Severe Autoimmune Disease Research Articles

The E3 ubiquitin ligase Itch deficiency promotes antigen-driven B-cell responses in mice.

Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B-cell-specific Itch deficiency promoted antigen-induced B-cell activation and antibody-expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19cre Itchf/f ) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)-like SP 2/0 cells, Itch deficiency promoted B-cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen-induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen-driven B-cell response. This may provide hints for Itch-targeted treatment of patients with autoimmune disease.

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs.

Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA which changes its sequence, coding potential and secondary structure. Catalysed by the adenosine deaminase acting on RNA (ADAR) proteins, ADAR1 and ADAR2, A-to-I editing occurs at approximately 50 000–150 000 sites in mice and into the millions of sites in humans. The vast majority of A-to-I editing occurs in repetitive elements, accounting for the discrepancy in total numbers of sites between species. The species-conserved primary role of editing by ADAR1 in mammals is to suppress innate immune activation by unedited cell-derived endogenous RNA. In the absence of editing, inverted paired sequences, such as Alu elements, are thought to form stable double-stranded RNA (dsRNA) structures which trigger activation of dsRNA sensors, such as MDA5. A small subset of editing sites are within coding sequences and are evolutionarily conserved across metazoans. Editing by ADAR2 has been demonstrated to be physiologically important for recoding of neurotransmitter receptors in the brain. Furthermore, changes in RNA editing are associated with various pathological states, from the severe autoimmune disease Aicardi-Goutières syndrome, to various neurodevelopmental and psychiatric conditions and cancer. However, does detection of an editing site imply functional importance? Genetic studies in humans and genetically modified mouse models together with evolutionary genomics have begun to clarify the roles of A-to-I editing in vivo. Furthermore, recent developments suggest there may be the potential for distinct functions of editing during pathological conditions such as cancer.

Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses.

Neuromyelitis optica spectrum disorders are a group of rare, but severe autoimmune diseases characterized by inflammation of the optic nerve(s) and/or spinal cord. Although naive B cells are considered key players by escaping central tolerance checkpoints, it remains unclear how their composition and outgrowth differ in patients with neuromyelitis optica spectrum disorders. Under complete treatment-naive circumstances, we found that naive mature/transitional B-cell ratios were reduced in the blood of 10 patients with aquaporin-4 immunoglobulin G-positive disease (neuromyelitis optica spectrum disorders) as compared to 11 both age- and gender-matched healthy controls, eight patients with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders and 10 patients with multiple sclerosis. This was the result of increased proportions of transitional B cells, which were the highest in patients with neuromyelitis optica spectrum disorders with relapses and strongly diminished in a separate group of nine patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders who received corticosteroid treatment. These findings need to be confirmed in longitudinal studies. For purified naive mature B cells of seven patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders with relapses, Toll-like receptor 9 ligand synergized with interferon-γ to enhance plasmablast formation during germinal centre-like cultures. This was not seen for 11 patients without relapses and nine healthy controls. In the neuromyelitis optica spectrum disorders group, in vitro plasmablast formation corresponded to total and anti-aquaporin-4 immunoglobulin G secretion, of which the latter was found only for relapsing cases. These data indicate that naive B-cell homoeostasis is different and selectively targeted by corticosteroids in patients with neuromyelitis optica spectrum disorders. This also supports further exploration of naive B cells for their use in Toll-like receptor 9-dependent in vitro platforms in order to predict the activity of neuromyelitis optica spectrum disorders.

Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion.

Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum-derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG dose dependent, AQP4 dependent, and, unexpectedly, microglia dependent. In vivo spinal cord imaging revealed a striking physical interaction between microglia and astrocytes that required signaling from astrocytes by the C3a fragment of their upregulated complement C3 protein. Astrocytes remained viable but lost AQP4. Previously unappreciated crosstalk between astrocytes and microglia involving early-activated CNS-intrinsic complement components and microglial C3a receptor signaling appears to be a critical driver of the precytolytic phase in the evolving NMO lesion, including initial motor impairment. Our results indicate that microglia merit consideration as a potential target for NMO therapeutic intervention.

