G. G. Song

Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis.

The aim of this study was to assess the efficacies and toxicities of immunosuppressive treatments for lupus nephritis (LN) versus cyclophosphamide (CYC). A meta-analysis was performed to determine treatment efficacy and toxicity outcomes between mycophenolate mofetil (MMF) and CYC induction therapies, between MMF and azathioprine (AZA) as maintenance therapies, and between low-dose intravenous (IV) CYC and high-dose IV CYC therapy. Ten randomized controlled trials (RCTs) were included in the meta-analysis. In terms of induction therapies, MMF did not increase complete remission or partial remission rates as compared with CYC. However, the relative risks (RRs) of amenorrhea and leukopenia tended to be lower in the MMF group than in the CYC group. Meta-analysis of MMF versus AZA as a maintenance therapy showed no difference between the two groups in terms of response rates or the risk of developing end-stage renal disease. Low-dose IV CYC therapy had lower relapse rates than high-dose IV CYC therapy (RR 0.465, 95% confidence interval [CI] 0.261—0.830, p-value 0.010), and was associated with a lower infection risk (RR 0.688, 95% CI 0.523—0.905, p-value 0.008). In conclusion, MMF was found to be as effective as CYC and tended to have a better safety profile as an induction therapy for LN than CYC.

Omega-3 Polyunsaturated Fatty Acids and the Treatment of Rheumatoid Arthritis: A Meta-analysis

BACKGROUND AND AIMS We undertook this study to assess the effects of omega-3 polyunsaturated fatty acids (PUFAs) (administered at ≥2.7 g/day) for a minimum duration of 3 months on clinical outcomes in patients with rheumatoid arthritis (RA). METHODS The authors surveyed randomized controlled trials (RCTs) that examined the effects of omega-3 PUFAs on clinical outcomes in RA patients using Medline and the Cochrane Controlled Trials Register and by performing manual searches. Meta-analysis of RCTs was performed using fixed and random effects models. Outcomes are presented as standardized mean differences (SMD). RESULTS Ten RCTs involving 183 RA patients and 187 placebo-treated RA controls were included in this meta-analysis. The analysis showed that omega-3 PUFAs clearly reduced nonsteroidal anti-inflammatory drug (NSAID) consumption (SMD -0.518, 95% CI -0.915 to -0.121, p = 0.011) without between-study heterogeneity (I(2) = 0%). Tender joint count (SMD -0.214, 95% CI-0.489-0.062, p = 0.128), swollen joint count (SMD -0.170, 95% CI-0.454-0.114, p = 0.241), morning stiffness (SMD -0.224, 95% CI-0.955-0.212, p = 0.221), and physical function (SMD 0.264, 95% CI-0.232-0.724, p = 0.314) showed a trend to improve more in patients treated with omega-3 PUFAs than in placebo-treated controls, but they did not reach statistical significance. CONCLUSIONS This meta-analysis suggests that the use of omega-3 PUFAs at dosages >2.7 g/day for >3 months reduces NSAID consumption by RA patients. Further studies are needed to explore the clinical and NSAID-sparing effects of omega-3 PUFAs in RA.

Lipoprotein(a) and Lipids in Relation to Inflammation in Rheumatoid Arthritis

Abstract: The aim of this study is to evaluate whether lipoprotein(a) (Lp(a)) acts as the acute phase reactant and whether changes of lipids are related to inflammation in rheumatoid arthritis (RA). Lp(a) and lipids were measured after an overnight fast, before and after 14 days use of antiinflammatory agents and correlated with laboratory findings in 21 untreated RA patients and 19 healthy controls. Nine (42.3%) of 21 RA patients and 6 (31.6%) of 19 controls had high Lp(a) levels (> 30 mg/dl) and the Lp(a) level was higher in RA patients compared with controls (27.1 ± 5.3 vs 19.0 ± 4.2 mg/dl) without significant difference (p > 0.05). There was no significant correlation between ESR and Lp(a) and lipids in RA patients except for HDL cholesterol (r=–0.563, p = 0.008). After antiinflammatory agent use for 14 days, change in ESR (ESRsample1–ESRsample2) was significantly and negatively correlated to changes in total and HDL cholesterols in RA patients. In conclusion, although Lp(a) tended to be higher in RA, we could not find a distinct acute phase pattern of Lp(a). But changes in total and HDL cholesterols were negatively correlated with inflammation in RA. Our data support the phenomenon that dyslipoproteinemia observed in RA is associated with inflammation.

Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis.

