation. Various cell surface molecules, such as adhesion receptors, CD40-CD40 ligand or members of the RANK-RANK ligand-osteoprotegerin system, as well as soluble pro-inflammatory cytokines, chemokines, autoantibodies and proteases have been implicated in RA and vascular damage. The early assessment of atherosclerosis and early intervention would decrease cardiovascular risk in RA.

Epigenetic Modulation: A Promising Avenue to Advance Hematopoietic Stem Cell-Based Therapy for Severe Autoimmune Disorders

Severe autoimmune disorders, such as certain serious forms of multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, lead to poor prognosis for patients and can be fatal. Traditional immunosuppression therapies are rarely curative but only temporarily relieve patients from the flares. Arising “epigenetic” medications may enhance specificity but limitations still exist for their applications to severe autoimmune disorders due to the medications targeting differentiated immune cells. Hematopoietic stem cell-based therapy represents a different therapeutic strategy, which aims to reconstitute the functionality of the whole immune system. Such a re-constitutive approach has demonstrated long-lasting clinical benefits. Currently, hematopoietic stem cell transplantation remains a challenging and risky procedure, but recent scientific discoveries indicate that targeting epigenetics in hematopoietic stem cells bears promise to improve both the success rate and safety profile of hematopoietic stem cell-based therapy for treating severe autoimmune disorders.

Biologic Therapy in Inflammatory Immunomediated Systemic Diseases: Safety Profile

The discovery of some key molecular mechanisms underlying the dysregulation of the immune system responsible for inflammatory systemic diseases as severe as Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), and Systemic Vasculitides, led to the development and subsequent introduction into clinical practice of biological drugs which are significantly improving the management of such complex disorders. This novel molecular targeted therapeutics represents in fact a valid alternative or complementary treatment to conventional immunosuppressive strategies, characterized by broad, unspecific actions and severe adverse effects. Main advantages of the use of biologic drugs reside in their steroid-sparing effect and in the ability of inducing remission of refractory disease states or curing specific organ involvements. Aim of this article is to review and briefly discuss the scientific evidence supporting the use of biologics in these diseases, with a particular emphasis on their efficacy and safety profile compared to the canonical drugs.

Targeting IL-17 and IL-23 in Immune Mediated Renal Disease

T helper (Th) cells belong to the adaptive immune system and provide an effective and antigen-specific means of host protection. Th17 cells are a subset of Th cells, characterized by the production of the inflammatory cytokines interleukin (IL)-17A (IL-17A) and IL-17F, which bind to a receptor complex comprised of IL-17RA and IL-17RC subunits. Th17 cells combat extracellular and fungal infections, but have been implicated in autoimmune diseases. In many autoimmune conditions, the dysregulated immune response involves several parts of the immune system, including autoantibodies, B and T cells. Targeted biological therapies are appealing, as they may prevent unwanted side effects in patients. There is evolving evidence that Th17 cells are important in the kidney, mediating injury in response to vascular or chemical insults to the renal tubules, and in autoimmune diseases of the glomerulus, either through a specific attack on the glomerular basement membrane or as part of a generalized systemic inflammatory disease. Therapies targeting IL-17A, IL-12p40 and IL-17RA are being explored in clinical trials or are being utilized in clinical practice for the treatment of other IL-17 mediated diseases, such as psoriasis. This review explores the current evidence that IL-17A and Th17 cells may be pathogenic in immune kidney disease, including anti-glomerular basement membrane disease, antineutrophil cytoplasmic antibody associated vasculitis and lupus nephritis, as well as in acute kidney injury. It will discuss the place that biological agents against IL-17A, IL-12p40 and IL-17RA may have in the treatment of these conditions.

Atherosclerotic and Non-Atherosclerotic Coronary Heart Disease in Women

Atherosclerotic Coronary heart disease (CHD) and non-atherosclerotic CHD in individuals less than 50 years of age is considered a “men’s case”. Undoubtedly, premenopausal women develop atherosclerotic/non-atherosclerotic CHD relatively rarely compared with men. This is attributed mostly to the cardioprotective role of estrogens (mainly estradiol). Nevertheless, there are predisposing conditions, which also make young women vulnerable to develop atherosclerotic/non-atherosclerotic CHD. Women who have classical cardiovascular (CV) risk factors, such as hypertension, diabetes mellitus, smoking, obesity, and dyslipidaemia, are more likely to develop cardiac events, even at a young age. Moreover, there are also other conditions that cause acute coronary syndromes, even in the absence of coronary atheromatic plaques such as myocardial bridge, coronary artery dissection, coronary artery spasm, coronary artery embolism and congenital anomalies of coronary arteries. Also, autoimmune diseases, some of which are more prevalent in women can cause atherosclerotic/ non-atherosclerotic CHD. In this narrative review we have summarized some of the causes that predispose young women to develop atherosclerotic/non-atherosclerotic CHD.

