Disentangling the Pathogenesis of Systemic Lupus Erythematosus: Close Ties between Immunological, Genetic and Environmental Factors.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that attacks various organ systems with a variety of clinical implications, ranging from mild skin and mucosal manifestations to severe central nervous system manifestations and death. Cases of SLE have been documented nearly two centuries ago when scholars used the terms 'erythema centrifugum' and 'seborrhea congestiva' to describe the discoid skin lesions and the butterfly or malar rash in SLE. Since then, knowledge about this disease has developed rapidly, especially knowledge related to the underlying pathogenesis of SLE. To date, it is known that immune system dysregulation, supported by genetic and environmental predisposition, can trigger the occurrence of SLE in a group of susceptible individuals. Various inflammatory mediators, cytokines and chemokines, as well as intra- and intercellular signaling pathways, are involved in the pathogenesis of SLE. In this review, we will discuss the molecular and cellular aspects of SLE pathogenesis, with a focus on how the immune system, genetics and the environment interact and trigger the various clinical manifestations of SLE.

The Increasing Level of DKK-1 as a New Bone Formation Factor in Patients with Early Spondyloarthritis.

The role of dickkopf-related protein 1 (DKK-1) in radiographic development may become a robust marker for early spondyloarthritis (SpA) diagnosis. This study aimed at determining the serum DKK-1 profile in patients with SpA and investigating its relationship with SpA progression. Supported by analyzing the BMD data which aims to affirm the potential of DKK-1 as a biomarker for early diagnosis of SpA, this research may become the early study to produce a robust tool to diminish the fatal impacts in SpA. This cross-sectional study included patients with SpA using ASAS 2010 criteria from Dr. Soetomo General Hospital, Indonesia. Collected data included patients' general characteristics, disease duration, disease activity using ASDAS-CRP and ASDAS-ESR, serum DKK-1 levels, and BMD. The patients were classified as early SpA if the disease duration was ≤5 years and established SpA if the disease duration was >5 years, while the low BMD was indicated by Z score ≤ -2.00. The correlation was tested using the Spearman or Pearson test. The differences in patients' characteristics among early and established SpA and also between low and normal BMD were tested using the unpaired T-test or the Mann-Whitney test. The serum DKK-1 levels in early SpA (7365 ± 2067 pg/dL) were significantly higher than those in established SpA (5360 ± 1054 pg/dL). Serum DKK-1 levels were also associated with disease duration (r = -0.370, p = 0.040) and BMD at the total hip (r = 0.467, p = 0.028). The differences in all patients' clinical parameters were not found between patients with low BMD at any site and patients with normal BMD unless in the BMI (p = 0.019). Our findings found DKK-1 as a potential diagnostic marker for early SpA. Early diagnosis may lead to rapid treatment to delay disease progression and prevent future impairment.

The Association of Complements, TGF-ß, and IL-6 with Disease Activity, Renal Damage, and Hematological Activity in Patients with Naïve SLE.

Several key player factors, such as cytokine and complement, play an important role in the pathogenesis of systemic lupus erythematosus (SLE). The purpose of this study was to reveal the association between complement 3 (C3), complement 4 (C4), interleukin-6 (IL-6), and transforming growth factor-ß (TGF-ß) with SLE disease activity, renal damage, and hematological activity in patients with naïve SLE. The Laboratory of Clinical Pathology Dr. Soetomo General Hospital in Surabaya performed all laboratory examinations on thirty women with naïve SLE. The SLE diagnosis is based on ACR criteria (1998 revised criteria) from Dr. Soetomo General Hospital Surabaya, Indonesia, and the systemic lupus activity measurement (SLAM) score is used to assess the disease activity. The correlation was statistically tested using the Spearman and Pearson tests. The differences in cytokine and complement levels are between SLE severity groups using the two-way Anova and Kruskal-Wallis. The unpaired T-test and Mann-Whitney test were used to determine the differences between the relatively normal and the more severe groups of organ damage and hematological activity. All tests were two-tailed, analyzed with GraphPad Prism 9 for windows, and a p value of less than 0.05 was considered statistically significant. This study found a significant decrease in C3 (20.2, 16.4-24.2 mg/dL) and C4 (7, 6-14.3 mg/dL) and an increase in IL-6 (35.60 ± 7.43 mg/dL) and TGF-ß (311.1 ± 290.8 mg/dL) in the group of severe patients with SLAM scores >30. Although there is no significant relationship between SLAM and renal impairment or hematologic activity, patients with higher SLAM had a significant decrease in complement; this complement decrease was also significant in patients with higher leukocyte counts. An insignificant increase in cytokines was also observed in patients with higher SLAM. Patients with high serum creatinine levels had a significant increase in TGF-ß, whereas those with a faster ESR had a significant increase in IL-6. In conjunction with complements evaluation, assessment of the cytokine profile may become a promising marker for reliable diagnosis and treatment of SLE in the future.

