Current Rheumatology Reviews - Current Issue

The purpose of this study was to determine the association between single nucleotide polymorphisms (SNPs) at the rs4331, rs4341, and rs4351 loci of the angiotensin- converting enzyme (ACE) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in the Hainan population.

This study involved a total of 428 participants, with 214 individuals diagnosed with SLE and an equal number of healthy controls. The SNaPshot sequencing technique was used to determine the base sequences at the ACE gene rs4331, rs4341, and rs4351 loci in the study subjects. Logistic regression was employed to compare the frequency distribution of genotypes and allele frequencies at each locus between the case group and the control group. HaploView 4.2 software was used to analyze the relationship between haplotypes at each locus and genetic susceptibility to SLE.

The GG genotype and G allele frequency at the rs4341 locus were higher in the case group compared to the control group. In the rs4341 recessive model, carriers of the GG genotype were more likely to develop SLE compared to carriers of the CG+CC genotype (OR = 1.889, 95% CI: 1.195-2.988, P = 0.006). In the rs4351 overdominant model, carriers of the AC genotype had an increased risk of developing SLE compared to carriers of the AA+CC genotype (OR = 1.514, 95% CI: 1.033-2.219, P = 0.033). The rs4341 and rs4351 loci exhibited linkage disequilibrium, and the CA haplotype (OR = 0.630, 95% CI: 0.481-0.826, P = 0.001) was a protective factor against SLE. The GA haplotype (OR = 2.849, 95% CI: 1.901-4.270, P < 0.01) and the CC haplotype (OR = 2.309, 95% CI: 1.210-4.405, P = 0.009) were risk factors for genetic susceptibility to SLE in the Hainan population.

The rs4341 locus of the ACE gene is associated with genetic susceptibility to SLE in the Hainan population.

Clinically relevant fatigue in rheumatoid arthritis (RA) patients significantly affects their quality of life. Almost all studies have assessed fatigue in this population using non-specific scales. The present multi-centric study aimed to assess the validity, reliability, and clinical significance of the Arabic version of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ).

The present cross-sectional multicentric study was conducted at Aswan, Mansoura, Port Said, and Al-Azhar University Hospitals over a 6-month duration. The study included 311 patients with RA diagnosed according to the 2010 criteria of the American College of Rheumatology. The Arabic version of BRAF-MDQ was developed to assess fatigue in these patients. All patients were subjected to careful history taking, thorough clinical assessment, and standard laboratory work-up. The obtained Arabic BRAF-MDQ was tested for construct validity, internal consistency, test-retest reproducibility, and criterion validity. Construct validity was evaluated using factor analysis with the Kaiser Meyer Olkin tool of sampling adequacy and Bartlett's sphericity test. Internal consistency of subscales was assessed using Cronbach’s alpha. Test-retest reproducibility was assessed after a 1-week interval using the intraclass correlation coefficient. Pearson’s correlation coefficient was used to correlate numerical variables. Predictors of fatigue were identified using binary logistic regression analysis.

The present study included 311 RA patients. Construct validity assessment showed a high loading of questionnaire items within the proposed construct subscales with a KMO measure of sphericity of 0.927 and Bartlett's test of sphericity p-value < 0.001. Internal consistency assessment showed adequate Cronbach’s alpha of Arabic BRAF-MDQ subscales. Total Arabic BRAF-MDQ had excellent criterion validity, as indicated by the high correlations with MAFS (r=0.95, p < 0.001) and SF-36 vitality subscale (r=-0.91, p < 0.001). Clinically significant fatigue was identified in 214 patients (68.8%). Multivariate logistic regression analysis revealed age (OR (95% CI): 1.07 (1.02-1.12), p < 0.001), disease duration (OR (95% CI): 1.82 (1.43-2.33), p < 0.001), DAS28CRP (OR (95% CI): 8.62 (4.63-16.02), p < 0.001), and mHAQ (OR (95% CI): 3.85 (1.07-13.9), p = 0 .039) as significant predictors of fatigue development in the studied patients.

The Arabic version of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire is a valid, consistent, and reliable tool for the assessment of fatigue in Egyptian rheumatoid arthritis patients. Clinically significant fatigue was identified in 214 patients (68.8%). Further, risk factors for fatigue included older age, longer disease duration, and higher disease activity.

Juvenile-onset systemic lupus erythematosus (jSLE) is an uncommon yet severe autoimmune/inflammatory condition affecting multiple bodily systems, typically manifesting before the age of 18. This disease exhibits significant complexity, displaying considerable variation among patients. Its effects can range in severity from minor to fatal, characterized by a pattern of recurring flare-ups and periods of remission, making its natural progression difficult to predict.

The aim of this work is to investigate the correlation between semaphorin 3A and systemic lupus erythematosus patients who follow up at Pediatric Rheumatology Unit Children's Hospital at Cairo University.

This cross-sectional research was performed at the Pediatric Rheumatology Unit Cairo University Children's Hospital and included cases with jSLE under treatment and follow-up from the period of August 2021 to August 2022.