Cardiovascular Risk Factors in Chronic Inflammatory Rheumatic Diseases: Modern Assessment and Diagnosis

The current view is that systemic inflammation, which is specific to all chronic inflammatory rheumatic diseases (CIRD), accelerates atherogenesis; this hypothesis is supported by the high cardiovascular (CV) morbidity and mortality rates and the high prevalence of all atherosclerosis stages and complications in CIRD patients. The assessment of traditional CV risk factors underestimates the actual risk in patients with CIRD. A comprehensive evaluation and follow-up of both traditional and non-traditional CV risk factors, as well as the correct classification of risk reduction categories are necessary. Imaging techniques (e.g. carotid intima-media thickness and flow-mediated vasodilation) can be used for the early diagnosis of endothelial dysfunction. Immunologic and metabolic markers (anti-cyclic citrullinated peptide (CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, proinflammatory cytokines, TH0/TH1 lymphocytes and homocysteine) may be involved in the atherosclerotic disease development specific to CIRD. A modern therapeutic approach should include the early diagnosis of endothelial dysfunction and atherosclerosis, treatment of CIRD, specific medication designed to control atherosclerosis, changes in patient lifestyle and periodic follow-ups. The assessment and diagnosis of traditional and non-traditional CV risk factors, followed by aggressive prevention and therapy, are necessary to achieve efficient control over the inflammation, immunologic and metabolic disorders specific to CIRD.

The Role of Disproportionality Analysis of Pharmacovigilance Databases in Safety Regulatory Actions: a Systematic Review

Introduction: Disproportionality analysis (DA) of adverse drug reactions spontaneous reporting (SR) databases is used to identify signals of disproportionate reporting (SDR). The objective of this study was to identify the generation of SDR in the published literature and whether it led to regulatory action.

Methods: A systematic literature search in MEDLINE and Cochrane Central Register for Controlled Trials (CENTRAL) in a 10-year period, from 2005 to 2014, was conducted, to identify studies designed to detect drug safety signals through the use of disproportionality measures applied to spontaneous reporting databases of adverse drug reactions.

Results: Seventy three studies were included. The number of publications has been rising over the study time period. Forty nine studies focus on drug-event combinations. Large international and smaller national or regional databases were identified. The disproportionality measures applied included frequentist and Bayesian methods and some studies used more than one method. SDRs were identified in more than ninety percent of the studies. Ten studies were found to be confirmatory of previous regulatory decision.

Conclusion: It was not found any safety signal issued by drug regulatory agencies exclusively generated by DA. More research devoted to this issue is needed, since the value of these methods on drug safety signaling and their impact on drug regulation actions remains to be established.

Mammalian Antimicrobial Peptides: Promising Therapeutic Targets Against Infection and Chronic Inflammation

Antimicrobial peptides (AMPs) are integral components of the host innate immune system and functional throughout the plant and animal kingdoms. AMPs are short cationic molecules and lethal against a wide range of bacteria, viruses, fungi, yeast and protozoa due to their membranolytic effects on the negatively-charged microbial membranes. In addition, they exert multiple immunomodulatory roles like chemotaxis, modulation of cytokine and chemokine expression, leukocyte activation etc. Since AMPs suffer loss of microbicidal properties under serum and tissue environments, their capacity to modulate the immune system may predominates under the physiological conditions. Discovery of new antibiotics is lagging far behind the rapidly spreading drug resistance among the microorganisms. Both natural and synthetic AMPs have shown promise as ‘next generation antibiotics’ due to their unique mode of action, which minimises the chance of development of microbial resistance. In addition, they have therapeutic potential against non-infectious diseases like chronic inflammation and cancer. Many of the synthetic AMPs are currently undergoing clinical trials for the treatment of debilitating diseases, such as catheter-related infections, diabetic foot ulcers, chemotherapy-associated infections etc. Some of them have already entered the market as topical preparations. In this review, we synopsise the current literature of natural and synthetic AMPs in different infectious and inflammatory diseases of human microfloral habitats, especially the gastrointestinal, respiratory and genitourinary tracts and the skin. We also discuss the classification of AMPs, their mode action and antimicrobial spectrum, including the pathogen evasion mechanisms. In short, we tried to present the locus standi of AMPs in relation to human diseases and highlight the most promising synthetic peptides emerging from the clinical trials. Finally, we focused on the limitations and hurdles in terms of cost of production, bioavailability, pharmacokinetic stability and toxicity faced by commercial development and clinical use of the AMPs and strategies to overcome these hurdles.

Histopathology of Connective Tissue Disease-Associated Pleuropulmonary Disease

Pulmonary complications associated with autoimmune connective tissue disease (CTD) are common causes of clinical interstitial lung disease (ILD). Pleural manifestations are dominated by inflammation and varying amounts of diffuse fibrosis. In the lung, a wide spectrum of histologic injury patterns are encountered in every anatomic location including small airway disease most commonly in the form of chronic bronchiolitis, vascular changes, and interstitial lung disease ranging from diffuse alveolar damage to advanced pulmonary fibrosis. The most common interstitial pattern, seen in nearly all of the different CTDs, is a cellular and variably fibrotic ILD referred to as nonspecific interstitial pneumonia (NSIP). Each of the major CTDs has particular manifestations more commonly manifested, but the histopathologic changes found in these CTDs are often not specific and a definitive diagnosis usually requires detailed clinical, serologic, and pathologic correlation as well as close patient follow-up.

