Pyoderma gangrenosum, as the first clinical presentation of systemic lupus erythematous, a case report and comprehensive literature review

Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with 'normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in 'normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions.

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Human γδ T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of γδ T cells in autoimmune diseases is not clear. Few autoimmune disease-related antigens recognized by T cell receptor (TCR) γδ have been defined. In this study, we compared Vδ2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jδ gene fragment usage between these two groups. According to the dominant CDR3δ sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit ζ (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK-2 cells. Cytotoxicity of only Vδ2 γδ T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vδ2 γδ T cells, which deepens our understanding of mechanisms in autoimmune diseases.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with numerous abnormalities recorded at the cellular, molecular, and genetic level. Expression of the basic leucine zipper transcription factor cAMP-responsive element modulator (CREM)α was reported to be abnormally increased in T cells from SLE patients. CREMα suppresses IL-2 and T cell receptor ζ chain gene transcription by direct binding to the respective promoters. Here, we show that increased CREM expression is the result of enhanced promoter activity. DNA binding analyses reveal direct binding of transcription factor specificity protein-1 (SP-1) to the CREM promoter resulting in enhanced transcriptional activity and increased CREM expression. Protein phosphatase 2A is known to activate SP-1 through dephosphorylation at its serine residue 59. Our results show that nuclei from SLE T cells contain lower levels of Ser(59)-phosphorylated SP-1 protein and a stronger SP-1 binding to the CREM promoter. We conclude that protein phosphatase 2A accounts for enhanced SP-1 dephosphorylation at Ser(59) in SLE T cells. More importantly, CREM promoter activity mirrors reliably disease activity in SLE patients, underscoring its potential role as a biomarker for the prediction of flares in SLE patients.

Type I Interferon in Systemic Lupus Erythematosus and Other Autoimmune Diseases

Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.

Objective. To evaluate the prevalence of traditional risk factors in systemic lupus erythematosus (SLE) patients, assess the 10-years risk of developing type 2 diabetes mellitus (DM) in SLE patients and identify those necessitating preventive interventions following altered glucose metabolism using the Finnish Type 2 Diabetes Risk Score (FINDRISK) questionnaire.Materials and methods. The study included 119 SLE patients (107 women, 12 men, with median age 39 [33; 47] years and mean disease duration 6 [1,12] years.The control group included 100 age and sex matched individuals without immune-mediated inflammatory rheumatic diseases and without previous DM history. The 10-years risk of developing type 2 DM in SLE patients and the controls assessed using the Russian adaptation of Finnish Type 2 Diabetes Risk Score questionnaire. Fasting glucose levels in venous blood were measured in all SLE patients. Glucose levels ≥6.1 mmol/L were interpreted as fasting hyperglycemia.Results. The prevalence of traditional type 2 DM risk factors in SLE patients was as follows: abdominal obesity was found in 63.9%, lack of physical activity – in 62.2%, intake of antihypertensive drugs— in 52.9%, BMI ≥25 kg/m2 in 42.0%, unhealthy diets – in 40.3%, family history of DM – in 35.3%, age over 45 years – in 32.8%, history of hyperglycemia episodes – in 15.1%. Abdominal obesity and intake of antihypertensive drugs were more often documented in SLE patients, while all other risk factors were equally represented in SLE and control groups. On average 3 [2; 5] risk factors were found in each SLE patient. Low type 2 DM risk was a more rare phenomenon in SLE patients vs healthy controls (36.1 and 51%, р<0.05). Primary type 2 DM prophylaxis recommended in case of moderate, high and very high risk was more often indicated in SLE vs the healthy controls (29.4 and 17.0%, р=0.03), including those younger than 45 years (18.3 and 6.1% respectively, р=0.05). Fasting hyperglycemia was found in 1.2% patients with low-slightly increased type 2 DM risk and in 16.1% individuals with moderate, high and very high risk (p=0.04).Conclusions. High prevalence of such traditional type 2 DM risk factors as abdominal obesity, lack of physical activity and intake of antihypertensive drugs was demonstrated in SLE patients. Finnish Type 2 Diabetes Risk Score questionnaire identified moderate, high and very high 10-year risk of developing type 2DM in 29.4% SLE patients, necessitating prophylactic interventions in view of altered glucose metabolism.

