Tolerogenic probiotics Lactobacillus delbrueckii and Lactobacillus rhamnosus promote anti-inflammatory profile of macrophages-derived monocytes of newly diagnosed patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is known as an autoimmune disorder that is characterized by the breakdown of self-tolerance, resulting in disease onset and progression. Macrophages have been implicated as a factor in the development of SLE through faulty phagocytosis of dead cells or an imbalanced M1/M2 ratio. The study aimed to investigate the immunomodulatory effects of Lactobacillus delbrueckii and Lactobacillus rhamnosus on M1 and M2 macrophages in new case lupus patients. For this purpose, blood monocytes were collected from lupus patients and healthy people and were cultured for 5 days to produce macrophages. For 48 h, the macrophages were then cocultured with either probiotics or lipopolysaccharides (LPS). Flow cytometry and real-time polymerase chain reaction were then used to analyze the expression of cluster of differentiation (CD) 14, CD80, and human leukocyte antigen - DR (HLADR) markers, as well as cytokine expression (interleukin [IL]1-ß, IL-12, tumor necrosis factor α [TNF-α], IL-10, and transforming growth factor beta [TGF-ß]). The results indicated three distinct macrophage populations, M0, M1, and M2. In both control and patient-derived macrophage-derived monocytes (MDMs), the probiotic groups showed a decrease in CD14, CD80, and HLADR expression compared to the LPS group. This decrease was particularly evident in M0 and M2 macrophages from lupus patients and M1 macrophages from healthy subjects. In addition, the probiotic groups showed increased levels of IL-10 and TGF-ß and decreased levels of IL-12, IL1-ß, and TNF-α in MDMs from both healthy and lupus subjects compared to the LPS groups. Although there was a higher expression of pro-inflammatory cytokines in lupus patients, there was a higher expression of anti-inflammatory cytokines in healthy subjects. In general, L. delbrueckii and L. rhamnosus could induce anti-inflammatory effects on MDMs from both healthy and lupus subjects.

Lactobacillus rhamnosus and Lactobacillus delbrueckii Ameliorate the Expression of miR-125a and miR-146a in Systemic Lupus Erythematosus Patients.

The microRNAs are non-coding RNA molecules involved in physiological and pathological processes, causing autoimmune diseases such as systemic lupus erythematosus (SLE). Probiotics are living microorganisms that possess beneficial effects on the host immune system and modulate it. The effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii on the expression of miR-125a and miR-146a was studied in peripheral blood mononuclear cells (PBMCs) from newly diagnosed lupus patients in this in vitro study. During this study, 20 recently diagnosed SLE patients and 20 healthy individuals participated. Ficoll method was used to isolate the PBMCs from whole blood, which were cultured for 48 h with Lactobacillus rhamnosus and Lactobacillus delbrueckii. In the next step, total RNA containing microRNA was extracted. cDNA was synthesized for miR-125a and miR-146a genes and analyzed by real-time PCR. Results were presented as fold changes. As compared to healthy controls, SLE patients expressed lower levels of miR-125a and miR-146a. PBMCs treated with Lactobacillus rhamnosus, Lactobacillus delbrueckii, or both probiotics had significantly higher levels of miR-125a and miR-146a compared to the untreated group. Treatment of PBMCs with both L. rhamnosus and L. delbrueckii upregulated the expression of miR-125a and miR-146a in treated cells compared with untreated cells in SLE patients (p = 0.02, p = 0.001). Lactobacillus rhamnosus and Lactobacillus delbrueckii modify lupus patients' immune responses and disease effects by regulating miR-125a and miR-146a.

Evaluation of assessable telemedicine in patients with rheumatoid arthritis: A systematic review.

OBJECTIVE: Nowadays, the use of telemedicine diagnosis and treatment of various diseases has been considered by physicians, especially in such diseases as rheumatoid arthritis (RA), where patients have more weakness and inability to move. This systematic review aimed to evaluate the extent of measurable and nonmeasurable factors in patients with RA and their satisfaction with this method of care. METHODS: The articles published by March 3, 2022, were searched in four databases, including Web of Sciences, Medline, PubMed, and Scopus. This research was conducted using the seven steps of the Cochrane Handbook as a guide. The searched keywords included telemedicine, tele-rheumatoid, rheumatoid arthritis, and immune diseases. RESULTS: A total of 18 articles were included in the present study. In most of these studies, physicians and patients were satisfied with this approach. Nonetheless, there was a dearth of studies on the measurement of evaluable and nonevaluable factors. CONCLUSION: Studies on the benefits of telemedicine for rheumatology are still limited. The effectiveness of this new healthcare approach in diagnosing and evaluating disease activity is still unclear. Some studies demonstrated patient and physician satisfaction with this treatment. In some cases, there is a tendency to show a high risk of bias. In addition, it is unclear to what extent the use of rheumatology traps affects the establishment of medical relationships. It is recommended that more clinical trials be conducted to examine this relationship.