High-Resolution CT Imaging Findings of Collagen Vascular Disease- Associated Interstitial Lung Disease

The increased sensitivity and specificity of high-resolution computed tomography (HRCT) has allowed medical imaging to become an essential part of the diagnosis and management of interstitial lung disease (ILD). ILD is a common finding of many different collagen vascular diseases (CVDs) especially rheumatoid arthritis and scleroderma. As our understanding of CVD-associated ILD (CVD-ILD) improves, HRCT becomes an increasingly important tool for diagnosis and management.

Management of Connective Tissue Interstitial Lung Disease

The connective tissue diseases (CTD) are frequently associated with Interestitial lung diseases (ILD). The presence of an ILD in a patient with CTD is associated with a higher morbidity and mortality. Management of a patient with connective tissue interstitial lung disease (CTD-ILD) depends on disease severity with a focus on improving quality of life. Therapeutic interventions include medications, which aim to prevent progression to fibrosis and decrease inflammation or alveolitis, supplemental oxygen; and pulmonary rehabilitation. Comorbidities including gastroesophageal reflux disease (GERD) and obstructive sleep apnea should be addressed in all CTD-ILD patients. Appropriate referral to support groups, lung transplantation centers, and palliative care are considerations for all patients with CTDILD. The management of a patient with CTD-ILD is a multidisciplinary personalized process that is driven by the specific disease, clinical pattern, and associated comorbidities.

Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy

Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases of infectious or autoimmune etiology and accounts for more than 10% of severe visual handicaps in the United States. Pathology derives from the presence of inflammatory cells in the optical axis and sustained production of cytotoxic cytokines and other immuneregulatory proteins in the eye. The main therapeutic goals are to down-regulate the immune response, preserve the integrity of the ocular architecture and eventually eliminate the inciting uveitogenic stimuli. Current therapy is based on topical or systemic corticosteroid with or without second line agents and serious adverse effects of these drugs are the impetus for development of less toxic and more specific therapies for uveitis. This review summarizes the pathophysiology of uveitis, molecular mechanisms that regulate the initiation and progression of uveitis and concludes with emerging strategies for the treatment of this group of potentially blinding diseases.

Aging and immunopathology in primary Sjögren's syndrome

Sicca complaints (sensation of dry mouth and/or eyes) are present in about a quarter of the individuals above the age of 65 years old and are mainly due to medication. However, physiological changes that occur during aging might also lead to a diminished glandular function. These age-related changes are, at least in part, to be the consequence of decreased androgen levels. In addition to these physiological effects that occur during normal aging, sicca complaints can also be caused by Sjögren’s syndrome (SS): a systemic auto-inflammatory disorder mainly affecting exocrine glands. Genetic factors, lowered levels of gonadal hormones and (viral) infections appear to contribute to the etiology of the syndrome. The incidence of SS is higher among aged individuals, which might be due to earlier diagnosis, as the onset of SS in an individual with age-related exocrine gland dysfunction lowers the threshold for sicca complaints. On the other hand, physiological aging might be considered as a risk factor for development of SS, resulting in a faster development of the syndrome. Differentiating physiological sicca complaints from SS in the elderly can be challenging, since apparently healthy individuals might present with auto-antibodies and lymphocytic infiltrates in salivary glands might be present as well. The drop in the level of androgens and estrogens upon aging, immunosenescence and pro-inflammatory features of the aging immune system may all contribute to the etiology of pSS in the elderly. In this review, we describe the physiological effects of aging and the influence of SS on exocrine gland morphology and function.

Cardiovascular Involvement in Pediatric Systemic Autoimmune Diseases: The Emerging Role of Noninvasive Cardiovascular Imaging

Cardiac involvement in pediatric systemic autoimmune diseases has a wide spectrum of presentation ranging from asymptomatic to severe clinically overt involvement. Coronary artery disease, pericardial, myocardial, valvular and rythm disturbances are the most common causes of heart lesion in pediatric systemic autoimmune diseases and cannot be explained only by the traditional cardiovascular risk factors. Therefore, chronic inflammation has been considered as an additive causative factor of cardiac disease in these patients.

Rheumatic fever, juvenile idiopathic arthritis, systemic lupus erythematosus, ankylosing spondylitis/spondyloarthritides, juvenile scleroderma, juvenile dermatomyositis/polymyositis, Kawasaki disease and other autoimmune vasculitides are the commonest pediatric systemic autoimmune diseases with heart involvement.

Noninvasive cardiovascular imaging is an absolutely necessary adjunct to the clinical evaluation of these patients. Echocardiography is the cornerstone of this assessment, due to excellent acoustic window in children, lack of radiation, low cost and high availability. However, it can not detect disease acuity and pathophysiologic background of cardiac lesions. Recently, the development of cardiovascular magnetic resonance imaging holds the promise for early detection of subclinical heart disease and detailed serial evaluation of myocardium (function, inflammation, stress perfusion-fibrosis) and coronary arteries (assessment of ectasia and aneurysms).