Optimal use of tocilizumab for severe and critical COVID-19: a systematic review and meta-analysis.

Background: Several studies have revealed the potential use of tocilizumab in treating COVID-19 since no therapy has yet been approved for COVID-19 pneumonia. Tocilizumab may provide clinical benefits for cytokine release syndrome in COVID-19 patients. Methods: We searched for relevant studies in PubMed, Embase, Medline, and Cochrane published from March to October 2020 to evaluate optimal use and baseline criteria for administration of tocilizumab in severe and critically ill COVID-19 patients. Research involving patients with confirmed SARS-CoV-2 infection, treated with tocilizumab and compared with the standard of care (SOC) was included in this study. We conducted a systematic review to find data about the risks and benefits of tocilizumab and outcomes from different baseline criteria for administration of tocilizumab as a treatment for severe and critically ill COVID-19 patients. Results: A total of 26 studies, consisting of 23 retrospective studies, one prospective study, and two randomised controlled trials with 2112 patients enrolled in the tocilizumab group and 6160 patients in the SOC group, were included in this meta-analysis. Compared to the SOC, tocilizumab showed benefits for all-cause mortality events and a shorter time until death after first intervention but showed no difference in hospital length of stay. Upon subgroup analysis, tocilizumab showed fewer all-cause mortality events when CRP level ≥100 mg/L, P/F ratio 200-300 mmHg, and P/F ratio <200 mmHg. However, tocilizumab showed a longer length of stay when CRP <100 mg/L than the SOC. Conclusion: This meta-analysis demonstrated that tocilizumab has a positive effect on all-cause mortality. It should be cautiously administrated for optimal results and tailored to the patient's eligibility criteria.

Th17/Treg Ratio and Disease Activity in Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by T-cells imbalance. There are ongoing controversies about the role of specific T-helper cell subsets and their cytokines. The study aimed to confirm the disturbance of Th17/Treg ratio in SLE patients. METHODS: Subjects were SLE patients who met the American College of Rheumatology 1997 criteria. Disease activity assessment was measured by SLAM index. Th17 and Treg level was measured by flow cytometry. Th17 level was evaluated as CD4+L17 whilst Treg as CD4+Foxp3+. Final result is stated as Th17/Treg ratio. RESULTS: Thirty female subjects with active SLE had mean SLAM Score of 29.3±3.88, C3 level 25.2 (6-59.5), C4 level 15.25 (5-54.3), ESR 62.1±37.85, CRP 30.16±59.45, and anti-dsDNA 155.32±186.10. Higher Th17 level was found in SLE patients compared to healthy subjects (30.09 pg/ml vs 13.01pg/ml; 12.60% vs 0.91%). However, it did not correlate to disease activity (p>0.05; r=-0.28). Regarding Treg level, there was no significant difference between active SLE and healthy subjects (12.85 vs 11.05 pg/ml; 9.57% vs 2.05%). Treg level negatively correlated to SLE disease activity (p<0.01; r=-0.73). Th17/Treg ratio was 3.28±2.22% and it positively correlated to SLE disease activity (p<0.01; r=0.78). CONCLUSION: Th17/Treg ratio is positively correlated with disease activity. Th17 level is elevated but not correlated with disease activity. Decrease of Treg level is not significant though correlated with disease activity in SLE patients.