Curcumin and Berberine Arrest Maturation and Activation of Dendritic Cells Derived from Lupus Erythematosus Patients.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disease recognized by elevated activity of autoimmune cells, loss of tolerance, and decreased regulatory T cells producing inhibitory cytokines. Despite many efforts, the definitive treatment for lupus has not been fully understood. Curcumin (CUR) and berberine (BBR) have significant immunomodulatory roles and anti-inflammatory properties that have been demonstrated in various studies. This study aimed to investigate the anti-inflammatory properties of CUR and BBR on human monocyte-derived dendritic cells (DCs) with an special focus on the maturation and activation of DCs. METHODS: Human monocytes were isolated from the heparinized blood of SLE patients and healthy individuals, which were then exposed to cytokines (IL-4 and GM-CSF) for five days to produce immature DCs. Then, the obtained DCs were characterized by FITC-uptake assay and then cultured in the presence of CUR, BBR, or lipopolysaccharide (LPS) for 48 h. Finally, the maturation of DCs was analyzed by the level of maturation using flow cytometry or real-time PCR methods. RESULTS: The results showed promising anti-inflammatory effects of CUR and BBR in comparison with LPS, supported by a significant reduction of not only co-stimulatory and antigen-presenting factors such as CD80, CD86, CD83, CD1a, CD14, and HLA-DR but also inflammatory cytokines such as IL-12. CONCLUSION: CUR and BBR could arrest DC maturation and develop a tolerogenic DC phenotype that subsequently promoted the expression of inhibitory cytokines and reduced the secretion of proinflammatory markers.

Lupus mice derived mesenchymal stromal cells: Beneficial or detrimental on SLE disease outcome.

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear genes, deposition of immune complexes, and autoimmune T cells, through which, tissue damage would ultimately occur. Furthermore, loss of immune tolerance and imbalance of Th1/Th2 cells in addition to Th17/Treg are contributed to the pathogenesis of SLE. Mesenchymal stromal cells (MSCs) infusion is a potential therapy for SLE disease. Despite a majority of SLE patients achieving clinical remission after allogeneic MSC infusion from healthy individuals, SLE patients have less benefited from autologous MSC infusion, justifying the probable compromised function of SLE patients-derived MSCs. In this study, we aim to further investigate the potential immunoregulatory mechanisms in which mesenchymal stromal cells derived from pristane-induced lupus mice, following injection into healthy and lupus mice, exert their possible effects on the lupus process. METHOD: 40 female Balb/c mice aged 3 weeks were purchased and randomly divided into six groups. First, lupus disease was induced into the lupus groups by intraperitoneal injection of pristane and then the mice were surveyed for 6 months. The body weight, anti-dsDNA autoantibody levels, serum creatinine, and Blood Urea Nitrogen (BUN) levels were measured in two-month intervals. After 6 months, the group of lupus mice was sacrificed, and lupus MSCs were isolated. Two months later, cultured lupus MSCs were intravenously injected into two groups of healthy and lupus mice. After two months, the mice were euthanized and the kidneys of each group were examined histologically by hematoxylin & eosin (H&E) staining and the immunofluorescence method was also performed to evaluate IgG and C3 deposition. The frequency of splenic Th1, Th2, Th17, and Treg cells was measured by flow cytometry. Moreover, the cytokine levels of IFN-γ, IL-4, IL-17, and TGF-ß in sera were measured by ELISA method. RESULTS: Our results showed that the induction of lupus disease by pristane in Balb/c mice caused the formation of lipogranuloma, increased levels of anti-dsDNA autoantibodies, and impaired renal function in all pristane-induced lupus groups. In addition, the injection of lupus mesenchymal stromal cells (L-MSC) into healthy and lupus mice led to a further rise in anti-dsDNA serum levels, IgG and C3 deposition, and further dysfunction of mice renal tissue. Also, the flow cytometry results implicated that compared to the control groups, splenic Th1, Th2, and Th17 inflammatory cell subtypes and their secreted cytokines (IFN-γ, IL-4, and IL-17) in the sera of healthy and lupus mice were increased after the intake of L-MSC. Additionally, the splenic Treg cells were also significantly increased in the lupus mice receiving L-MSC. However, a decrease in serum levels of TGF-ß cytokine was observed in healthy and lupus mice following L-MSC injection. In contrast, the lupus mice receiving healthy mesenchymal stem cells (H-MSC) manifested opposite results. CONCLUSION: In a nutshell, our results suggest that although allogeneic MSCs are encouraging candidates for SLE treatment, syngeneic MSCs may not be eligible for treating SLE patients due to their defects in regulating the immune system in addition to their capability in promoting inflammation which would consequently worsen the SLE disease status.