Celastrol Inhibits Inflammatory Stimuli-Induced Neutrophil Extracellular Trap Formation

Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNFα) with an IC50 of 0.34 µM and by ovalbumin:anti-ovalbumin immune complexes (Ova IC) with an IC50 of 1.53 µM. Celastrol also completely inhibited neutrophil oxidative burst and NET formation induced by immunoglobulin G (IgG) purified from RA and SLE patient sera. Further investigating into the mechanisms, we found that celastrol treatment downregulated the activation of spleen tyrosine kinase (SYK) and the concomitant phosphorylation of mitogen-activated protein kinase kinase (MAPKK/MEK), extracellular-signal-regulated kinase (ERK), and NFκB inhibitor alpha (IκBα), as well as citrullination of histones. Our data reveals that celastrol potently inhibits neutrophil oxidative burst and NET formation induced by different inflammatory stimuli, possibly through downregulating the SYK-MEK-ERK-NFκB signaling cascade. These results suggest that celastrol may have therapeutic potentials for the treatment of inflammatory and autoimmune diseases involving neutrophils and NETs.

Interstitial Lung Disease Associated with Collagen Vascular Disease

Collagen vascular diseases (CVDs), also known as connective tissue disorders (CTDs), include a diverse group of immunologically mediated inflammatory disorders. Systemic inflammatory response may affect many organs. Lung disease—especially interstitial lung disease (ILD)—is frequent in the course of rheumatological diseases and causes mortality and morbidity rates to increase. Since the overall incidence of ILD has been estimated at 15%, physicians are urged to make an early diagnosis and decide the best treatment for ILD in CVDs. There are several tests to improve the accuracy of diagnosis, treatment and prognosis, such as high-resolution computed tomography (HRCT), pulmonary function test, broncho-alveolar lavage (BAL), and surgical lung biopsy. A multi-disciplinary team made up of specialists with extensive expertise in this area must determine when to use each. This document is a review of the diagnosis, treatment and prognosis of ILD in CVDs.

Adverse Drug Reactions Amongst Adult Patients Admitted in Lagos State University Teaching Hospital Lagos, Nigeria

Background: Adverse drug reaction (ADR) is a global drug therapy problem. It has been rated as one of the top leading causes of morbidity and mortality. In Nigeria, not much is known about ADRs especially with the existing weak post marketing surveillance for monitoring drug use, and its effect on the population.

Objectives: The study is aimed at determining the incidence of ADRs, presentations of ADRs, classes of drugs that frequently cause ADRs and predictors of ADRs in adult medical in-patients in LASUTH.

Method: A retrospective study of six hundred and twenty four (624) case notes of all patients admitted to the medical wards in LASUTH between January 1, 2009 and December 31, 2009 was carried out. Information obtained included age, gender, and adverse drug reaction and drug details. The results obtained were analyzed using SPSS version 16 statistical software. Level of significance was set at p ≤ 0.05.

Results: A total of 624 case notes consisting of 358 males and 266 females were assessed. The number of patients who experienced adverse drug reactions was 67 (n = 624, 10.7%). The incidence rate of ADRs in LASUTH from the study was 10.7 per 100 patients’ population. Most of the ADRs observed were type A reactions (97.8%). Mostly implicated classes of drugs were antidiabetics (26.7%) and NSAIDs (29.3%).

Conclusion: The incidence rate of ADRs was 10.7%. ADRs which are predictable and preventable occur in hospitalized patients, such may be prevented or minimized by implementing measures to target specific drugs that are commonly suspected.

Animal Models of Lupus and Lupus Nephritis

This article reviews the commonly used murine strains for studying lupus and lupus nephritis, including strains that develop lupus spontaneously, congenic strains, induced models of lupus, as well as genetically engineered mouse models of lupus bearing transgenes or knockouts. The review then summarizes the main cellular and molecular pathways that lead to the pathogenesis of this autoimmune disease, including autoantibodies. Finally, it concludes with therapeutic insights gained from using mouse models of lupus. To sum, much of what we have learned about lupus has arisen from studying mouse models of the disease, and the laboratory mouse continues to be one of the best tools for studying human SLE.

History and Milestones of Mouse Models of Autoimmune Diseases

Autoimmune diseases are a group of disorders mediated by self-reactive T cells and/or autoantibodies. Mice, as the most widely used animal for modeling autoimmune disorders, have been extensively used in the investigation of disease pathogenesis as well as in the search for novel therapeutics. Since the first mouse model of multiple sclerosis was established more than 60 years ago, hundreds of mouse models have been established for tens of autoimmune diseases. These mouse models can be divided into three categories based on the approaches used for disease induction. The first one represents the induced models in which autoimmunity is initiated in mice by immunization, adoptive transfer or environmental factors. The second group is formed by the spontaneous models where mice develop autoimmune disorders without further induction. The third group refers to the humanized models in which mice bearing humanized cells, tissues, or genes, develop autoimmune diseases either spontaneously or by induction. This article reviews the history and highlights the milestones of the mouse models of autoimmune diseases.