Regarding demographic data of the studied subjects, highly significant variances were noted among the patient group and control group regarding age (years) and sex. However, there were non-significant variances among the patient group and control group concerning weight.

In the current research, median (IQR) onset of disease was 2 (1-3) years, mean ± SD age at disease diagnosis was 8.98 ± 2.13 years, median (IQR) disease duration 2 (1-3) years, family history was negative in 36 (90.0%) patients and consanguinity was negative in 28 (70.0%).

The distribution of the manifestations within the patients group was as follows 7 (17.5%) with mucocutaneous, 7 (17.5%) with vasculitis, 4 (10.0%) with serositis, 11 (27.5%) with cardiac, 17 (42.5%) with renal, 11 (27.5%) with GIT, 5 (12.5%) with hematological, and 4 (10.0%) with neurological manifestations. In addition, there were 2 (5.0%) with arthritis, 31 (77.5%) with arthralgia, and 2 (5.0%) with fever, mean ± SD systolic BP was 115.95 ± 8.38 and mean ± SD diastolic BP was 75.60 ± 6.11.

Regarding treatments in the patients’ group, the median steroid dose was 15 mg (5-25) with median duration of 2 (1-3), 38 (95.0%) patients received hydroxychloroquine with mean ± SD hydroxychloroquine dose of 205.26 mg ± 51.71. 23 (57.5%) patients received cyclophosphamide with mean ± SD number of cyclophosphamide doses 7.17 mg ± 2.42. Mycophenolate was received in 27 (67.5%) with mean ± SD dose of 614.07 mg ± 225.85.

There were highly statistically significant differences between control group and patients’ group concerning TLC, creatinine, and ESR. Highly statistically significant variance was noted among the control group and patients group concerning CRP.

Regarding the patients' group, the mean ± SD serum C3 was 99.89 mg/dl ± 28.45, median (IQR) serum C4 was 14.5 mg/dl (8.8-25.5), and median (IQR) albumin creatinine ratio was 27 IU/ML (16-186). There was positive ANA with titre and pattern in 34 patients (85.0%), positive antids-DNA in 25 patients (62.5%), and positive anticardiolipin IgM and IgG in 5 patients (12.5%).

Renal biopsy was found to be normal in 23 (57.5%), lupus nephritis class II, III in 3 (7.5 percent), lupus nephritis class III in 10 (25.0%), and lupus nephritis class IV in 4 (10.0%). Urine analysis results showed the following: normal in 28 (70.0%), albumin in 2 (5.0%), casts in 2 (5.0%), pus cell in 4 (10.0%), albumin + casts in 2 (5.0%) and albumin + pus cell in 2 (5.0%).

Regarding semaphorin 3A level, a highly statistically significant variance was noted among the control and patients group concerning semaphorin 3A level found to be lower in cases than control with a p-value below 0.001. In patients’ group, a negative correlation for semaphorin 3A with SBP, DBP, AST and ESR and also a positive correlation with steroid duration in the studied patients was noted. In addition, highly significant association between semaphorin 3A and positive CRP was also observed. However, no significant relationship between semaphorin 3A and SLE manifestations except arthritis was found related to semaphorin 3A level.

ROC curve shows that the semaphorin 3A cut-off point to predict SLE ≤ 3 with sensitivity = 47.50, specificity=92.50, PPV=86.4, and NPV=63.8.

Reduced plasma Semaphorin 3A levels were found in this study; furthermore, their clinical relationship in SLE proposes their significant job in this illness. Furthermore, the ROC results demonstrated that Semaphorin 3A could be a new symptomatic biomarker in SLE with very high sensitivity for the determination of SLE, demonstrating that they might be helpful biomarkers for the evaluation of SLE. However, extra studies that focus on the potential role of Semaphorin 3A in SLE are needed.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Several studies have suggested that interleukin-18 (IL-18) is associated with SLE pathogenesis. The genotype distribution of IL-18 promoter polymorphisms differs among ethnic populations. The present study aimed to investigate the correlation between IL-18 polymorphisms at positions -137 and -607 in patients situated in Northeastern Iran.

This case-control study examined the prevalence of IL-18 -137C/G and -607C/A polymorphic variants among 95 SLE patients referred to the Department of Rheumatology, who were referred to the general clinics of Ghaem Hospital and Imam Reza Hospital in Mashhad, Iran, were included in the study. In addition, 100 healthy individuals were included in the control group. DNA from whole blood was extracted by the salting-out method using a commercial kit (Biogene, US). Allelic and genotypic frequencies of polymorphisms (-137G/C, -607C/A) in the IL-18 promoter gene were analyzed using a polymerase chain reaction (PCR)-based amplification refractory mutation system (ARMS) method.

The results of this study demonstrated that the frequency of SLE patients with the homozygous C/C genotype of the IL-18 promoter gene at position -137 was significantly higher than that of the homozygous G/G genotype (P < 0.001) in normal controls. Furthermore, the polymorphism analysis performed illustrated a significant association between (-137G/C) and (-607C/A) polymorphisms in the IL-18 promoter gene and SLE (P < 0.005).