A new generation of mesenchymal stromal/stem cells differentially trained by immunoregulatory probiotics in a lupus microenvironment.

BACKGROUND: Increasing evidence suggests that multipotent mesenchymal stem/stromal cells (MSCs) are a promising intervention strategy in treating autoimmune inflammatory diseases. It should be stated that systemic immunoregulation is increasingly recognized among the beneficial effects of MSCs and probiotics in treating morbid autoimmune disorders such as lupus. This study aimed to determine if immunoregulatory probiotics L. rhamnosus or L. delbrueckii can change the immunomodulatory effects of MSCs in lupus-like disease. METHODS: Pristane-induced lupus (PIL) mice model was created via intraperitoneal injection of Pristane and then confirmed. Naïve MSCs (N-MSCs) were coincubated with two Lactobacillus strains, rhamnosus (R-MSCs) or delbrueckii (D-MSCs), and/or a combination of both (DR-MSCs) for 48 h, then administrated intravenously in separate groups. Negative (PBS-treated normal mice) and positive control groups (PBS-treated lupus mice) were also investigated. At the end of the study, flow cytometry and enzyme-linked immunosorbent assay (ELISA) analysis were used to determine the percentage of Th cell subpopulations in splenocytes and the level of their master cytokines in sera, respectively. Moreover, lupus nephritis was investigated and compared. Analysis of variance (ANOVA) was used for multiple comparisons. RESULTS: Abnormalities in serum levels of anti-dsDNA antibodies, creatinine, and urine proteinuria were significantly suppressed by MSCs transplantation, whereas engrafted MSCs coincubation with both L. strains did a lesser effect on anti-dsDNA antibodies. L. rhamnosus significantly escalated the ability of MSCs to scale down the inflammatory cytokines (IFN-É£, IL-17), while L. delbrueckii significantly elevated the capacity of MSCs to scale down the percentage of Th cell subpopulations. However, incubation with both strains induced MSCs with augmented capacity in introducing inflammatory cytokines (IFN-É£, IL-17). Strikingly, R-MSCs directly restored the serum level of TGF-ß more effectively and showed more significant improvement in disease parameters than N-MSCs. These results suggest that R-MSCs significantly attenuate lupus disease by further skew the immune phenotype of MSCs toward increased immunoregulation. CONCLUSIONS: Results demonstrated that Lactobacillus strains showed different capabilities in training/inducing new abilities in MSCs, in such a way that pretreated MSCs with L. rhamnosus might benefit the treatment of lupus-like symptoms, given their desirable properties.

Expression pattern of glucocorticoid receptor α gene and associations with clinicolaboratory features in patients with systemic lupus erythematosus.