The Contribution of Transcriptomics to Biomarker Development in Systemic Vasculitis and SLE

A small but increasing number of gene expression based biomarkers are becoming available for routine clinical use, principally in oncology and transplantation. These underscore the potential of gene expression arrays and RNA sequencing for biomarker development, but this potential has not yet been fully realized and most candidates do not progress beyond the initial report. The first part of this review examines the process of gene expression- based biomarker development, highlighting how systematic biases and confounding can significantly skew study outcomes. Adequate validation in an independent cohort remains the single best means of protecting against these concerns.

The second part considers gene-expression based biomarkers in Systemic Lupus Erythematosus (SLE) and systemic vasculitis. The type 1 interferon inducible gene signature remains by far the most studied in autoimmune rheumatic disease. While initially presented as an objective, blood-based biomarker of active SLE, subsequent research has shown that it is not specific to SLE and that its association with disease activity is considerably more nuanced than first thought. Nonetheless, it is currently under evaluation in ongoing trials of anti-interferon therapy. Other candidate markers of note include a prognostic CD8+ T-cell gene signature validated in SLE and ANCA-associated vasculitis, and a disease activity biomarker for SLE derived from modules of tightly correlated genes.

Rheumatoid Arthritis: An Evolutionary Force in Biologics

The advent of biologic therapy has transformed the outcomes of patients with Rheumatoid Arthritis (RA), but has also highlighted important issues for their development. Early attempts at T-cell driven therapies gave mixed results with difficulties extrapolating from non-human models to first in man trials. There is currently one T-cell modulating therapy – abatacept – licenced for use in RA. Cytokine inhibition has proven to be more fruitful with a number of anti-TNF and IL6 agents either licenced for use in RA or in development. The B-cell depleting therapy rituximab has also shown good efficacy as a chemotherapy agent repurposed for RA treatment.

Overall the biologics show good efficacy in RA and have been shown to retard progression of radiographic joint damage. However, this benefit comes with a burden of increased infection risk and a financial cost significantly higher than conventional disease modifying therapies. As a result current UK licencing holds the biologics in reserve following failure of a conventional therapy and the presence of moderate to severely active disease.

The long term use of the biologics in RA has highlighted the risk of immunogenicity, with significant proportions of patients developing anti-drug antibodies and losing therapeutic effect. The side effect profile and cost also raise the question around duration of therapy and trials of drug tapering following disease remission are now taking place with several biologic agents. Our inability to stratify patients to the most appropriate biologic drug (stratified or precision medicine) has also catalysed a large and critically important research agenda. Beyond identifying new biologic targets, the development of biosimilar agents will likely drive the future shape of the RA biologics market as lower cost alternatives are developed, thereby improving access to these therapies.

Immunotherapy Strategies for Spinal Cord Injury

Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with protein or DNA vaccines targeting Nogo, MAG, OMgp, and their co-receptors, may be an effective strategy for the treatment of SCI. However, immunotherapy such as anti-inflammtory therapy or vaccine targeting MAIs or their receptors, accompanied with the potential in risking autoimmune diseases. As a result, in order to optimize the anti-inflammtory therapy and design of protein or DNA vaccines for their use in the future clinical application, we need to further understand the possible mechanisms of neuroprotective immunity. This review presents recent advances in the development of immunotherapy strategies for the treatment of axonal degeneration and demyelination, and improvement of motor function after SCI.

Pentraxin 3 Serum Levels in Celiac Patients: Evidences and Perspectives

Celiac disease (CD) is now considered, more than a just gluten sensitivity enteropathy, a multiple and systemic immune-mediate disorder triggered by the ingestion of wheat gluten and related proteins. Following the discovery of a link between gluten and CD, it was demonstrated that gliadin, one of the two principal protein groups comprising gluten, plays a key role in CD. It has since become clear that the different and crucial roles of gliadin in CD result from its ability to activate multiple signaling pathways that modulate CD pathology. Most of these pathways involve the host innate and adaptive immune responses, but some pathways are activated when gliadin interacts with the intestinal cellular compartment. The long pentraxin (PTX3), a marker of the acute-phase inflammatory response, plays an important role in innate immunity and in modulation of the adaptive immune response.

We investigated whether CD patients, considered as a model of gluten-sensitivity condition, have increased PTX3 levels. Our data showed that PTX3 serum levels were high in active CD patients and serum levels of PTX3 correlated with DGP IgA levels. We provide evidences that the bad compliance of GFD in patients 2 concurred with a pathological PTX3 concentration that could follow the improvement of both gastrointestinal and extraintestinal symptoms. We hypothesized that PTX3 is able to modulate the innate response to gliadin in CD and it could regulate the adaptive immune response.