P1792SUCCESSFUL TRANSPLANTATION OF STEM CELLS AND KIDNEY IN REFRACTORY LUPUS NEPHRITIS: REMOTE OUTCOMES

Abstract Background and Aims Lupus nephritis is a common part of systemic lupus erythematosus (SLE), severe autoimmune disease that affects multiple organ systems and associated with pure prognosis. Patients with lupus nephritis who experience persisted disease activity despite conventional immunosuppression are at high risk of early death. Re-setting of the immune system and self-tolerance by high-dose immunosuppressive therapy with autologous stem cell transplantation (ASCT) is a new approach in the treatment of refractory SLE. Remote outcomes of this method and effectiveness relapse treatment are still unclear and were the aims of this study. Method We report a sick woman 39 years old, with refractory severe lupus nephritis. Standard therapy was ineffective, SLEDAI score remains 22 so patient was underwent high dose immunosuppressive therapy with ASCT and included in European Group for Blood and Marrow Transplantation European League against Rheumatism (EBMT/EULAR) registry on 53 pts who received ASCT for SLE between 1996 and 2005. Ethical approval was obtained for this study from Cambridge University Hospital Ethics Committee. Results The ASCT induced complete clinical and serological remission (SLEDAI score was 0) for 3 years. Than relapse with nephritic syndrome and anti-dsDNA positivity occurred and caused renal failure, creatinine clearance decreased to 21. Despite therapy including prednisolone, 45 mg daily, and mycophenolate mofetil, 2000 mg daily, disease activity persisted, creatinine clearance remained decreasing and 3 years later became 15 ml/min. During 1 year patient was on regular hemodialysis, then renal transplantation performed. Now, follow up is 15 years after ASCT and 8 years after kidney transplantation. Patient received a standard post-transplant immunosuppression with prednisolone, 5 mg daily, tacrolimus, 2.5 mg daily, and azathioprine, 100 mg daily, and her conditions remains stable, she has functioning renal allograft, SLEDAI score is 2 (anti-dsDNA positivity in low titer). Conclusion We present the successful remote outcomes of first case of immunoablation and double transplantation of autologous stem cells and allogeneic kidney in severe refractory to conventional immunosuppression SLE with lupus nephritis.

BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer

The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator's choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.

European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology

Treatment of severe dermatological autoimmune diseases and toxic epidermal necrolysis (TEN) with high-dose intravenous immunoglobulin (IVIg) is awell-established procedure in dermatology. As treatment with IVIg is usually considered for rare clinical entities or severe cases, the use of immunoglobulin is not generally based on data from randomized controlled trials usually required for evidence-based medicine. Since the indications for the use of IVIg are rare, it is unlikely that such studies will be available in the foreseeable future. Because first-line use is limited by the high costs of IVIg, the first clinical guidelines on the use of IVIg in dermatological conditions were established in 2008 and renewed in 2011. The European guidelines presented here were prepared by apanel of experts nominated by the European Dermatology Forum (EDF) and European Academy of Dermatology and Venereology (EADV). The guidelines were developed to update the indications for treatment currently considered effective and to summarize the evidence for the use of IVIg in dermatological autoimmune diseases and TEN. The current guidelines represent consensual expert opinions and definitions on the use of IVIg reflecting current published evidence and are intended to serve as adecision-making tool for the use of IVIg in dermatological diseases.