Excerpt During the last six years the author has had the opportunity personally to study and treat 175 patients with systemic lupus erythematosus. The purpose of this paper is to review the current...

BackgroundPopulation-based studies on Systemic Lupus Erythematosus (SLE) patients with a verified diagnosis is considered the gold standard to find true outcomes in SLE, but few population-based SLE cohorts have follow-up...

The aim of this study was to determine the distribution of the FcgammaRlla and FcgammaRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgammaRlla 131 R/H and FcgammaRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgammaRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE and the controls (P=0.002 for R/R131 vs R/H131 and H/H131, OR 2.5 (95% Cl 1.4-4.5), but not in FcgammaRIIIa genotypes. FcgammaRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% Cl 1.03-1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgammaRlla-R/R131 and in FcgammaRIIa-R allele. In 300 SLE patients, high binding allele combination H131/V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131/F176 allele combination among four FcgammaRIIa/FcgammaRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgammaRIIa-R/R131 or R131-allele than male controls, but FcgammaRIIa or FcgammaRIIIa genotypes had no association with renal involvement in male SLE patients. FcgammaRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anticardiolipin antibody (+) and anti-Ro antibody (+) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgammaRIIa or FcgammaRIIIa genotypes between female SLE and female controls, but FcgammaRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgammaRIIa R/R131 among three FcgammaRIIa genotypes, and serositis in FcgammaRIIIa-F/F176 among three FcgammaRIIIa genotypes. FcgammaRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgammaRIIa-RI31 homozygote and R131 allele were a predisposing factor, and H131/V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgammaRIIa and FcgammaRIIIa showed somewhat different clinical associations between the genders.

To detect the serum level of mannose binding lectin (MBL) and its genovariation in systemic lupus erythematosus (SLE) patients and to investigate the role of MBL in the pathogenesis of SLE. ELISA was used to measure the serum MBL level of 40 SLE patients and 30 healthy blood donors. Tm genotyping method was used for the first timer in China. Primers and specific fluorophore-labelled hybridization probes for the exon 1 and promoter regions of MBL gene were designed based on the haplotype MBL2(*) LXPA (GenBank X15422). The genotyping of MBL in these two groups were performed using real-time PCR through Light Cycler Instrument. (1) The serum MBL of the SLE patients was 107.2 microg/L, significantly lower than that of the healthy blood donors (290.2 microg/L, P = 0.0002). (2) MBL mutation in exon 1 region was mainly at codon 54, with a mutation rate of 37.1% in the SLE group, significantly higher than that of the control group (13.3%, p = 0.049). (3) Polymorphisms of H/L in MBL gene were present in both SLE patients and controls, and there was no difference in the L allele frequency between the two groups. (4) The serum MBL level of the SLE patients with MBL mutation in codon 54 was 49.8 microg/L, significantly lower than that of the SLE patients without MBL mutation in codon 54 (141.7 microg/L, P = 0.000 27). The SLE disease activity index (SLEDAI) of the SLE patients with MBL mutation in codon 54 was 7.44, significantly lower than that of the SLE patients without MBL mutation in codon 54 (12.87, P = 0.0029). A negative correlation was observed between SLEDAI score and serum MBL (r = -0.48). Mutation occurring in MBL exon 1 region at codon 54 may be a predisposing factor of the pathogenesis of SLE. Serum MBL may be a potential biomarker of disease activity in SLE patients.