Background: Glucocorticoid receptor α (GRα) gene is a transcription factor with clinically significant immune-modulating properties in various autoimmune diseases. However, the expression pattern of the GRα gene and associations with clinical features in patients with systemic lupus erythematosus (SLE) is controversial. This study aimed to assess the correlation between the GRα expression and different clinical and laboratory-related parameters in SLE patients. Methods: A total of 45 women with newly diagnosed SLE and 31 gender and age-matched healthy controls were enrolled in this cross-sectional study. The real-time quantitative PCR (qRT-PCT) method evaluated the differences in GRα expression in peripheral blood mononuclear cells from cases and controls. The correlation between the GRα gene expression levels, clinicolaboratory features, and potential prognostic application was also analyzed. Results: Compared to the healthy individuals, the GRα gene expression in newly diagnosed SLE patients who did not receive any treatment was numerically reduced, but this reduction did not achieve statistical significance (P=0.87). No significant correlation was also found with the activity and severity of SLE according to SLEDAI2K (P=0.41). The GRα gene expression showed a negative correlation with CRP (P=0.034) and a positive correlation with lupus anticoagulant (P=0.039) levels in SLE. The receiver operating characteristic (ROC) curve analysis indicated that the GRα expression level might be a predictor biomarker for low CRP and positive lupus anticoagulant in SLE, respectively. Conclusion: This study proposed that expression of the GRα in newly diagnosed lupus patients has no statistically significant difference with healthy age and sex-matched controls. Besides, its expression does not correlate with lupus disease activity according to SLEDAI2k. However, further studies in this area are required.

Dysregulated balance in Th17/Treg axis of Pristane-induced lupus mouse model, are mesenchymal stem cells therapeutic?

BACKGROUND: Despite advances in general and targeted immunosuppressive therapies, limiting all mainstay treatment options in refractory systemic lupus erythematosus (SLE) cases has necessitated the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have recently emerged with unique properties, including a solid propensity to reduce inflammation, exert immunomodulatory effects, and repair injured tissues. METHODS: An animal model of acquired SLE mice was induced via intraperitoneal immunization with Pristane and affirmed by measuring specific biomarkers. Bone marrow (BM) MSCs were isolated from healthy BALB/c mice and cultured in vitro, then were identified and confirmed by flow cytometry and cytodifferentiation. Systemic MSCs transplantation was performed and then several parameters were analyzed and compared, including specific cytokines (IL-17, IL-4, IFN-É£, TGF-ß) at the serum level, the percentage of Th cell subsets (Treg/Th17, Th1/Th2) in splenocytes, and also the relief of lupus nephritis, respectively by enzyme-linked immunosorbent assay (ELISA), flow cytometry analysis and by hematoxylin & eosin staining and also immunofluorescence assessment. Experiments were carried out with different initiation treatment time points (early and late stages of disease). Analysis of variance (ANOVA) followed by post hoc Tukey's test was used for multiple comparisons. RESULTS: The rate of proteinuria, anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies, and serum creatinine levels decreased with BM-MSCs transplantation. These results were associated with attenuated lupus renal pathology in terms of reducing IgG and C3 deposition and lymphocyte infiltration. Our findings suggested that TGF-ß (associated with lupus microenvironment) can contribute to MSC-based immunotherapy by modulating the population of TCD4+ cell subsets. Obtained results indicated that MSCs-based cytotherapy could negatively affect the progression of induced SLE by recovering the function of Treg cells, suppressing Th1, Th2, and Th17 lymphocyte function, and downregulating their pro-inflammatory cytokines. CONCLUSION: MSC-based immunotherapy showed a delayed effect on the progression of acquired SLE in a lupus microenvironment-dependent manner. Allogenic MSCs transplantation revealed the ability to re-establish the balance of Th17/Treg, Th1/Th2 and restore the plasma cytokines network in a pattern dependent on disease conditions. The conflicting results of early versus advanced therapy suggest that MSCs may produce different effects depending on when they are administered and their activation status.

Comparison of the efficacy and safety of methotrexate alone or in combination with leflunomide in the treatment of juvenile idiopathic arthritis: a double-blind, placebo-controlled, randomized trial.

Introduction: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder in children. Although methotrexate (MTX) is the first line disease-modifying antirheumatic drug for JIA, many patients do not respond well or cannot tolerate MTX. The aim of this study was to compare the effect of combination therapy of MTX and leflunomide (LFN) with MTX in patients who do not respond to MTX. Material and methods: Eighteen patients (2-20 years old) with polyarticular, oligoarticular or extended oligoarticular subtypes of JIA who did not respond to conventional JIA therapy participated in this double-blind, placebo-controlled, randomized trial. The intervention group received LFN and MTX for 3 months while the control group received oral placebo and MTX at a similar dose to the intervention group. Response to treatment was assessed every 4 weeks using the American College of Rheumatology Pediatric criteria (ACRPed) scale. Results: Clinical criteria, including number of active joints and restricted joints, physician and patient global assessment, Childhood Health Assessment Questionnaire (CHAQ38) score, and serum erythrocyte sedimentation ratelevel, did not differ significantly between groups at baseline and at the end of the 4th and 8th weeks of treatment. Only the CHAQ38 score was significantly higher in the intervention group at the end of the 12th week of treatment. Analysis of the effect of treatment on study parameters revealed that only the global patient assessment score differed significantly between groups (p = 0.003). Conclusions: The results of this study showed that combining LFN with MTX does not improve clinical outcomes of JIA and may increase side effects in patients who do not respond to MTX.