It is also evidenced that a common “wooden horse” of CD and Non Celiac Gluten Sensitivity (NCGS) is the ingestion of gluten and related toxic peptides. At the moment we don’t have adequate elements to suggest the use of PTX3 in diagnosis of NCGS, but we are obliged to speculate about the possible role of PTX3 molecules in NCGS pathogenesis.

The identified new strategies and uses of PTX3 could improve the management of gluten sensitivity conditions in the next future.

Transitional Connective Tissue Diseases: Description of Four Cases

The term overlap syndromes (OS) is used to define a group of disorders characterized by the presence, in the same patient, of clinical features typical for more than one definite connective tissue disease (CTD).

Objective: To show that patients may not only have an overlap of two or more CTDs but may also change their disease phenotype from that of a definite CTD to another.

Patients and methods: Retrospective analysis of medical records of four patients with a disease duration of about thirty years and a transition from a well definite CTD into another.

Results: The first patient was diagnosed, at the beginning of the 1980s, as affected by diffuse cutaneous systemic sclerosis (dcSSc) and developed systemic lupus erythematosus (SLE) twenty-five years later. The second and the third patients were diagnosed with SLE at the beginning of their disease: the second patient developed, in the course of her disease, an overlap syndrome (OS) SSc/rheumatoid arthritis (RA) and the third SSc and finally microscopic polyangiitis (MPA). The fourth patient was diagnosed as primary Sjogren’s syndrome (SS) then as rheumatoid arthritis (RA) and finally developed SLE.

Conclusions: Patients may not only show an overlap of two or more CTDs but also a transition from a well definite CTD into another. We propose the term “transitional connective tissue diseases” (TCTDs) to define their disease. A higher number of patients may allow us to better identify this new subgroup of CTDs and probably, also, predictors of evolution.

Diagnosis of Systemic Lupus Erythematosus in an Unusual Presentation: What a Primary Care Physician Should Know

Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease affecting millions of people worldwide. It can affect any organ systems of the body. However, all systems may not be involved initially rather than they may be affected gradually, sometimes over years. Diagnosis depends on characteristic clinical features and laboratory test results. Some features such as skin rash, joint symptoms and oral ulcers are common in SLE. But initial presentation of many patients is unusual because either they do not have these common features of the disease or the presentation mimics other illnesses. As a result, delayed diagnosis and misdiagnosis are common. Therefore, high index of initial suspicion of SLE is critical. In clinical practice, SLE should be suspected in any patient presenting with an unexplained disease process involving two or more organ systems. To make a diagnosis in an unusual presentation, thorough clinical evaluation with details history of both present and past illnesses as well as laboratory tests for SLE should be performed. Usually primary-care physicians first evaluate SLE patients; but there is no single article, where all the information on when to suspect SLE in an unusual presentation, is available in an integrated form. In this article, a list of conditions, when SLE should be suspected in an unusual presentation, has been given and some relatively common areas with diagnostic challenges of SLE have been briefly described.

To prepare this manuscript, most articles have been identified through ‘Pubmed’ search using keywords-atypical/ unusual presentation of SLE, case reports on SLE, gastrointestinal manifestations of SLE, neuropsychiatric SLE, diagnostic challenges with SLE, etc. Selected most articles are from currently medline-indexed journals.

Cardiovascular Magnetic Resonance for Evaluation of Heart Involvement in ANCA-Associated Vasculitis. A Luxury or a Valuable Diagnostic Tool?

Antineutrophil cytoplasmic antibody (ANCA)-related vasculitis is a systemic small-vessel vasculitis, including 3 clinical syndromes: granulomatosis with polyangiitis, known as Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and the Churg-Strauss syndrome (CSS). ANCA-related vasculitis usually presents with severe kidney or pulmonary disease, has a mortality of 28% at 5 years, and also contributes to increased morbidity in vasculitis patients.

Cardiac involvement in this entity may have different forms, including coronary vessels, pericarditis, myocarditis, endocarditis, myocardial infarction and subendocardial vasculitis that can contribute to reduced life expectancy.

Cardiovascular magnetic resonance using oedema and fibrosis imaging can early reveal, noninvasively and without radiation, heart involvement during vasculitis, undetected by other imaging techniques and guide further risk stratification and treatment of these patients.

Clinical Queries Addressed in Patients with Systemic Autoimmune Diseases. Can Cardiovascular Magnetic Resonance Give the Final Solution?

Objectives: To evaluate the potential of cardiovascular magnetic resonance (CMR) to answer queries, addressed in systemic autoimmune diseases (SAD).

Methods: Thirty-six patients aged 52±6 years, (range 27-71) with SAD and suspected cardiac disease underwent CMR by a 1.5 T, after routine evaluation, including clinical, ECG and echocardiographic examination. Steady-state, free precession cines, STIR T2-W and late gadolinium enhanced (LGE) images were evaluated.

Results: Abnormal findings were detected by: clinical evaluation in 14/36, ECG in 17/36, echocardiography in 11/36 and CMR in 30/36 SAD. Clinical, ECG and echocardiographic examination could not assess cardiac disease acuity and lesions’pathophysiology. In contrary, CMR identified cardiac lesions’ etiology, acuity, need for catheterization and heart disease persistence, even if SAD was quiescent.