These results indicated that the 607A/A and 137C/C polymorphisms are more prevalent in SLE. Further research involving larger sample sizes from various populations is necessary to elucidate the role of these polymorphisms and the distribution of alleles in SLE patients.

Juvenile idiopathic arthritis pathogenesis involves a large number of different immune system cells, which are both sources and targets of chemokines, that affect not only their migration but also survival, proliferation, differentiation, production of all cytokine types, degranulation, and also directly stimulating or suppressing angiogenesis. Studyingthe contribution of chemokines to this disease pathogenesis will make it possible to identify new sensitive and specific markers for its diagnosis and subsequent dynamic monitoring of treatment effectiveness.

The study aimed to identify a list of the most informative diagnostic markers from a wide range of juvenile idiopathic arthritis patients' blood plasma chemokines.

The case-control study included 40 diagnosed pathology patients and 20 healthy age- matched children. The content of MCP-1/CCL2, MCP-3/CCL7, MIG/CXCL9, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, IFN-γ, IP-10/CXCL10, and MDC/CCL22 were measured by enzyme-linked immunosorbent assay in blood plasma of each person.

The following chemokines were included in the list of the most promising diagnostic markers: MCP-1, MIP-1α, MIG, RANTES, and IFN-γ. Their blood plasma content in patients with a diagnosed pathology was from 3 to 60 times (MIG) higher than in the conditionally healthy group. Their sensitivity and specificity exceeded 90%.

An increase in their content leads to active monocytes/macrophages migration to the site of inflammation, where they suppress effector T-cell activity by binding suppressor exosomes and activate B-cells by autoantigens presentation received due to joint tissue destruction. This allows us to speak about the predominance of the Th1-mediated immune response during the development of studied disease chronic inflammation.

Modern sedentary lifestyles are prevalent among individuals with osteoarthritis. However, direct evidence linking such behaviours as causative factors of osteoarthritis remain limited due to the presence of confounding variables.

This study aims to determine the extent to which lifestyle factors have causal effects on osteoarthritis through a two-sample Mendelian randomisation (MR) study.

Exposure-outcome relationships were evaluated using inverse variance weighted two-sample MR and summary statistics of genome-wide association studies of lifestyle factors and osteoarthritis. Weighted median, MR-PRESSO, and MR-Egger regression were used as sensitivity analyses. We obtained causality estimates, 95% confidence intervals (CI), and P-values from each MR method. Steiger filtering and radial filtering were used to exclude SNPs demonstrating reverse causality and significant heterogeneity, respectively.

MR analyses demonstrated that certain lifestyle factors had causal effects on osteoarthritis, particularly insomnia (OR 1.09 (0.387-1.79), P = 0.0024), BMI (OR 6.45 (4.48-8.42), P = 1.38e-10) and protein intake (OR 2.94 (0.361-5.52), P = 0.026). Effects were consistent across sensitivity analyses using median-based MR methods. ZNF131 & SEMA3F, and potentially RWDD2B & USP8 are genetic loci identified to mediate these causal effects.

Our results illustrate that lifetime exposure to certain lifestyle factors has causal effects on osteoarthritis. Further studies are required to determine the efficacy of lifestyle-based interventions in reducing the population-wide disease burden of osteoarthritis.

Rituximab (RTX) is used off-label for refractory cases of systemic lupus erythematosus (SLE) with extrarenal activity, including neurological and/or psychiatric (N/P) presentations. However, evidence from randomized controlled trials is limited.

This study aimed to conduct a pooled analysis of the effectiveness and safety of RTX therapy for adult refractory SLE with N/P manifestations.

Electronic searches in PubMed, Epistemonikos, and ICTRP databases and statistical analysis were conducted in May 2023.

Electronic searches identified 20 studies (25 reports). A total of 59 patients (53 females; 90%) were included, with a mean age of 33.5±10.6 years and a median disease duration of 3.5 years (range, 0.08 to 25.0) who were followed up post-RTX therapy for a median time of 12 months (range, 3.0 to 46.2). The rate of clinical response (partial or major) was 90% (95% CI, 83 to 96) (n = 57 patients). A third of responders relapsed after a median time of 9.5 months (range, 3.0 to 33.0). Pooled pre-RTX/post-RTX scores for Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (n = 13) were 19±15/7±5 and for neurological British Isles Lupus Assessment Group (BILAG) (n = 29) were A/D (13), A/C (5), B/D (7), B/C (2), and A/A (2). Patients without mood disorder had a higher chance of clinical response (relative risk (RR) 1.4 (1.03 to 1.48)). Patients who benefited the most from RTX therapy were those with psychosis (a higher chance of major clinical response; RR 1.9 (1.02 to 2.34)), without acute confusional state (a lower chance of relapse; RR 0.08 (0.006 to 0.791)), and with disease duration <3 years (a lower chance of relapse; RR 0.18 (0.014 to 0.992)). Infection rate during treatment was 33% (7/21).

RTX therapy had good effectiveness. The pooled evidence for safety outcomes was limited and of low certainty.