Modulation of Mesenchymal Stem Cells-Mediated Adaptive Immune Effectors' Repertoire in the Recovery of Systemic Lupus Erythematosus.

The breakdown of self-tolerance of the immune response can lead to autoimmune conditions in which chronic inflammation induces tissue damage. Systemic lupus erythematosus (SLE) is a debilitating multisystemic autoimmune disorder with a high prevalence in women of childbearing age; however, SLE incidence, prevalence, and severity are strongly influenced by ethnicity. Although the mystery of autoimmune diseases remains unsolved, disturbance in the proportion and function of B cell subsets has a major role in SLE's pathogenesis. Additionally, colocalizing hyperactive T helper cell subgroups within inflammatory niches are indispensable. Despite significant advances in standard treatments, nonspecific immunosuppression, the risk of serious infections, and resistance to conventional therapies in some cases have raised the urgent need for new treatment strategies. Without the need to suppress the immune system, mesenchymal stem cells (MSCs), as ''smart" immune modulators, are able to control cellular and humoral auto-aggression responses by participating in precursor cell development. In lupus, due to autologous MSCs disorder, the ability of allogenic engrafted MSCs in tissue regeneration and resetting immune homeostasis with the provision of a new immunocyte repertoire has been considered simultaneously. In Brief The bone marrow mesenchymal stem cells (BM-MSCs) lineage plays a critical role in maintaining the hematopoietic stem-cell microstructure and modulating immunocytes. The impairment of BM-MSCs and their niche partially contribute to the pathogenesis of SLE-like diseases. Allogenic MSC transplantation can reconstruct BM microstructure, possibly contributing to the recovery of immunocyte phenotype restoration of immune homeostasis. In terms of future prospects of MSCs, artificially gained by ex vivo isolation and culture adaptation, the wide variety of potential mediators and mechanisms might be linked to the promotion of the immunomodulatory function of MSCs.

Serum Level of Soluble Human Leukocyte Antigen G in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis.

BACKGROUND: This study aimed to evaluate the serum level of human leukocyte antigen G [HLA-G] in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) compared to healthy controls; moreover, it attempted to assess its relationship with SLE and RA disease activity indices. METHODS: This descriptive study was conducted on 31 SLE patients (17 cases with a recent diagnosis and 14 cases with a previous diagnosis), 21 RA patients (7 cases with a recent diagnosis and 14 cases with a previous diagnosis), and 18 healthy controls who visited Ghaem Hospital affiliated to Mashhad University of Medical Sciences, Mahhad, Iran. SLE and RA activity indices were measured and recorded. Furthemore, soluble isoforms, including shed HLA-G1 and HLA-G5, were measured in serum samples via the ELISA method. RESULTS: A comparison of the five groups showed no significant differences in the serum level of sHLA-G. However, sHLA-G serum level was significantly higher in SLE and RA patients compared to healthy controls (P<0.05). sHLA-G level showed no correlation with disease duration and activity in SLE and RA patients (P>0.05). However, a strong positive correlation was observed between the serum level of sHLA-G and 24-h urine protein in the previously diagnosed SLE group (r=0.83, P=0.01). CONCLUSION: It seems that the serum level of sHLA-G is higher in RA and SLE patients compared to healthy controls. Furthermore, a strong correlation was found between sHLA-G serum levels and 24-h urine protein in cases with a previous diagnosis of SLE.

Cross Talk between Mesenchymal Stem/Stromal Cells and Innate Immunocytes Concerning Lupus Disease.