Conclusion: Clinical, ECG and echocardiographic abnormalities may suggest, but not always interpret cardiac involvement in SAD. CMR can help to identify both etiology and acuity of cardiac lesions and guide further diagnostic and/or therapeutic approach in these patients.

A Review on Response of Immune System in Spinal Cord Injury and Therapeutic Agents useful in Treatment

Every year more than 12,000 people in US alone suffer from spinal cord injury. However, complete recovery of physical function is difficult due to multiple factors involved in disease progression. Currently available therapeutic regimens do not address all the factors concerned with the disease progression. The present review focuses mainly on the role of immune cells in progression of spinal cord injury and the drugs that target these immune cells. Literature search shows that inflammatory reactions and subsequent reactions that follow direct injury to spinal cord are sometimes responsible for the severity of the disease. Therefore, for design of proper treatment regimen a deep understanding in this area is required. Understanding the pathophysiology will help in creating delivery system that can target multiple factors involved in progression of spinal cord injury. A combination of various treatment strategies is required to reduce the disability in patients with spinal cord injury.

Rheumatoid Arthritis: Genetic Variants as Biomarkers of Cardiovascular Disease

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with premature mortality, severe morbidity, and functional impairment leading to considerable financial burden for both patients and society. Since disease progression and complications can differ from one patient to another, genetic markers are of potential relevance for identifying those individuals at a higher risk of more severe disease. RA is a complex polygenic disease. Cardiovascular (CV) disease due to accelerated atherogenesis is the most common cause of premature mortality in patients with RA. Several studies support the implication of genetic factors in the development of CV disease in RA. In addition to the strong association between alleles of the HLA-DRB1*04 shared epitope and both subclinical and clinically evident CV disease, genes implicated in inflammation and metabolism, such as TNFA, MTHFR, and CCR5, seem to be associated with a higher risk of CV disease in patients with RA. We propose the use of these genetic variants as molecular biomarkers that could help to predict disease outcome at diagnosis of RA and, therefore, to optimize the treatment and management of other risk factors from an early stage of the disease.

Are Patient Self-Report Questionnaires as "Scientific" as Biomarkers in "Treat-totarget" and Prognosis in Rheumatoid Arthritis?

Information from patients traditionally is regarded as “subjective,” in contrast to “objective,” “scientific” laboratory data. However, patient questionnaire scores for physical function are more significant to predict severe outcomes of rheumatoid arthritis (RA), such as work disability and mortality, than radiographs or laboratory tests. Furthermore, the 3 RA Core Data Set patient self-report measures of physical function, pain, and patient global estimate are as effective as radiographs or laboratory tests to distinguish active from control treatments in clinical trials. A multidimensional health assessment questionnaire (MDHAQ) has been developed in routine clinical care, to be completed by patients in 5-10 minutes and contribute to clinical decisions, in contrast to research questionnaires which may provide extensive information, but often are lengthy, unfeasible for routine care, and not designed to add to clinical care. RAPID3 (routine assessment of patient index data) is an index included on the MDHAQ which is calculated in 5 seconds, compared with almost 2 minutes for RA indices that require a formal joint count, such as DAS28 (disease activity score with 28-joint count) or CDAI (clinical disease activity index). MDHAQ with included RAPID3 scores appears as “scientific” as laboratory tests, formal joint counts, and indices such as DAS28 and CDAI, to assess patient status using standard, protocolized, quantitative measurement. MDHAQ/RAPID3 helps the patient prepare for the visit, enhances doctor-patient communication, and saves time for the physician. MDHAQ/RAPID3 is useful in all rheumatic diseases, and can be incorporated into routine clinical care with minimal extra work for physicians and staff. MDHAQ in no way prevents collection of formal joint counts, radiographs and other imaging studies, laboratory tests, or any other information regarded as important by a rheumatologist. MDHAQ provides quantitative, "scientific” data, rather than gestalt impressions, regarding patient status, change in status, prognosis, and outcomes of RA and all rheumatic diseases.

Impaired Clearance of Neutrophils Extracellular Trap (NET) May Induce Detrimental Tissular Effect

Neutrophils Extracellular Trap (NET) is composed of nuclear chromatin with hyper segmentation of nuclear lobes, citrullination of histone-associated DNA and mixing with cytoplasmic proteins including the enzyme myeloperoxidase. It is believed that neutrophils trap can kill microorganisms and constitutes a new form of innate defense. However, in some conditions, NET formation may be detrimental to the organism due to its association with autoantibody formation. Thus, NETs can be beneficial or detrimental depending of the DNA clearance recent registered patents describing the processes, products, methods and therapeutic indications of the neutrophil extracellular trap (NET) phenomenon have been reported. The patents US8710039; EP2465536; EP2651440; US20130302345; US20140099648; US20130183662; WO2012166611; and RU2463349C2, related to NETosis, suggest an association between NET formation and autoimmunity. However, its function is still not fully understood. Some parasites have learned to escape from NET using nucleases. NET persistence could be due to a possible enzymatic inhibition as suggested in Grabar´s theory for explaining the induction of physiologic or pathologic autoantibodies. In the present mini-review NET persistence due to impairment in the homeostasis clearance of DNA is discussed.

