Association between shortened telomere length and systemic lupus erythematosus: a meta-analysis.

Objective We aimed to evaluate the relationship between telomere length and systemic lupus erythematosus (SLE). Methods PUBMED and EMBASE databases were searched; meta-analyses were performed comparing telomere length in SLE patients and healthy controls, and on SLE patients in subgroups based on ethnicity, sample type, assay method and data type. Results Eight studies including 472 SLE patients and 365 controls were ultimately selected which showed that telomere length was significantly shorter in the SLE group than in the control group (standardized mean difference (SMD) = -0.835, 95% confidence interval (CI) = -1.291 to -0.380, p = 3.3 × 10-4). Stratification by ethnicity showed significantly shortened telomere length in the SLE group in Caucasian, Asian and mixed populations (SMD = -0.455, 95% CI = -0.763 to -0.147, p = 0.004; SMD = -0.887, 95% CI = -1.261 to -0.513, p = 3.4 × 10-4; SMD = -0.535, 95% CI = -0.923 to -0.147, p = 0.007; respectively). Furthermore, telomere length was significantly shorter in the SLE group than in the control group in whole blood and peripheral blood mononuclear cell groups (SMD = -0.361, 95% CI = -0.553 to -0.169, p = 2.3 × 10-4; SMD = -1.546, 95% CI = -2.583 to -0.510, p = 0.003; respectively); a similar trend was observed in leukocyte groups (SMD = -0.699, 95% CI = -1.511 to -0.114, p = 0.092). Meta-analyses based on assay method or data type revealed similar associations. Conclusions Our meta-analysis demonstrated that telomere length was significantly shorter in patients with SLE, regardless of ethnicity, sample type or assay method evaluated.

Associations between SLC2A9 polymorphisms and gout susceptibility : A meta-analysis.

OBJECTIVE: The aim of this study was to determine whether polymorphisms in solute carrier family 2 and facilitated glucose transporter member 9 (SLC2A9) are associated with susceptibility to gout. METHODS: A meta-analysis was conducted on associations between the rs12510549, rs16890979, and rs1014290 polymorphisms of SLC2A9 and gout susceptibility using fixed and random effects models. RESULTS: Eleven comparative studies comprising 1,472 patients and 3,269 controls from Caucasian and Asian populations were included in this meta-analysis. The meta-analysis identified a significant negative association between gout and allele 2 (minor) of the rs12510549 polymorphism in the overall population (OR = 0.641, 95 % CI = 0.540-0.761, P = 4.1 × 10-7). Stratification by ethnicity identified a significant negative association between this polymorphism and gout in Caucasians (OR = 0.647, 95 % CI = 0.542-0.771, P = 1.2 × 10-6) but not in Asians (OR = 0.515, 95 % CI = 0.214-1.236, P = 0.137). The meta-analysis showed a significant negative association between gout and allele 2 of the rs16890979 polymorphism in all study subjects (OR = 0.229, 95 % CI = 0.084-0.628, P = 0.004). Stratification by ethnicity identified a significant negative association between this polymorphism and gout in Caucasians (OR = 0.469, 95 % CI = 0.317-0.695, P = 1.6 × 10-6) and in Asians (OR = 0.192, 95 % CI = 0.072-0.513, P = 0.001). A significant negative association was found between allele 2 of the rs1014290 polymorphism and gout susceptibility in Asians (OR = 0.597, 95 % CI = 0.478-0.746, P = 5.4 × 10-6) but not in Caucasians (OR = 0.778, 95 % CI = 0.595-1.043, P = 0.095). CONCLUSIONS: This meta-analysis shows that the rs12510549, rs16890979, and rs1014290 polymorphisms of SLC2A9 protect against the development of gout in Caucasians and/or Asians.

Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update.