Lupus is known as a systemic immune-mediated disorder. Like other diseases in this category, its cause and definitive treatment remain unknown. Gold standard therapies, which mainly include immunosuppressive agents, have been able to have therapeutic effects on patients. However, a significant percentage of cases still do not respond to this kind of treatment, resulting in death from complications. Recently, a new source of non-hematopoietic cells, mesenchymal stem/stromal cells (MSCs), with the potency to re-establishment immune homeostasis and tissue regeneration, has been wildly used in both primary and clinical research. One of the remarkable features of MSCs is their anti-inflammatory and immunosuppressive properties and stimulating tissue differentiation programs. Under the influence of background signals, MSCs migrate to inflammatory bioactive substances and then regulate overactive immune responses to restore immune tolerance. MSCs have shown a two-way interaction with most immunocytes, which plays a significant role in resolving sterile inflammation. Restricting the entry of inflamed cells into the site of inflammation and re-educated infiltrated cells to achieve a tolerant phenotype have been reported as mechanisms of MSCs in tissue repair. Stimulation of the endogenous and tissue-dwelling stem cells in addition to releasing immunomodulatory agents, suggests MSCs transplantation as a potential modality in the treatment of future immune-mediated disorders.

Coronavirus disease 2019 in patients with Behcet's disease: a report of 59 cases in Iran.

OBJECTIVES: To present the clinical characteristics, disease course, management, and outcomes of COVID-19 infection in patients with Behcet's disease (BD). METHODS: In this retrospective cohort study, we retrieved BD patients with definite diagnosis of COVID-19 infection. Demographic data, comorbidities, features related both to BD and COVID-19 infection, treatments, and outcomes were collected. Comparisons between patients with or without hospitalization were performed. All statistical analyzes were performed using SPSS version 25. We considered p < 0.05 statistically significant. RESULTS: We identified 61 episodes of COVID-19 infection in 59 BD patients. The prevalence was 0.69%. The median age was 45 years (IQR = 20), and the median disease duration was 162 months (IQR = 195). BD features were similar except for higher rate of arterial involvement and positive pathergy test in infected patients. Thirty-five episodes (62.5%) happened in non-active patients; 39% had a comorbid disease. COVID manifestations were the same as the general population. Flu-like symptoms were the most common (85%), followed by fever (66%), ageusia/anosmia (56%), headache (51%), and pulmonary involvement (48%). There was no change in BD symptoms in 74%. Fifteen patients (25.4%) were hospitalized, and one patient (1.7%) died. Receiving glucocorticoids (p < 0.03) and cytotoxic drugs (p < 0.02) were associated with an increased rate of hospitalization. CONCLUSION: The incidence of COVID-19 infection in BD patients was not higher than general population in Iran. They showed milder form of disease with lower morbidity and mortality rate. Most were on immunosuppressive drugs, or had a comorbidity apart from BD. No significant effect on BD course was shown. Key Points • The incidence of COVID-19 infection in patients with Behcet's disease is not higher. • They showed milder form of infection with lower morbidity and mortality rate. • No significant effect on Behcet's disease course was shown with COVID19 infection. • BD patients can be managed according to the guidelines used for general population.

ABO and Rh blood groups in patients with lupus and rheumatoid arthritis.

BACKGROUND: Systemic lupus erythematous (SLE) and rheumatoid arthritis (RA) are autoimmune diseases in which the antigen-antibody system plays an important role. As blood group and Rh are determined by the presence or absence of antigens on the surface of red blood cells (RBCs), we aimed to determine the distribution of ABO and Rh blood groups in SLE and RA patients and its association with disease manifestations. METHODS: This short communication is based on a study that was conducted on 434 SLE and 828 RA patients. We evaluated the distribution of ABO and Rh blood groups in RA and SLE patients. RESULTS: This study projected that in lupus patients, Coombs-positive autoimmune hemolytic anemia and arthritis were more common among the B blood type and Rh-positive group, respectively. Furthermore, there was no relation between ABO and Rh blood group and rheumatoid factor (RF) and anti-Cyclic Citrullinated Peptide (anti-CCP) seropositivity. Moreover, there was no difference in distribution of blood groups in RA and SLE patients. CONCLUSION: The higher frequency of blood group B in hemolytic anemia, and positive Rh in arthritis in lupus patients, develop the hypothesis of probable role of ABO blood group antigen in some manifestations of lupus.