Objective To investigate the function of megakaryocytic cells in systemic lupus erythematosus(SLE)patients with thrombocytopenia. Methods Standard hematological tests，bone marrow examinations and immunological tests were carried out to scan thrombocytopenia in a total of 176 consecutive SLE patients，the clinical and laboratory data were compared between SLE patients with or without thrombocytopenia，and bone marrow examinations for analysis of megakaryocytic function in SLE patients with thrombocytopenia were compared with that in 32 SLE patients without thrombocytopenia. Results Thrombocytopenia was identified in 64 SLE patients(36.4%)，among whom，48(75%)with mild thrombocytopenia and 16(25%)with severe thrombocytopenia. In comparison with patients without thrombocytopenia，SLE patients with thrombocytopenia had higher incidence of serositis，more sever renal damage，lower serum C3 levels(P<0.05)，and higher disease activity scores(P<0.05). The total numbers of megakaryocytes was decreased in SLE patients with thrombocytopenia in comparision with that in SLE patients without thrombocytopenia(P=0.001)，especially the platelete-forming megakaryocyte. Whereas，the numbers of promegakaryocytes was markedly increased in SLE patients with thrombocytopenia(P=0.019). Conclusions Thrombocytopenia in SLE is more likely developed in patients with active and severe disease. Impaired function in megakaryocytic proliferation and differentiation may contribute to the thrombocytopenia occurred in SLE patients.

BACKGROUND AND OBJECTIVESSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by humoral autoimmunity. The etiology of SLE is thought to be multifactorial including environmental, hormonal, and genetic factors. The human leukocyte antigen (HLA) has extensively been associated with the susceptibility to SLE; however, the association is heterogeneous among different ethnic groups. The aim of this study was to determine the association of HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 with SLE susceptibility in the Saudi population.DESIGN AND SETTINGSA total of 86 consecutive SLE patients attending the rheumatology clinic at King Abdulaziz Medical City, Riyadh, were recruited for this study.METHODSHLA types were determined by the polymerase chain reaction sequence-specific oligonucleotide (PCR-SSP) method in 86 patients and 356 control subjects.RESULTSThe following HLA alleles were found to be positively associated with SLE: HLA-A*29 (OR=2.70; 95% CI=1.03–7.08; P=.0035), HLA-B*51 (OR=1.81; 95% CI=1.17–2.79; P=.0066), HLA-DRB1*15 (OR=1.45; 95% CI=0.98–2.29; P=.063), and HLA-DQB1*06 (OR=1.67; 95% CI=1.19–2.36; P=.0032), whereas HLA-DRB1*16 was negatively associated with the disease (OR=0.18; 95% CI=0.02–1.3; P=.055). HLA-DRB1*15 haplotypes were significantly associated with SLE (OR=2.01, 95% CI=1.20–3.68, P=.008); this was mainly due to the HLA-DRB1* 15-DQB1*06 association.CONCLUSIONSOur data suggest an association between MHC class I and class II (HLA-A*29, HLA-B*51, HLA-DRB1*15, and HLA-DQB1*06) and susceptibility to SLE in the Saudi population. HLA-DRB1*15-DQB1*06 haplotype showed the highest risk factor for the disease that is similar to what was seen in the African American patients, suggesting shared susceptibility genetic factors among these ethnic groups.