OBJECTIVE: The aim of this study was to determine whether polymorphisms of the Toll-like receptor (TLR) genes are associated with susceptibility to systemic lupus erythematosus (SLE). METHODS: The authors conducted a meta-analysis of the relationship between 12 TLR polymorphisms and SLE susceptibility. RESULTS: In total, 26 studies that involved 11,984 patients and 14,572 controls were included in the meta-analysis. The meta-analysis showed no association between the two alleles of the rs352140, rs5743836, and rs352139 polymorphisms of TLR9 and SLE, but indicated an association between the two alleles of the rs187084 polymorphism (TLR9) and SLE in the overall population (OR = 0.869, 95% CI = 0.762-0.992, P = 0.038). No association was detected between rs3764880 (TLR8) and SLE; however, our meta-analysis indicated an association between rs3764879 (TLR8) and SLE in Caucasians (OR = 1.414, 95% CI = 1.139-1.756, P = 0.002). An association between rs179008 (TLR7) and SLE was found in the African (OR = 0.430, 95% CI = 0.238-0.775, P = 0.005), but not in the Caucasian population (OR = 1.206, 95% CI = 0.932-1.614, P = 0.145). Furthermore, our meta-analysis indicated a significant association between rs3853839 (TLR7) and SLE in the Asian population (OR = 0.773, 95% CI = 0.735, 0.823, P < 1.0 × 10(-9)). No associations were found between rs5744168 (TLR5), rs4986791 (TLR4), rs4986790 (TLR4), and rs3775291 (TLR3) polymorphisms and SLE susceptibility. CONCLUSIONS: Our meta-analysis suggests that TLR7, TLR8, and TLR9 polymorphisms are associated with the development of SLE in Caucasian, Asian, and African populations.

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.

Diagnostic accuracy of 18F-FDG PET or PET/CT for large vessel vasculitis : A meta-analysis.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) or positron-emission tomography/computed tomography (PET/CT) for patients with large vessel vasculitis. METHODS: Based on a search in the PubMed, Embase, and Cochrane Library databases, a meta-analysis was performed on the diagnostic accuracy of 18F-FDG PET or PET/CT in patients with large vessel vasculitis. RESULTS: A total of eight studies involving 400 subjects (170 vasculitis patients and 230 controls) were selected for meta-analysis. The pooled sensitivity and specificity of 18F-FDG PET or PET/CT were 75.9 % (95 % confidence interval, CI 68.7-82.1) and 93.0 % (95 % CI 88.9-96.0), respectively. The positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 7.267 (95 % CI 3.707-14.24), 0.303 (95 % CI 0.229-0.400), and 32.04 (95 % CI 13.08-78.45), respectively. The area under the curve (AUC) was 0.863 and the Q* index 0.794, indicating good diagnostic accuracy. There was no evidence of a threshold effect (Spearman's correlation coefficient = 0.120, p = 0.776). When the data were limited to giant cell arteritis (GCA), the pooled sensitivity and specificity of 18F-FDG PET or PET/CT were 83.3 % (95 % CI 72.1-91.4) and 89.6 % (95 % CI 79.7-95.7), respectively; AUC was 0.884, and the Q* index 0.815, indicating modest accuracy with a small increase in diagnostic accuracy. CONCLUSION: This meta-analysis of published studies demonstrates that 18F-FDG PET or PET/CT has good diagnostic accuracy for large vessel vasculitis and plays an important role in the diagnosis of this condition.

Associations between the functional CD40 rs4810485 G/T polymorphism and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis.

OBJECTIVE: The aim of this study was to determine whether the functional CD40 rs4810485 G/T polymorphism is associated with susceptibility to rheumatoid arthritis (RA) or with susceptibility to systemic lupus erythematosus (SLE). METHODS: A series of meta-analyses were conducted to test for association between the CD40 rs4810485 G/T polymorphism and RA or SLE. RESULTS: A total of 21 comparisons involving 15,095 patients and 27,050 controls for RA, and 1353 patients and 2342 controls for SLE were considered. Meta-analysis showed a significant association between the CD40 rs4810485 T allele and RA in all subjects (odds ratio (OR) 0.890, 95% confidence interval (CI) 0.846-0.936, p = 5.5 × 10(-7)). After stratification by ethnicity, the CD40 T allele was found to be significantly associated with RA in Europeans (OR 0.879, 95% CI 0.848-0.901, p = 3.0 × 10(-9)). A similar pattern of association was observed between the CD40 T allele and RA when the analysis was performed using the recessive, dominant, and additive models. Meta-analysis also showed a significant association between the CD40 polymorphism and SLE in Europeans (OR for the T allele 0.715, 95% CI 0.641-0.832, p = 1.4 × 10(-6)). CONCLUSIONS: Our meta-analyses confirm that the CD40 rs4810485 G/T polymorphism is associated with susceptibility to RA and SLE in Europeans.