Nanotechnology as a promising platform for rheumatoid arthritis management: Diagnosis, treatment, and treatment monitoring.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that develops in about 5 per 1000 people. Over the past years, substantial progresses in knowledge of the disease's pathophysiology, effective diagnosis methods, early detection, and efficient treatment strategies have been made. Notably, nanotechnology has emerged as a game-changer in the efficacious management of many diseases, especially for RA. Joint replacement, photothermal therapy (PTT), photodynamic therapy (PDT), RA diagnosis, and treatment monitoring are nano-based avenues in RA management. Here, we present a brief overview of the pathogenesis of RA, risk factors, conventional diagnostic methods and treatment approaches, and then discuss the role of nanomedicine in RA diagnosis, treatment, and treatment monitoring with an emphasis on functional characteristics distinctive from other RA therapeutics.

A Survey on Sleep Disorders and Related Hormones in Patients with Newly Diagnosed Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVES: Systemic lupus erythematosus (SLE) is reportedly associated with sleep disorders. Thus, the present study aimed to investigate sleep disorders in newly diagnosed SLE patients. MATERIALS AND METHODS: This study was conducted on patients with newly diagnosed SLE (ie, case group) and a control group. The case and control groups were matched in terms of gender, age, socioeconomic status, and educational level. Venous blood samples were obtained from the participants to measure prolactin and melatonin levels. Furthermore, they were subjected to polysomnography. The data were analysed by SPSS (version 16) at a significance level of 0.05. RESULTS: A total of 28 women were enrolled in this study (ie, 14 individuals in each group). The frequencies of sleep disorder in the case and control groups were obtained as 64.3% and 50%, respectively (P=0.4). These two groups had the mean sleep onset times of 10.76±10.64 and 8.67±7.12 min (P=0.5) and the respiratory disturbance indices of 9.20±10.23 and 8.44±9.27, respectively (P=0.8). The frequency of sleep apnoea was obtained at 50% for both case and control groups (P=1). There was no significant difference between these groups in terms of the mean serum prolactin and melatonin levels (P=0.3 and P=0.2, respectively). Serum melatonin level showed a direct correlation with sleep latency to N1 (i.e., the first part of non-rapid eye movement in sleep) and spontaneous arousal index in the case group (P=0.02, r=0.602 and P=0.04, r=0.544, respectively). CONCLUSION: According to the findings, there was no significant difference in the frequency of sleep disorders between the healthy subjects and patients at the onset of lupus. Additionally, melatonin and prolactin levels showed no significant difference between the groups. Our results are inconsistent with previous studies, due to the difference in disease duration probably. It seems that the chronicity and complications of the disease, as well as the adoption of glucocorticoid therapy for the chronic disease affect sleep quality in SLE patients more than disease duration.

A double-blind placebo-controlled randomized trial of oral saffron in the treatment of rheumatoid arthritis.

OBJECTIVE: Recently, saffron (Crocus sativus L. from the Iridaceae family) has been characterized by its antioxidant, anti-inflammatory and analgesic effects. This study aimed to evaluate the effect of saffron on disease activity in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: This is a double-blind, placebo-controlled, randomized clinical trial (RCT) performed on 55 newly- diagnosed RA patients without previous treatment, who were randomly divided into intervention (included 28 cases) and control groups (consisted of 27 individuals). Standard therapy including prednisolone, oral methotrexate, folic acid, vitamin D, calcium, and alendronate, was administered similarly in both groups. Patients received a 100 mg saffron pill/day (pure saffron powder) or placebo besides the standard protocol. The placebo had the same shape as the saffron pills. Follow up of DAS28ESR disease activity score was done on the 30th, 45th and 90th day of the study. RESULTS: There was no difference between the intervention and control groups regarding to the DAS28ESR at the end of the study. However, a significant decrease in DAS28-ESR was observed in each group compared to the first visit (p=0.001). The results also showed no significant difference in the incidence of side effects in both groups. CONCLUSION: In summary, patients who received pure saffron pills (100 mg/day) in addition to standard therapy did not have a significant difference in improvement of disease activity from the patients on standard therapy.

Correlations and Influence of TAP2 Genes Polymorphisms and Systemic Lupus Erythematosus Propensity.