Summary of immunotherapy efficacy ordered in accordance with drug reimbursement program in melanoma patients

Nivolumab and pembrolizumab are monoclonal antibodies of the IgG4 class, which target the cell death receptor (PD-1) found on T cells. The binding of the anti-PD-1 drug to the receptor therefore prevents the inhibition of these T cells and increases the immune response against melanoma cells. Pembrolizumab and nivolumab monotherapy has similar efficacy, including PFS and OS. Nivolumab and pembrolizumab immunotherapy are effective regardless of the BRAF mutation status. Currently, the choice between nivolumab and pembrolizumab is primarily dependent on to the frequency of infusions (every 3 weeks for pembrolizumab vs. every 2 weeks for nivolumab or every 6 weeks vs. every 4 weeks). Based on the available data, it can be concluded that autoimmune disease is not an absolute contraindication to the use of immunotherapy, but close clinical monitoring of these patients and specialist consultations (e.g. rheumatologist, dermatologist) must be provided. Patients with severe autoimmune disease who are treated with biologicals or have a history of life-threatening autoimmune disease complications (e.g. severe Crohn’s disease) should not be qualified for immunotherapy, as opposed to patients with minimally symptomatic autoimmune disease (e.g., mild dermal psoriasis).

КЛИНИЧЕСКИЕ ПРОЯВЛЕНИЯ ПОРАЖЕНИЯ СЛИЗИСТОЙ ОБОЛОЧКИ РТА ПРИ РАЗЛИЧНЫХ ДЕРМАТОЗАХ

Subject. This review presents a modern literature review on the clinical manifestations of severe autoimmune disease — pemphigus vulgaris, chronic genetic determinate dermatosis — by the example of epidermolysis bullosa, dermatosis — lichen planus, acute immuno-mediated disease — multiforme exudative erythema.
 The goal is to conduct a systematic analysis of modern domestic and foreign literature to determine some features of the clinical manifestations of chronic dermatoses with lesions of the oral mucosa.
 Methodology. A review of the studies allows us to consider the etiology and pathogenesis of the development of these nosologies, approaches to modern classification, as well as an analysis of their clinical features with an emphasis on differential diagnosis.
 Results. It was noted that with combined damage to the skin and oral mucosa, the diagnosis of these dermatoses in patients does not present any particular difficulties. However, the significance of determining pathognomonic signs of damage to the oral mucosa with a particular dermatosis increases significantly with an isolated lesion of the oral mucosa, and when it is the primary and only manifestation of skin disease.
 Conclusions. Undoubtedly, the principle of continuity of the interested specialties among which are undoubted - dermatovenerologists, dentists, gastroenterologists, gynecologists, neuropsychiatrists, has great prospects in both diagnosis and complex treatment. Nevertheless, for their widespread use, the local and general treatment of these patients needs to be verified, solving urgent problems of introducing and adapting modern technologies for rapid prototyping them into practical healthcare, which together will allow significant progress in their diagnosis and prevention.

Pathogenesis of ANCA-associated vasculitis: an emerging role for immunometabolism.

ANCA-associated vasculitis (AAV) is a severe systemic autoimmune disease. A key feature of AAV is the presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against myeloperoxidase (MPO) or proteinase-3 (PR3). ANCA are key to the pathogenesis of AAV, where they activate innate immune cells to drive inflammation. Pre-activation or 'priming' of immune cells appears to be important for complete cellular activation in AAV. The burgeoning field of immunometabolism has illuminated the governance of immune cell function by distinct metabolic pathways. There is ample evidence that the priming events synonymous with AAV alter immune cell metabolism. In this review we discuss the pathogenesis of AAV and its intersection with recent insights into immune cell metabolism.

Neuromyelitis Optica Spectrum Disorder Attack Triggered by Herpes Zoster Infection.

Neuromyelitis optica spectrum disorder is a severe autoimmune disease of the central nervous system characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. Recently, a triggering role of infectious events in the development of NMOSD has been suggested. Varicella zoster virus is the most common viral infection involved, though the linkage with anti-aquaporin-4 antibodies is so far unknown. We report, to the best of our knowledge, the first pediatric case report about NMOSD relapse triggered by herpes zoster infection. The strict temporal relationship between VZV infection and NMO attacks seems to be more than simply due to chance; however, further reports are needed to be confirmed.

The Influence of Socio-Demographic Factors, Lifestyle and Psychiatric Indicators on Adherence to Treatment of Patients with Rheumatoid Arthritis: A Cross-Sectional Study.