The association between susceptibility to inflammatory arthritis and miR-146a, miR-499 and IRAK1 polymorphisms. A meta-analysis.

OBJECTIVE: The aim of this study was to explore whether polymorphisms in miR-146a, miR-499 and IRAK1 are associated with susceptibility to inflammatory arthritis. METHODS: Manual searches performed in the MEDLINE and EMBASE databases were used to identify published articles in which the roles of microRNA (miRNA) and IRAK1 polymorphisms in inflammatory arthritis were determined. A meta-analysis was conducted to investigate associations of the miR-146a rs2910164, miR-499 rs3746444, IRAK1 rs3027898 and IRAK1 rs1059703 polymorphisms with susceptibility to inflammatory arthritis. RESULTS: Nine studies containing 1224 patients and 1841 controls were included in the meta-analysis. The meta-analysis revealed no association between inflammatory arthritis and the rs2910164 C allele of miR-146a (odds ratio, OR = 0.974; 95 % confidence interval, CI = 0.810-1.091; p = 0.650). Stratification by ethnicity or disease type revealed no association between the miR-146a C allele and inflammatory arthritis in European, Middle Eastern or Asian patients with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA). However, the meta-analysis revealed an overall association between RA and the miR-499 rs374644 C (OR = 1.123, 95 % CI = 1.019-2.586, p = 0.041); stratification by ethnicity revealed a particular association in Middle Eastern populations (OR = 1.943, 95 % CI = 1.508-2.504, p = 2.7 × 10(-8)). The meta-analysis of IRAK1 polymorphisms revealed an association between inflammatory arthritis and the rs3027898 CC genotype (OR = 2.602, 95 % CI = 1.387-4.879, p = 0.003). An analysis using the homozygote contrast showed the same pattern for the rs3027898 CC genotype (OR = 2.472, 95 % CI = 1.300-4.700, p = 0.006). No association between inflammatory arthritis and the rs1059703 polymorphism was found. CONCLUSION: This meta-analysis suggests that the miR-499 rs374644 and IRAKI rs3027898 polymorphisms are associated with susceptibility to inflammatory arthritis.

Meta-analysis of SLC22A4 and RUNX1 polymorphisms : Associations with rheumatoid arthritis susceptibility.

OBJECTIVE: The aim in this study was to determine whether solute carrier family 22, member 4 (SLC22A4), and runt-related transcription factor 1 (RUNX1) polymorphisms are associated with susceptibility to rheumatoid arthritis (RA) in populations of different ethnicities. METHODS: We conducted a literature search using the MEDLINE and EMBASE, and performed a meta-analysis using a fixed or random effects model. RESULTS: A total of 26 comparative studies from 14 articles met the study inclusion criteria. Studies on the SLC22A4 polymorphism involved 12,458 RA patients and 9283 controls, and studies on the RUNX1 polymorphism involved 3958 RA patients and 3773 controls. The meta-analysis showed no association between the 22 + 21 genotype of the SLC22A4 F1 and RA in overall group [odds ratio (OR) 1.074, 95 % confidence interval (CI) 0.952-1.212, p = 0.245]. After stratification by ethnicity, the meta-analysis indicated that the 22 + 21 genotype of the SLC22A4 F1 was associated significantly with RA in the East Asian population, but not in the European population (OR 1.124, 95 % CI 1.018-1.240, p = 0.021; OR 0.981, 95 % CI 0.773-1.243, p = 0.871). CONCLUSION: This meta-analysis demonstrates that the SLC22A4 F1 polymorphism is associated with susceptibility to RA in East Asians, but not in Europeans.

Meta-analysis of functional MBL polymorphisms. Associations with rheumatoid arthritis and primary Sjögren's syndrome.