Nanofiber Scaffolds for Treatment of Spinal Cord Injury

Spinal cord injury (SCI) is a common neurologic disorder that results in loss of sensory function and mobility. It is well documented that tissue engineering is a potential therapeutic strategy for treatment of SCI. In this connection, various biomaterials have been explored to meet the needs of SCI tissue engineering and these include natural materials, synthetic biodegradable polymers and synthetic non- degradable polymers. Nanofiber scaffolds are newly emerging biomaterials that have been widely utilized in tissue engineering recently. In comparison to the traditional biomaterials, nanofibers have advantages in topography and porosity, thus mimicking the naturally occurring extracellular matrix. Besides, they exhibit excellent biocompatibility with low immunogenicity, and furthermore they are endowed with properties that help to bridge the lesion cavity or gap, and serve as an effective delivery system for graft cells or therapeutic drugs. This review summarizes some of the unique properties of nanofiber scaffolds which are critical to their potential application in treatment of injured spinal cord.

Neutrophil Derived Microvesicles: Emerging Role of a Key Mediator to the Immune Response

In response to infection and trauma, exquisite control of the innate inflammatory response is necessary to promote an anti-microbial response and minimize tissue injury. Over the course of the host response, activated leukocytes are essential for the initial response and can later become unresponsive or undergo apoptosis. Leukocytes, along the continuum of activation to apoptosis, have been shown to generate microvesicles. These vesicles can range in size from 0.1 to 1.0 μm and can retain proteins, RNA and DNA of their parent cells. Importantly, neutrophil-derived microvesicles (NDMV) are robustly increased under inflammatory conditions. The aim of this review is to summarize the research to date upon NDMVs. This will include describing under which disease states NDMVs are increased, mechanisms underlying formation, and the impact of these vesicles upon cellular targets. Altogether, increased awareness of NDMVs during the host innate response may allow for diagnostic tools as well as potential novel therapies during infection and trauma.

Biologics for ANCA-Associated Vasculitis

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of necrotizing vasculitides with a potential fatal outcome. Conventional therapy is based on the use of glucocorticoids (GCs) and cyclophosphamide (CYC), which is associated with severe toxic effects and is unable to control the disease activity in some refractory and relapsing cases. Several authors focused their efforts on the identification of safe and more efficient drugs, primarily investigating biological agents. Rituximab (RTX) demonstrated to be an alternative to CYC as remission-induction therapy for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in two clinical controlled randomized trials. Contrasting data emerged regarding anti-TNF-α agents, and their use should be limited to some selected refractory or relapsing cases. Mepolizumab (MPZ) and Omalizumab (OMZ) are potentially beneficial treatments for patients with eosinophilic granulomatosis with polyangiitis (EGPA). Hereby, we perform a review focused on the use of biological drugs for AAV treatment.

The Use of Interferons in Respiratory Diseases

Interferons (IFNs) are a subclass of lymphocyte-released cytokines that interfere with intracellular viral replication. These drugs are classified into three groups: IFN type 1 (IFN-α, IFN-β, and IFN-ω), IFN type 2 (IFN-γ), and IFN type 3 (IFN-λ). Despite numerous trials, IFN therapy has yet to conclusively demonstrate superiority in the treatment of various pulmonary diseases. In addition to the FDA-approved and ongoing investigational uses for IFN therapy, there is a debate regarding the appropriate dosage of these agents. A retrospective literature review is moving experts towards low-dose therapies in nearly every application of IFN therapy. It is speculated that known and unknown toxicity may limit the beneficial effects of IFN therapy.

Cardiac and Muscular Involvement in Idiopathic Inflammatory Myopathies: Noninvasive Diagnostic Assessment and the Role of Cardiovascular and Skeletal Magnetic Resonance Imaging

Idiopathic inflammatory myopathies (IIMs) are rare autoimmune diseases and include dermatomyositis, polymyositis, necrotizing myopathy and inclusion body myositis; they are characterized by inflammation of skeletal muscle and other internal organs and may potentially lead to irreversible damage and death. Only a small percentage of IIM has clinically overt cardiac disease; however, heart involvement is one of the leading causes of death and therefore, early detection remains a challenge.

Biochemical markers and non-invasive methods such as the electrocardiogram and echocardiography have a role in diagnosis, but lack sensitivity in identifying patients with early, sublinical cardiac abnormalities. Endomyocardial and skeletal muscle biopsies are very useful, but invasive techniques and cannot be used for routine follow-up. Cardiac and skeletal magnetic resonance imaging, due to their capability to perform tissue characterization, has emerged as novel techniques for the early detection and follow-up of myocardial and skeletal muscle tissue changes (oedema, inflammation, fibrosis) in IIM. However, the clinical implications of using these approaches and their cost /benefit ratio require further evaluation.