Background and Objectives: Rheumatoid arthritis (RA) is a severe autoimmune disease characterized by chronic inflammation of the joints accompanied by the progressive deformation and destruction of cartilage and joint bones. This study aims to gain insight into the outcomes related to adherence in patients with rheumatoid arthritis. Predicting the medication adherence in RA patients is a key point to improve the treatment outcome. Materials and Methods: A number of 119 Romanian patients with RA were included and divided into two groups: first group included 79 patients treated with conventional therapy and second group included 40 patients treated with biologic therapy. A CQR-9 (compliance questionnaire rheumatology with nine items) and PDSQ (psychiatric diagnostic screening questionnaire) were performed to assess correlations between medication adherence, patient sociodemographic variables, 11 psychiatric scales (major depressive disorder, posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, psychosis, agoraphobia, social phobia, drug abuse/dependence, generalized anxiety disorder, somatization disorder, hypochondriasis) and lifestyle (bulimia, alcohol intake). Results: Whilst modelling factors associated with adherence, it was found that women and patients with higher education are more adherent. From the psychiatric indicators, only major depressive disorder and post-traumatic stress disorder were found to be positively correlated with therapeutic adherence. None of the assessed lifestyle factors influenced the adherence of RA patients. Conclusion: The knowledge of factors that impact on treatment adherence can be useful for clinicians to guide patient-centred care.

Animal Models of ANCA Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.

Diagnosis and Management of Secondary HLH/MAS Following HSCT and CAR-T Cell Therapy in Adults; A Review of the Literature and a Survey of Practice Within EBMT Centres on Behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP).

Introduction: Secondary haemophagocytic lymphohistiocytosis (sHLH) or Macrophage Activation Syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, malignancy or autoimmune diseases. It is also a rare complication of haematopoetic stem cell transplantation (HSCT), with a high mortality. It may be associated with graft vs. host disease in the allogeneic HSCT setting. It is also reported following CAR-T cell therapy, but differentiation from cytokine release syndrome (CRS) is challenging. Here, we summarise the literature and present results of a survey of current awareness and practice in EBMT-affiliated centres of sHLH/MAS following HSCT and CAR-T cell therapy.Methods: An online questionnaire was sent to the principal investigators of all EBMT member transplant centres treating adult patients (18 years and over) inviting them to provide information regarding: number of cases of sHLH/MAS seen in their centre over 3 years (2016–2018 inclusive); screening strategies and use of existing diagnostic/classification criteria and treatment protocols.Results: 114/472 centres from 24 different countries responded (24%). We report estimated rates of sHLH/MAS of 1.09% (95% CI = 0.89–1.30) following allogeneic HSCT, 0.15% (95% CI = 0.09–5.89) following autologous HSCT and 3.48% (95% CI = 0.95–6.01) following CAR-T cell therapy. A majority of centres (70%) did not use a standard screening protocol. Serum ferritin was the most commonly used screening marker at 78% of centres, followed by soluble IL-2 receptor (24%), triglycerides (15%), and fibrinogen (11%). There was significant variation in definition of “clinically significant” serum ferritin levels ranging from 500 to 10,000 μg/mL. The most commonly used criteria to support diagnosis were HLH-2004 (43%) and the H score (15%). Eighty percent of responders reported using no standard management protocol, but reported using combinations of corticosteroids, chemotherapeutic agents, cytokine blockade, and monoclonal antibodies.Conclusions: There is a remarkable lack of consistency between EBMT centres in the approach to screening, diagnosis and management. Further research in this field is needed to raise awareness of and inform harmonised, evidence-based approaches to the recognition and treatment of sHLH/MAS following HSCT/CAR-T cell therapy.

ITCH as a potential therapeutic target in human cancers.