OBJECTIVE: The aim of this study was to determine whether functional mannose-binding lectin gene (MBL) polymorphisms are associated with the susceptibility to rheumatoid arthritis (RA) or primary Sjögren's syndrome (pSS). METHODS: A meta-analysis was conducted to investigate the potential association of RA or pSS with MBL polymorphisms, including the codon 54 (allele B), codon 57 (allele C), and codon 52 (allele D) variants of exon 1, and the - 550 (allele L) and - 221 (allele X) promoter variants. RESULTS: A total of 12 comparative studies, including eight RA (1623 patients and 1671 controls) and four pSS (280 patients and 516 controls) studies, were included in the meta-analysis. The meta-analysis revealed no association between the MBL B allele and RA in the overall study population (odds ratio [OR] 0.991, 95 % confidence interval [CI] 0.726-1.355, p = 0.957). However, the meta-analysis showed significant associations between the MBL D, H, and X alleles and RA in the overall population (OR 1.708, 95 % CI 1.077-2.707, p = 0.023; OR 1.936, 95 % CI 1.218-3.078, p = 0.005; OR 1.582, 95 % CI 1.216-2.057, p = 0.001, respectively). An association was found between the MBL B allele and pSS in the overall study population (OR 0.691, 95 % CI 0.541-0.917, p = 0.010). Stratification by ethnicity indicated a trend toward an association between the B allele and pSS in European populations, but no association in Asian populations (OR 0.689, 95 % CI 0.465-1.021, p = 0.063; OR 0.896, 95 % CI 0.311-2.562, p = 0.838, respectively). CONCLUSION: This meta-analysis demonstrated an association between the MBL D, L, and X alleles and the risk of RA. It also demonstrated an association between the MBL B allele and the susceptibility to pSS, suggesting a protective role of the MBL B allele against the development of pSS.

Association of miR-146a polymorphisms with systemic lupus erythematosus: a meta-analysis.

OBJECTIVE: miR-146a may play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Several studies have examined the association of miR-146a gene polymorphisms with SLE, but these studies have shown inconclusive results. To verify whether an association exists, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed and EMBASE before August 2013. METHODS: Meta-analyses were performed on three published studies of the association between the miR-146a rs57095329 SNP and SLE for 5934 patients with SLE and 5591 controls as well as on four published studies of the association between miR-146a rs2910164 SNP and SLE for 2505 patients with SLE and 3248 controls. In addition, two studies involving 1920 SLE patients and 2472 controls were included in a meta-analysis of the association between miR-146a rs2431697 SNP and SLE. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were pooled by the inverse of their variance. RESULTS: Of three SNPs analyzed, rs57095329 (OR 1.25, 95%CI 1.17-1.35) and rs2431697 (OR 1.24, 95% CI 1.13-1.37) were genetically associated with SLE. However, no significant association was found between rs2910164 and SLE susceptibility (OR 0.98, 95% CI 0.90-1.06). There was no significant heterogeneity across studies and no evidence of publication bias. CONCLUSIONS: The results of our meta-analysis suggest that miR-146a rs57095329 and rs2431697 SNPs are associated with SLE susceptibility. In addition, our results suggest that there is an ethnical difference between Asian and European populations in the association between miR-146a SNPs and SLE susceptibility.

Long PCR-RFLP of 16S-ITS-23S rRNA genes: a high-resolution molecular tool for bacterial genotyping.

AIMS: To perform a systematic evaluation of the applicability, validity and reliability of the long PCR-RFLP of 16S-ITS-23S rRNA genes for bacterial genotyping using both sequences retrieved from public genome databases and the experimental data obtained on bacterial cultures. METHODS AND RESULTS: 3301 Full-length sequences of 16S-ITS-23S rRNA genes were retrieved from 885 published bacterial genomes. Copy numbers of the whole set of 16S-ITS-23S rRNA genes per genome ranged from 1 (n = 161) to 14 (n = 4) with an average of 3.71. Their length varied greatly, from 4319 to 6568 bp with an average of 4952 bp. Computer-simulated RFLP analyses of the 16S-ITS-23S fragments flanked by the conserved primers 27F and 2241R suggested MspI, RsaI, HhaI and TaqI as the most appropriate enzymes for long PCR-RFLP analysis of the 16S-ITS-23S sequence. MspI was used to screen over 900 bacterial cultures isolated from the Huguangyan Maar Lake in southern China. An experimental sequencing of 16S rRNA genes of the isolates possessing a unique RFLP band pattern proved the broad applicability and high resolution of this approach. CONCLUSIONS: These results indicate that long PCR-RFLP of 16S-ITS-23S rRNA genes is a potentially universal and reliable bacterial genotyping tool with a high resolution. SIGNIFICANCE AND IMPACT OF THE STUDY: The methodology of long PCR-RFLP of 16S-ITS-23S rRNA genes will facilitate the exploration and tracing of cultivable microbial diversity in natural environments.