OBJECTIVES: The present study was designed to evaluate the association of transporters associated with antigen processing (TAP2) polymorphisms TAP2-379Ile > Val (rs1800454), TAP2-665Thr > Ala (rs241447) and TAP2-565Ala > Thr (rs2228396) as a candidate gene with susceptibility to the Systemic Lupus Erythematosus (SLE). METHODS: To analyze these three polymorphic variants, 88 patients with SLE and 100 healthy controls from northeastern Iran were enrolled from May 2018 to July 2019. Genomic DNA polymorphisms were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Data were analyzed by SPSS software. RESULTS: In this cross-sectional study, there was a stratification between patients and controls. The distribution of the frequency of Ala73 (41.5%) allele at TAP2/665 and Ile 19 (10.8%) allele at TAP2/379 was higher in patients. Additionally, the Ala/Ala 13(14.8%) and Ala/Thr 49(55.7%) genotypes distributions at 665 positions were higher in SLE patients compared to the controls. Furthermore, frequencies of TAP2*H allele significantly increased in SLE patients 10(5.71%) (P=0.01). Frequency of TAP2*A allele in the control group was 120(60%) (p=0.06) due to the dominant genetic model. This allele has a protective effect against SLE. There was no relationship between TAP2*D, TAP2*E, TAP2*F and TAP2*G alleles with the outbreak of SLE. CONCLUSION: Our data indicated that genetic variants in TAP2 gene may be associated with SLE disease. A correlation between Ala allele at TAP2/665 and Ile allele at TAP2/379 polymorphisms and pathogenesis of SLE was observed.

Serum interleukin-18 and its relationship with subclinical atherosclerosis in systemic lupus erythematosus.

BACKGROUND: Interleukin-18 (IL-18) is a pro-inflammatory and pro-atherogenic factor, and its blood level has shown a direct correlation with atherosclerosis. We aimed to evaluate the serum IL-18 level in patients with systemic lupus erythematosus (SLE) and its relationship with the intima-media thickness (IMT) of the carotid artery in these patients, as an indicator of atherosclerosis. METHODS: In this cross-sectional study, 60 patients as the patient group and 30 healthy volunteers as the control group [matched sex, age, and body mass index (BMI)] were selected, and their disease status and general data were gathered using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) form. A blood sample was also obtained from all participants to determine the serum level of IL-18 and other metrics, including high-sensitivity C-reactive protein (hs-CRP), cholesterol, triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), anti-double stranded deoxyribonucleic acid (anti-dsDNA), complement 3 (C3), and C4. The IMT of the carotid artery was calculated in both groups. We also evaluated the clinical cardiovascular manifestations. RESULTS: The serum IL-18 levels in patients were significantly higher than in the control group (P ˂ 0.005). It had no significant correlation with disease activity (P = 0.10). The patients with SLE with high IL-18 serum levels (> 280 pg/ml) had higher SLEDAI-2K (P = 0.02) than the patients with a low level (< 280), where 280 was the median of the IL-18 levels. The serum IL-18 level had no significant correlation with the carotid artery IMT. CONCLUSION: A high level of IL-18 reflects the disease activity, but it was not significantly correlated with subclinical atherosclerosis, denoted by the carotid artery IMT.

Serum Level of Soluble Lymphocyte-Activation Gene 3 Is Increased in Patients with Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is described as a systemic and chronic autoimmune disease characterized by inflammatory polyarthritis. Lymphocyte-activation gene 3 (LAG3) is a membrane glycoprotein expressed on activated, exhausted, and regulatory T cells. LAG3 plays a major role in the function of Treg cells. LAG3 also has a soluble form (sLAG3) with a controversial role. OBJECTIVE: To evaluate the serum level of sLAG3 in rheumatoid arthritis patients in comparison with healthy subjects and assess its association with the disease activity. METHODS: This cross-sectional study was performed on 105 patients with RA referred to Ghaem hospital of Mashhad, Iran. We divided the participants into four groups: 1) 35 untreated patients with newly diagnosed RA, 2) 35 active RA patients, 3) 35 patients in the remission phase of the disease, and 4) 35 healthy individuals matched in terms of age and sex. After completing the interview and questionnaire, the sLAG3 was evaluated by commercial ELISA. RESULTS: The serum level of sLAG3 significantly increased in RA patients (76.78 ng/ml) as compared with the healthy participants (51.67, p=0.002). However, there was no significant difference between RA patients in the remission phase of the disease (114.11 ng/ml) and those with moderate to high disease activity (63.06 ng/ml, p=0.076). CONCLUSION: This study provided insights into the role of sLAG3 in the immunopathogenesis of RA disease, but further investigations are also warranted.