The ITCH/AIP4 ubiquitin E3 ligase was discovered independently by two groups searching for atrophin-1 interacting proteins and studying the genetics of mouse coat color alteration, respectively. ITCH is classified as a NEDD4 family E3 ligase featured with the C-terminal HECT domain for E3 ligase function and WW domains for substrate recruiting. ITCH deficiency in the mouse causes severe multi-organ autoimmune disease. Its roles in maintaining a balanced immune response have been extensively characterized over the past two and a half decades. A wealth of reports demonstrate a multifaceted role of ITCH in human cancers. Given the versatility of ITCH in catalyzing both proteolytic and non-proteolytic ubiquitination of its over fifty substrates, ITCH's role in malignancies is believed to be context-dependent. In this review, we summarize the downstream substrates of ITCH, the functions of ITCH in both tumor cells and the immune system, as well as the implications of such functions in human cancers. Moreover, we describe the upstream regulatory mechanisms of ITCH and the efforts have been made to target ITCH using small molecule inhibitors.

Applicability of shear wave elastography for the evaluation of skin strain in systemic sclerosis

The assessment of skin fibrosis is vital for the diagnosis and monitoring of treatment in the systemic sclerosis (SSc)—a severe autoimmune disease. The elastography is a technique of skin fibrosis assessment through the evaluation of skin strain. We compared the efficacy of the shear wave elastography (SWE) and commonly used modified Rodnan skin score (RSS) in skin fibrosis assessment in SSc. The study included 40 SSc patients and 28 healthy individuals, with the exclusion of individuals with other skin/autoimmune diseases. Skin thickness using RSS and skin strain using SWE were assessed in the same 20 body localizations. Subjects’ informed consent and the bioethics committee approval were obtained. Elastographic skin strain correlated positively with both partial and overall RSS values, with strong positive correlation (r ≥ 0.75) for hands and fingers localizations in particular. In SSc patients with normal RSS values, the elastographic strain was significantly higher than in healthy controls. Elastographic strain of fingers’ skin evaluated in SWE is highly accurate for distinguishing SSc patients (sensitivity 0.897–0.923, specificity 0.929–0.964, positive predictive value 0.946–0.973, negative predictive value 0.867–0.900). ESW results are substantially more reproducible than those of RSS examination (intraclass correlation coefficients: 0.987 vs. 0.941). The shear wave elastography is more reproducible and has higher sensitivity than RSS in the evaluation of skin condition in SSc, especially in case of changes non-detectable on physical evaluation, indicating it might become a useful tool in SSc diagnosis.

Novel insights into dendritic cells in the pathogenesis of systemic sclerosis.

SummarySystemic sclerosis (SSc) is a severe autoimmune fibrotic disease characterized by fibrosis, vasculopathy, and immune dysregulation. Dendritic cells (DCs) are the most potent antigen‐presenting cells, specialized in pathogen sensing, with high capacity to shape the immune responses. The most recent technological advances have allowed the discovery of new DC subsets with potential implications in inflammatory conditions. Alterations of DC distribution in circulation and affected tissue as well as impaired DC function have been described in SSc patients, pointing towards a crucial role of these cells in SSc pathogenesis. In particular, recent studies have shown the importance of plasmacytoid DCs either by their high capacity to produce type I interferon or other inflammatory mediators implicated in SSc pathology, such as chemokine C‐X‐C motif ligand 4 (CXCL4). In‐vivo models of SSc have been vital to clarify the implications of DCs in this disease, especially DCs depletion and specific gene knock‐down studies. This review provides these new insights into the contribution of the different DCs subsets in the pathogenesis of SSc, as well as to the novel developments on DCs in in‐vivo models of SSc and the potential use of DCs and their mediators as therapeutic targets.