Associations between the p53 codon 72 polymorphisms and susceptibility to systemic lupus erythematosus and rheumatoid arthritis: a meta-analysis.

OBJECTIVE: The aim of this study was to determine whether the p53 codon 72 polymorphism confers susceptibility to systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). METHODS: A meta-analysis was conducted on the associations between the p53 codon 72 polymorphism and SLE or RA using: 1) allele contrast; 2) the recessive model; 3) the dominant model; and 4) the additive model. RESULTS: A total of 10 studies, that is, 6 SLE and 4 RA studies, involving 1578 patients and 3138 controls were considered in the meta-analysis. Meta-analysis of the p53 codon 72 polymorphism showed no association between patients and the C allele (odds ratio (OR) = 0.834, 95% confidence interval (CI) = 0.599-1.161, p = 0.282), or between SLE and the p53 C allele (OR = 0.998, 95% CI = 0.765-1.302, p = 0.989). However, stratification by ethnicity showed an association between the p53 C allele and SLE in Asians (OR = 1.410, 95% CI = 1.044-1.906, p = 0.025), but not in Europeans (OR = 0.871, 95% CI = 0.625-1.214, p = 0.415). Furthermore, an association was found between the polymorphism and SLE in Asians using recessive and additive models. However, no association was found between RA and the p53 codon 72 polymorphism in all study subjects or in Europeans. CONCLUSIONS: This meta-analysis demonstrates that the p53 codon 72 polymorphism may confer susceptibility to SLE in Asians, but not in Europeans.

Association between the valine/leucine247 polymorphism of ß2-glycoprotein I and susceptibility to anti-phospholipid syndrome: a meta-analysis.

OBJECTIVE: The objective of this paper is to explore whether the valine/leucine(247) (Val/Leu(247)) polymorphism of ß(2)-glycoprotein I (ß(2)GPI) confers susceptibility to anti-phospholipid syndrome (APS) and thrombosis and predicts positivity for anti-ß(2)GPI antibodies. METHODS: A meta-analysis was conducted on the associations between the ß(2)GPI Val/Leu(247) polymorphism and susceptibility to APS and thrombosis and positivity for anti-ß(2)GPI. RESULTS: A total of 1507 patients with APS and 1450 controls in 12 comparative studies were included in this meta-analysis. Meta-analysis of the ß(2)GPI Val/Leu(247) polymorphism showed significant associations between the ß(2)GPI Val allele and APS, thrombosis, and anti-ß(2)GPI positivity (odds ratio (OR) 1.316, 95% confidence interval (CI) 1.068-1.621, p = 0.010; OR 1.908, 95% CI 1.195-3.046, p = 0.007; OR 1.630, 95% CI 1.018-2.609, p = 0.042, respectively). A direct comparison between anti-ß(2)GPI-positive and -negative patients revealed that the frequency of the Val allele was significantly higher in anti-ß(2)GPI-positive patents (OR 1.514, 95% CI 1.017-1.253, p = 0.041). Furthermore, a direct comparison between thrombosis-positive and -negative patients also indicated that the Val/Val + Val/Leu and the Val/Val vs. Leu/Leu genotypes of the ß(2)GPI polymorphism were significantly elevated in patients with thrombosis (OR 2.817, 95% CI 1.200-6.610, p = 0.017; OR 3.312, 95% CI 1.338-8.200, p = 0.010, respectively). CONCLUSION: This meta-analysis shows that the ß(2)GPI Val/Leu(247) polymorphism is associated with susceptibility to APS and thrombosis and with anti-ß(2)GPI positivity.

