الفهرس 
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Abstract
Introduction:
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder, multisystemic, relapsing, and remitting disease affecting multiple organs including joints, skin, blood, serous membranes, kidneys, central nervous system (CNS) and others organs.
Renal involvement in SLE is still one of the strongest predictors for morbidity and mortality. Although over the last decades the therapeutic options for LN have increased leading to better results, the survival rate among patients with LN is still about 75 % after 15 years. LN may be presented by a wide range of abnormalities ranging from asymptomatic proteinuria or microscopic hematuria with normal renal function to severe nephrotic syndrome or renal failure. Till now there is no single biomarker can be used to detect lupus activity especially lupus nephritis. Renal biopsy is still the gold standard method but it’s invasive and mainly used in the initial assessment of the patients. According to all guidelines the physicians are still using proteinuria, hypocomplementemia and high titer of anti- ds DNA as predictors of renal flares but sometimes they have limitations because proteinuria may occur due to permanent
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glomerular damage not actually a recent activity and also the low C3,C4 and anti-ds DNA have low sensitivity and specificity. There is hope, and evidence, that early detection of LN activity may reduce renal damage and renal failure.
Measurement of disease activity in systemic lupus erythematosus (SLE) is essential to evaluate outcomes, differences among SLE patient groups, responses to a new drug proposed, and also for assessing disease longitudinally for observational and clinical trials. A lot of scoring systems are used to evaluate SLE activity.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a 249-amino acid cytokine that is a member of the TNF-ligand superfamily. Binding of TWEAK to its sole receptor, Fn14, can mediates multiple biologic effects as up- regulation of pro-inflammatory mediators known to be essential in LN pathogenesis, including MCP-1 an induction of cell death and apoptosis.
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. It is a leukocyte chemotactic factor that is involved in mediating inflammation and injury in lupus nephritis. In murine models of lupus nephritis, genetic depletion or blockade of MCP-1 ameliorates
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glomerular and interstitial inflammation and hence renal damage. In human lupus nephritis, increased expression of MCP-1 on endothelial cells, renal epithelial cells, and infiltrating mononuclear cells in the tubulointerstitial regions can be demonstrated by immunohistochemical staining and in situ hybridization. So the aim of this study was to assess the potential role of urinary tumor necrosis factor-like weak inducer of apoptosis (uTWEAK), and urinary monocyte chemoattractant protein-1 (uMCP-1) in lupus patients and to determine their correlation with disease activity.
Patients and Methods:
Study design:
The present study is a case control study was conducted on a total of 114 subjects ; 92 SLE patients who were recruited from the internal medicine department, rheumatology unit (inpatient wards and outpatient clinics), Tanta University hospital , Tanta, Egypt and 22 age and sex matched healthy volunteers were allocated as a control group.
Inclusion criteria:
The included SLE patients met the systemic lupus international collaborating clinics (SLICC) criteria for SLE classification 2012 or ACR criteria (1997).
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Exclusion criteria:
We excluded patients with diabetes mellitus, patients with a diagnosis of overlap syndrome, patients with urinary tract infections, patients with end stage renal disease, Hepatitis Patients, malignant diseases, and pregnant women patients.
Ethical approval:
This study is in agreement with the ethical guidelines of the Declaration of Helsinki and it follows the ethical standards of Tanta faculty of medicine. Informed consents from all patients were obtained in accordance with the local ethical committee. Privacy of all patients’ data was granted as there was a code number for every patient file that includes all investigations.
Methods:
All patients and controls were subjected to:-
1) Full history taking.
2) Complete clinical examination.
3) Routine laboratory tests as:
Complete blood count (CBC), blood urea, serum creatinine, erythrocyte sedimentation rate (ESR), C- reactive protein (CRP), liver function tests, fasting blood glucose (FBS), urine analysis and protein quantification in 24 hours urine, eGFR.
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4) Serological tests as:
Anti-double stranded deoxyribonucleic acid (anti-ds DNA) was assessed by ELISA, antinuclear antibody (ANA) by ELISA.
5) Immunologic parameters as:
- Complement factors (C3 and C4 levels) by ELISA, Lupus anticoagulant, anticardiolipin ab (when required).
6) Urinary TWEAK and urinary MCP-1 were measured by human TWEAK ELISA kit and human MCP-1 ELISA kit from Thermo Fisher Scientific, USA.
Renal biopsy:
Renal biopsy was done for patients with active renal disease (group I). The renal pathology will be classified according to the revised ISN/RPS system.
Assessment of the disease activity:
Assessment of the disease activity using SLE disease activity index 2000 update (SLEDAI-2k) which consists of 24 variables with weighted score for each variable. The maximum possible score is 105; patients with active disease have 8 or more points.
LN activity was assessed by renal SLEDAI (r-SLEDAI). r-SLEDAI (SLEDAI-2K renal scores) consists of the four
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kidney-related items of the SLEDAI -2K, including hematuria (>5 red blood cells/high-power field), pyuria (>5 white blood cells/high-power field), proteinuria (>0.5 g/24 hours or urine protein/creatinine ratio >0.5) and urinary casts (heme, granular, or red blood cell). The presence of each of the parameters is scored as 4 points; the renal activity score can therefore range from 0 to 16. For our inclusion criteria, any r-SLEDAI score ≥ 8 was taken as an indicator of active lupus nephritis.
According to the 2000 SLEDAI scores, our patients were divided into 4 groups: patients with active lupus nephritis (n=24); patients with non-active lupus nephritis (n=23); patients with active systemic lupus erythematosus without renal involvement (n=22); and patients with non-active systemic lupus erythematosus without renal involvement (n=23).
Results:
The results presented in this study revealed that:
• Statistically significant increase in the blood urea, ESR 1st hour, CRP, ANA, anti-ds DNA and proteinuria were observed and significant decrease in the eGFR, RBCs, hemoglobin, serum albumin, serum protein, C3, C4 among the SLE patients as compared to control group.
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• Also urinary TWEAK level and urinary MCP-1 level (uMCP-1) of SLE patients group were significantly higher than those of control group and after post hoc tests there was also a significant differences between all groups with highest level among active lupus nephritis then inactive lupus nephritis, active lupus without nephritis and inactive lupus without nephritis respectively.
• A significant positive correlation was present in SLE patients between urinary TWEAK and urinary MCP-1 levels and blood urea, serum creatinine, eGFR, proteinuria, ANA, Anti-ds DNA, SLEDAI and r-SLEDAI and negatively with albumin, total protein, RBCs, hemoglobin, C3 and C4.
• Receiver operating characteristic (ROC) curves analysis of urinary TWEAK in detecting SLE disease, SLE activity, lupus nephritis and lupus nephritis activity revealed a sensitivity of 100%, 80.43% , 100% and 100% and specificity of 100%, 50%, 100% and 100% respectively; while for urinary MCP-1 it revealed a sensitivity of 90.91%, 82.61%, 95.74% and 100% and specificity of 96.74%, 50.00%, 93.33% and 100% respectively.
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Conclusion
In conclusion, we can conclude from the present findings that both uTWEAK and uMCP-1 are new, easily obtained, accurate markers with high sensitivity and specificity in detection of lupus nephritis activity and further prospective studies should be performed to prove their beneficial effect in early detection of lupus flares.