A reverse translational study on the effect of rituximab, rituximab plus belimumab, or bortezomib on the humoral autoimmune response in SLE

ObjectivesSLE is a severe autoimmune disease characterized by autoreactive B cells and IC formation, which causes systemic inflammation. B cell–targeted therapy could be a promising treatment strategy in SLE patients; nevertheless, randomized clinical trials have not always been successful. However, some groups have demonstrated beneficial effects in severe SLE patients with off-label rituximab (RTX) with belimumab (BLM), or bortezomib (BTZ), which targeted different B cells subsets. This study assembled sera from SLE cohorts treated with RTX+BLM (n = 15), BTZ (n = 11) and RTX (n = 16) to get an in-depth insight into the immunological effects of these therapies on autoantibodies and IC formation.MethodsAutoantibodies relevant for IC formation and the avidity of anti-dsDNA were determined by ELISA. IC-mediated inflammation was studied by complement levels and ex vivo serum-induced neutrophil extracellular trap formation.ResultsReductions in autoantibodies were observed after all approaches, but the spectrum differed depending upon the treatment. Specifically, only RTX+BLM significantly decreased anti-C1q. Achieving seronegativity of ≥1 autoantibody, specifically anti-C1q, was associated with lower disease activity. In all SLE patients, the majority of anti-dsDNA autoantibodies had low avidity. RTX+BLM significantly reduced low-, medium- and high-avidity anti-dsDNA, while RTX and BTZ only significantly reduced medium avidity. IC-mediated inflammation, measured by C3 levels and neutrophil extracellular trap formation, improved after RTX+BLM and RTX but less after BTZ.ConclusionThis study demonstrated the impact of different B cell–targeted strategies on autoantibodies and IC formation and their potential clinical relevance in SLE.

Pulmonary Nocardiosis in Pemphigus Vulgaris Patients from Tehran, Iran.

Nocardiosis is an opportunistic infection in individuals who had organ transplants and in patients with immunosuppressive diseases such as pemphigus Vulgaris (PV), diabetes mellitus, and HIV. Nocardiosis rate has not been assessed in Iranian PV patients, and this was the first study to estimate nocardiosis rate in these patients. In this study, 103 patients with PV were examined. BAL samples were obtained and direct smear was prepared and visualized by microscopy after PAS staining. Samples were cultured on antibiotic-containing blood and chocolate agar media. DNA extraction and PCR were performed on positive cultures, and final identification was done by 16S rRNA gene sequencing. Drug susceptibility testing was done by microbroth dilution method. Four positive cultures (3.88%) were found in the samples (n = 103). According to sequence analysis, 2 isolates were identified as Nocardia cyriacigeorgica and 2 as Nocardia otitidiscaviarum and Nocardia cerradoensis. Nocardia cerradoensis was isolated from an invasive brain infection. Isolated bacteria were susceptible to majority of the tested antibiotics, except for 2 strains of Nocardia cyriacigeorgica and Nocardia cerradoensis. This was the first isolation of Nocardia cerradoensis of human infection in Asia. Patients with PV are susceptible to nocardiosis, similar to other immunocompromised patients. Pemphigus Vulgaris is a severe autoimmune disease which is treated by a high dosage of corticosteroids. Opportunistic infections are one of the greatest challenges of these patients. One of the neglected agents of opportunistic infection in this disorder is Nocardiosis which can cause a high mortality rate in PV patients.

Rheumatiod Arthritis: An Updated Overview of Latest Therapy and Drug Delivery.

Rheumatoid arthritis is a severe autoimmune disorder, related to joints. It is associated with serious cartilage destruction. This causes disability and reduces the excellence of life. Numerous treatments are existed to combat this disease, however, they are not very efficient and possess severe side effects, higher doses, and frequent administration.Therefore, newer therapies are developed to overcome all these limitations. These include different monoclonal antibodies, immunoglobulins, small molecules used for immunotherapy and transgenes for gene therapy. One of the main goals of these new generation therapeutics is to address the underlying distressing biological processes by specifically targeting the causative agents with fewer systemic side effects and greater patient console. It is very fortuitous that loads of progressive investigations are going on in this field and many of them have entered into the successful clinical trial. But till date, a limited molecule has got FDA clearance and entered the market for treating this devastating disease.This review highlights the overview of conventional therapy and advancements in newer therapeutics including immunotherapy and gene therapy for rheumatoid arthritis. Further, different novel techniques for the delivery of these therapeutics of active and passive targeting are also described.