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.

Tacrolimus for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this study was to assess the efficacy and safety of tacrolimus in patients with active rheumatoid arthritis (RA). METHODS: We surveyed randomized controlled trials (RCTs) and open-label studies that examined the efficacy and toxicity of tacrolimus in disease-modifying anti-rheumatic drug (DMARD)--and methotrexate (MTX)-resistant or -intolerant patients with active RA patients using Medline, the Cochrane Controlled Trials Register, and by performing manual searches. Meta-analysis of RCTs was performed to determine treatment efficacy and safety outcomes. The results are presented as risk ratios (RRs), weighted mean differences (WMDs), or standardized mean differences (SMDs). Open-label studies were included in the systematic review. RESULTS: The four RCTs included 1014 DMARD-resistant or -intolerant patients with DMARD-resistant or -intolerant RA. Median follow-up duration was 6 (range 4-6) months. American College of Rheumatology 20, 50, and 70% (ACR20, ACR50, and ACR70) response rates were significantly higher in the tacrolimus 3 mg/day group (n = 390) than in the controls (n = 402) [primary efficacy outcome, ACR50; risk ratio (RR) 2.583, 95% confidence interval (CI) 1.095-6.092, p = 0.030], and efficacies in the tacrolimus 1.5-2 mg/day group showed a similar pattern. Patients treated with tacrolimus withdrew from treatment because of adverse events (n = 222) (primary safety outcome, withdrawals due to adverse events; RR 1.475, 95% CI 0.895-2.187, p = 0.053) more frequently than controls (n = 231), although this was not significant. All four open-label studies found that tacrolimus was safe, well-tolerated, and provided clinical benefits. CONCLUSIONS: Tacrolimus, at dosages of 1.5-3 mg/day, was found to be effective in DMARD-resistant or -intolerant patients with active RA.

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.

Fcgamma 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 Fcgamma receptors (FcgammaRs) IIB T/I232 and FcgammaRIIIB NA1/NA2, confer susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN). The authors conducted a meta-analysis on associations between the FcgammaRIIB T/I232 and FcgammaRIIIB 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 FcgammaRIIB T/I232 polymorphism showed a significant association between the FcgammaRIIB T allele and the risk of developing SLE compared with the FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIIB NA1/NA2 polymorphism in all subjects, or in European and Asian populations. This meta-analysis shows that the FcgammaRIIB T/I232 polymorphism confers susceptibility to SLE, especially in Asian-derived populations.

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.

The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis.

OBJECTIVE: To assess whether combined evidence shows the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) C1858T polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases. METHODS: We surveyed studies on the PTPN22 C1858T polymorphism and autoimmune diseases using comprehensive Medline search and review of the references. Meta-analysis was performed for genotypes T/T (recessive effect), T/T + C/T (dominant effect) and T-allele in random effects models. RESULTS: Twenty-nine studies with 43 comparisons including 13 rheumatoid arthritis (RA), six systemic lupus erythematosus (SLE), six type-1 DM (T1D), three Grave's disease (GD), four inflammatory bowel diseases (IBD), three juvenile idiopathic arthritis (JIA), two psoriasis, two multiple sclerosis, two Addison's disease and two Celiac disease were available for the meta-analysis. The overall odds ratios (ORS) for T-allele, T/T and T/T + C/T genotypes were significantly increased in RA, SLE, GD and T1D (OR for T-allele = 1.58, 1.49, 1.85, 1.61, respectively, P < 0.00001). This meta-analysis showed the association between the T-allele and the T/T genotype and JIA (OR = 1.34, P = 0.03; OR = 1.97, P = 0.02) but did not reveal the association between the PTPN22 C1858T polymorphism and IBD, psoriasis, multiple sclerosis, Addison's disease and Celiac disease. CONCLUSION: This meta-analysis demonstrates that the PTPN22 1858T allele confers susceptibility to RA, SLE, GD, T1D and JIA, supporting evidence of association of the PTPN22 gene with subgroup of autoimmune diseases.