Programmed cell death 1 (PDCD1 or PD1) polymorphisms have been inconsistently reported to be associated with systemic lupus erythematosus (SLE). The aim of this study was to explore whether the PDCD1 polymorphisms confer a susceptibility to SLE and lupus nephritis (LN). We conducted a meta-analysis on the association of PDCD1 polymorphisms with SLE in overall and specific ethnic populations. A total of 15 separate comparisons were included in this meta-analysis consisting of nine Europeans, two Latin Americans, two Africans, one Asian and one unknown participant. In subgroup analysis, the PD1.3A allele was significantly associated with SLE in Latin Americans (OR = 3.073, 95% CI = 1.416–6.461, P = 0.003), but not in patients of European and African decent. The PD1.3A allele was a risk factor for LN in European descendants (OR = 2.207, 95% CI = 1.488–3.467, P < 0.001). The PD1.5C allele was a risk factor for SLE in Europeans (OR = 1.297, 95% CI = 1.024–1.643, P = 0.031). In conclusion, this meta-analysis demonstrated an association of the PD1.3A allele with LN in European and SLE in Latin-American populations. Furthermore, the PD1.5C allele was associated with SLE susceptibility in Europeans.

Fcγ receptor IIB and IIIB polymorphisms and susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis:

The aim of this study was to explore whether polymorphisms of the Fcγ receptors (FcγRs) IIB T/I232 and FcγRIIIB NA1/NA2, confer susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN). The authors conducted a meta-analysis on associations between the FcγRIIB T/I232 and FcγRIIIB NA1/NA2 polymorphisms and SLE and LN susceptibility as determined using 1) allele contrast, 2) recessive, 3) dominant models and 4) contrast of homozygotes. A total of 16 separate comparisons were considered, consisting of 2887 SLE patients and 3105 controls. Meta-analysis of the FcγRIIB T/I232 polymorphism showed a significant association between the FcγRIIB T allele and the risk of developing SLE compared with the FcγRIIB I allele (OR = 1.207, 95% CI = 1.061–1.373, P = 0.004). In subjects of Asian descent, a significant association was observed between the FcγRIIB T allele and SLE (OR = 1.332, 95% CI 1.138–1.558, P < 0.001). However, in Europeans no such association was found. In contrast, no association was found between SLE or LN and the FcγRIIIB NA1/NA2 polymorphism in all subjects, or in European and Asian populations. This meta-analysis shows that the FcγRIIB T/I232 polymorphism confers susceptibility to SLE, especially in Asian-derived populations.

FcγRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients

The aim of this study was to determine the distribution of the FcgRIIa and FcgRIIIa 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 FcgRIIa 131 R/H and FcgRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgRIIa genotypes between the SLE and the controls (P=0.002 for R =R131 vs R/H131 and H/H131, OR 2.5 (95% CI 1.4–4.5), but not in FcgRIIIa genotypes. FcgRIIa-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% CI 1.03–1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgRIIa-R/R131 and in FcgRIIa-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 FcgRIIa/FcgRIIIa 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 FcgRIIa-R/R131 or R131-allele than male controls, but FcgRIIa or FcgRIIIa genotypes had no association with renal involvement in male SLE patients. FcgRIIa-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, anti-cardiolipin antibody (/) and anti-Ro antibody (/) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgRIIa or FcgRIIIa genotypes between female SLE and female controls, but FcgRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgRIIa-R/R131 among three FcgRIIa genotypes, and serositis in FcgRIIIa-F/F176 among three FcgRIIIa genotypes. FcgRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgRIIa-R131 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 FcgRIIa and FcgRIIIa showed somewhat different clinical associations between the genders.

Polymorphisms of the CTLA-4 exon 1 and promoter gene in systemic lupus erythematosus.

The objective of this study was to determine whether the polymorphisms of the CTLA-4 exon 1 (/49) and promoter (7318) are associated with susceptibility to systemic lupus erythematosus (SLE) and its clinical features. Polymerase chain reaction of genomic DNA-restriction fragment length polymorphism was used to determine genotypes of the CTLA-4 exon 1 (/49) and promoter (7318) in 80 SLE patients and 86 healthy control subjects. The genotype distribution of the CTLA-4 exon 1 (/49) differed between SLE patients and controls (w2 = 6.74, 2 degrees of freedom (d.f.), P = 0.03). The CTLA-4 AG genotype occurred more frequently in patients with SLE (46.3% vs 33.7% controls). On the other hand, the CTLA-4 AA genotype as well as the CTLA-4 GG genotype was less frequent among SLE patients than among control subjects (1.3% vs 9.3% and 52.5% vs 57.0%, respectively). The genotype distribution of the CTLA-4 promoter (-318) different between SLE patients and control subjects (CT, TT, CC; genotype 27.5%, 0%, 72.5% vs 16.3%, 4.7%, 79.1% controls respectively, w2 = 6.36 2 d.f., P = 0.04). However, Fishers exact or w2 P-values for each genotypes of the CTLA-4 exon l (+49) and promoter (-318) between SLE and control group < 0.05. Clinically, in the lupus patients there was no significant difference according to the CTLA-4 polymorphism. In conclusion, no correlation was found between CTLA-4 exon 1 (+49) and promoter (-318) polymorphisms and SLE in our study.

Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis

Aims This study aimed to assess all-cause and cause-specific standardized mortality ratios (SMRs) in patients with systemic lupus erythematosus (SLE). Methods We surveyed studies examining all-cause and/or cause-specific SMR in patients with SLE compared to the general population using PUBMED, EMBASE and Cochrane databases and manual searches. We performed a meta-analysis of all-cause, sex-specific, ethnicity-specific, and cause-specific SMRs in SLE patients. Results Fifteen reports including 26,101 patients with SLE with 4640 deaths met the inclusion criteria. Compared to the general population, all-cause SMR was significantly increased 2.6-fold in patients with SLE (SMR 2.663, 95% CI 2.090–3.393, p < 1.0 × 10−8). Stratification by ethnicity showed that all-cause SMR was 2.721 (95% CI 1.867–3.966, p = 1.9 × 10−6) in Caucasians and 2.587 (95% CI 1.475–4.535, p = 0.001) in Asians. Sex-specific meta-analysis revealed that all-cause SMR was 3.141 (95% CI 2.351–4.198, p < 1.0 × 10−8) for women and 3.516 (95% CI 2.928–4.221, p < 1.0 × 10−8) for men. The risk of mortality was significantly increased for mortality due to renal disease (SMR 4.689, 95% CI 2.357–9.330, p = 1.10 × 10−5), cardiovascular disease (CVD) (SMR 2.253, 95% CI 1.304–3.892, p = 0.004), and infection (SMR 4.980, 95% CI 3.876–6.398, p < 1.0 × 10−8), although there was no significant increase in SMR for mortality due to cancer (SMR 1.163, 95% CI 0.572–2.363, p = 0.676). Conclusions Patients with SLE had higher rates of death from all causes, regardless of sex, ethnicity, renal disease, CVD or infection. However, the risk of death due to malignancy was not increased.

The association between interleukin-6 polymorphisms and systemic lupus erythematosus: a meta-analysis.

The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter -174 G/C and -572 G/C polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between the IL-6 polymorphisms and SLE using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) the additive model. A total of 11 studies were considered in this study, and ethnicity-specific meta-analysis was performed on European and Asian populations. Meta-analysis of the IL-6 -174 G/C polymorphism showed an association between SLE and the IL-6 -174 G allele in all study subjects (odds ratio (OR) = 1.344, 95% confidence interval (CI) = 1.052–1.718, p = 0.018). Furthermore, stratification by ethnicity indicated an association between the IL-6 -174 G allele and SLE in Europeans (OR = 1.264, 95% CI = 1.037–1.541, p = 0.020). Meta-analysis of the IL-6 -572 G/C polymorphism revealed that an association was found between SLE and the IL-6 -572 G/C polymorphism using the recessive model, but ethnicity-specific meta-analysis revealed no association between SLE and the IL-6 -572 G/C polymorphism in Asians. In conclusion, this meta-analysis demonstrates that the IL-6 -174 G/C polymorphism may confer susceptibility to SLE in Europeans, but that the IL-6 -572 G/C polymorphism is not associated with susceptibility to SLE in Asians.

Platelet‐Derived Growth Factor‐AA Increases IL‐1β and IL‐8 Expression and Activates NF‐κB in Rheumatoid Fibroblast‐Like Synoviocytes

The effect of platelet‐derived growth factor (PDGF)‐AA on the inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA) was investigated using cultured fibroblast‐like synoviocytes (FLS) obtained from RA and OA patients as well as control nonarthritic (NA) individuals. PDGF‐AA increased the mRNA and protein expressions of proinflammatory cytokines, interleukin (IL)‐1β and IL‐8 in RA FLS. Biological activity of IL‐1 in the culture supernatant of RA FLS was also increased by PDGF‐AA stimulation. Interestingly, PDGF‐AA synergized with tumour necrosis factor (TNF)‐α to upregulate the protein expressions of IL‐1β and IL‐8. PDGF‐induced enhancement of the IL‐1β and IL‐8 mRNA expressions was also observed in OA FLS. However, the expression of these proinflammatory cytokines in NA FLS did not change by PDGF treatment, suggesting that the inflammatory condition might have modified the biological effects of PDGF. In accordance with the enhanced expression of inflammatory cytokines, the activity of nuclear factor κB was also induced in response to PDGF‐AA in RA FLS. These results suggest that PDGF‐AA plays an important role in the progression of RA inflammation, and inhibiting PDGF activity may be useful for the effective RA treatment.