Background:The presence of anti-Ro antibodies in female patients diagnosed with systemic lupus erythematosus (SLE) and primary Sjögren syndrome (SS) in their fertile years raises concern among the medical team due to the risk of neonatal lupus in their newborns (NB).(1)Objectives:The aim of this study was to determine whether there are differences between the outcome of anti-Ro positive pregnancies in SLE and SS.Methods:This is a retrospective observational study carried out in a Rheumatology tertiary center. We included anti-Ro positive female SLE and SS patients, who were diagnosed before or during pregnancy and followed in our clinic between 2003-2020. The diagnosis of SLE or SS was established according to the 2012 SLICC criteria and the 2016 EULAR/ACR criteria, respectively. Clinical, immunological and pregnancy parameters were recorded before (where available), during and after pregnancy, as well as maternal risk factors (smoking, BMI, disease and medication history). Statistical analysis for continuous variables were performed with T-student test and categorical variables with Person Chi-square test, using IBM SPSS Statistics version 20.Results:Eleven out of 65 anti-Ro positive SLE patients and 10 out of 153 anti Ro-positive SS patients met the inclusion criteria and had 13 and 12 pregnancies, respectively. The mean age at diagnosis was 24,75 ± 5,19 years for SLE and 31,92 ± 4,05 years for SS, and the mean pregnancy age was 28,33 ± 4,05 years for SLE and 33,17 ± 3,63 years for SS. Nine (81,81%) SLE patients were diagnosed before pregnancy, while 6 (60%) of the SS patience were diagnosed during pregnancy.Two (18,18%) SLE and 1 (10%) SS were smokers, median BMI was 21 for both SLE and SS (1 SS patient was obese), 2 (18,18%) had a history of lupus nephritis, 6 (54.54%) LES patients had secondary antiphospholipid syndrome, out of which 1 had a previous miscarriage. In the SS group there were 3 previous miscarriages, one patient had a history of parotid lymphoma. The majority of both SLE and SS patients had moderate anti-Ro antibody titers (&lt;200 U/ml) before as well as during pregnancy: 6 (46.5%) and 8 (61.53%) in SLE, 5 (41.6%) and 7 (58.3%) in SS.More preterm NB and stillbirths were encountered in SLE mothers, possibly due to the association of secondary antiphospholipid syndrome, both groups encountered 1 pregnancy loss, and cesarean delivery outweighed vaginal ones in both SLE and SS patients. (Table 1)Table 1.Gestational age and delivery type according to maternal diseaseGestational ageSLEnumber (%)SSnumber (%)Full-term pregnancy4 (30.76%)10 (83.33%)Late preterm births4 (30.76%)1 (8.33%)Very preterm births2 (15.38%)0Stillbirth2 (15.38%)0Pregnancy loss1 (7.69%)1 (8.33%)Delivery typeVaginal3 (25%)4 (36.36%)Cesarean9 (75%)7 (63.63%)Distribution of pregnancy outcome is exhibited in figure 1. There were 4 (33.33%) NB with cutaneous neonatal lupus all from SS mothers, 3 of whom used HCQ before and/or during pregnancy; and there were 5 NB with complete fetal atrioventricular block (AVB), 3 (25%) from SS mothers and 2 (15.38%) from SLE mothers. A history of HCQ usage was recorded in 3 out of these 5 mothers, and all 5 NB with complete fetal AVB were treated with dexamethasone, without success. Two NB died (both from SLE mothers) and 3 NB (all from SS mothers) needed pacemaker implantation. From the latter, 1 developed pacemaker cardiomyopathy and 1 developed sepsis.Conclusion:Neonatal lupus seems to be more prevalent in anti-Ro positive SS patients than SLE patients, even though no difference was seen in anti-Ro titer between the two diseases. Fetal cardiac arrhythmia may lead to SS diagnosis. Dexamethasone did not improve the outcome of the fetal AVB.

Objective: The aim of the present study was to assess oxidative stress and iron metabolism in systemic lupus erythematosus (SLE) patients with and without insulin resistance (IR).Method: This study included 236 subjects (125 controls and 111 SLE patients). Patients with SLE were divided in two groups: with (n = 72) or without (n = 39) IR.Results: SLE patients with IR showed higher advanced oxidation protein product (AOPP) levels (p = 0.030) and gamma-glutamyltransferase (GGT) levels (p = 0.001) and lower sulfhydryl groups of proteins (p = 0.0002) and total radical-trapping antioxidant parameter (TRAP) corrected by uric acid (UA) levels (p = 0.04) when compared to SLE patients without IR. However, SLE patients with IR presented lower serum 8-isoprostane (p = 0.05) and carbonyl protein levels (p = 0.04) when compared to SLE patients without IR. Serum ferritin levels were significantly higher in SLE patients (p = 0.0006) than in controls, and SLE patients with IR presented higher serum ferritin levels (p = 0.01) than SLE patients without IR. Patients with SLE showed that IR was inversely correlated to TRAP/UA (r = −0.2724, p = 0.0008) and serum ferritin was positively correlated to AOPP (r = 0.2870, p = 0.004).Conclusions: This study found that oxidative stress was higher in the group of SLE patients with IR, and increased ferritin, whether caused by the inflammatory process per se or hyperinsulinaemia, can favour the redox process. In addition, the preset data reinforce the need to measure oxidative stress with several methodologies with different assumptions.