Association between plasminogen activator inhibitor­1 (PAI-1) 4G/5G polymorphism and circulating PAI-1 level in systemic lupus erythematosus and rheumatoid arthritis : A meta-analysis.

OBJECTIVE: This study systemically reviewed the evidence regarding the association between plasminogen activator inhibitor­1 (PAI­1) 4G/5G polymorphism and susceptibility to systemic lupus erythematous (SLE)/lupus nephritis (LN) and rheumatoid arthritis (RA) and the relationship between circulating PAI­1 levels and SLE/LN and RA. METHODS: We conducted a meta-analysis on the association between the PAI­1 4G/5G polymorphism and SLE/LN or RA risk and serum/plasma PAI­1 levels in patients with SLE/LN and RA and healthy controls. RESULTS: Nine articles including 657 patients with SLE and 668 controls and 567 patients with RA and 772 controls were included. No association was revealed between SLE and PAI­1 4G allele in all study subjects (odds ratio [OR] = 0.944, 95% confidence interval [CI] = 0.808-1.102, p = 0.463). Ethnicity-based stratification showed no association between the PAI­1 4G allele and SLE among Europeans and Asians. No association was detected between LN and RA and the PAI­1 4G allele (OR = 0.886, 95% CI = 0.713-1.102, p = 0.278; OR = 0.8736, 95% CI = 0.747-1.020, p = 0.088, respectively) or between SLE/LN and RA and the PAI­1 4G/5G polymorphism using the recessive and dominant models and homozygote contrast. The circulating PAI­1 level was significantly higher in the SLE group than in the control group (standardized mean difference [SMD] = 0.337, 95% CI = 0.057-0.619, p = 0.019). However, serum/plasma PAI­1 level showed no significant difference between RA and control group (SMD = 0.333, 95% CI = -0.6989-1.35, p = 0.527). CONCLUSIONS: There was no association between the PAI­1 4G/5G polymorphism and SLE/LN and RA development and significantly higher levels of circulating PAI­1 were observed in patients with SLE but not in those with RA.

Causal association between periodontitis and risk of rheumatoid arthritis and systemic lupus erythematosus: a Mendelian randomization.

OBJECTIVE: To investigate whether periodontitis is causally associated with risk of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: We performed two-sample Mendelian randomization (MR) analysis using the inverse variance-weighted (IVW), weighted median, and MR-Egger regression methods on publicly available summary statistics datasets using a periodontitis genome-wide association study (GWAS) as an exposure and RA and SLE GWASs on individuals of European descent as outcomes. RESULTS: We selected 7 or 20 single-nucleotide polymorphisms from a periodontitis GWAS as instrumental variables for RA or SLE. The IVW method results support a causal association between periodontitis and RA (beta = 0.168, SE = 0.080, p = 0.035) and SLE (beta = 0.0001, SE = 0.0001, p = 0.046) risk; however, the weighted median approach did not indicate a significant causal association. MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the RA (intercept = -0.115, p = 0.078) or SLE results (intercept = 4.68E-05, p = 0.394); no significant causal association was found between periodontitis and RA and SLE. The MR estimates from the IVW, weighted median, and MR-Egger regression analyses were not consistent. CONCLUSION: Only the results of MR analysis by the IVW method indicated that periodontitis is likely causally associated with an increased risk of RA and SLE incidence. Our MR showed weak causal association between periodontitis and RA or SLE. These findings may assist in elucidating the underlying mechanisms of the effects of periodontitis on RA and SLE incidence.

Association between the interferon regulatory factor 5 rs2004640 functional polymorphism and systemic lupus erythematosus: an updated meta-analysis.

OBJECTIVE: The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations. METHODS: A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population. RESULTS: Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370-1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs. CONCLUSIONS: This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.

Associations between paraoxonase-1 and systemic lupus erythematosus.

OBJECTIVE: The objective of this analysis was to explore associations between paraoxonase-1 levels, gene polymorphisms and systemic lupus erythematosus. METHODS: Meta-analyses of paraoxonase-1 levels and Q192R and L55M and polymorphisms in systemic lupus erythematosus were conducted. RESULTS: Nine articles were incorporated in our meta-analysis, which uncovered that the paraoxonase-1 level was decreased in systemic lupus erythematosus compared to control (standard mean difference = -1.626, 95% confidence interval = -2.829--0.424, p = 0.008). Ethnicity-specific meta-analysis demonstrated a relation tendency between decreased paraoxonase-1 activity and lupus in Europeans (standard mean difference = -1.236, 95% confidence interval = -2.634-0.163, p = 0.083). Paraoxonase-1 activity was reduced in systemic lupus erythematosus in a single Arab and African population. Decreased paraoxonase-1 activity was found in a small sample of systemic lupus erythematosus patients (standard mean difference = -1.642, 95% confidence interval = -3.076--0.247, p = 0.021). Ethnicity-specific analysis indicated a relationship between the paraoxonase-1 55 M allele in the Arab systemic lupus erythematosus population. However, a lack of association with systemic lupus erythematosus and the paraoxonase-1 192 R allele was observed. CONCLUSIONS: Meta-analyses revealed reduced paraoxonase-1 activity in patients with systemic lupus erythematosus and found possible associations between systemic lupus erythematosus and paraoxonase-1 L55M polymorphism in a specific ethnic group.

Association between CD40 polymorphisms and systemic lupus erythematosus and correlation between soluble CD40 and CD40 ligand levels in the disease: a meta-analysis.

OBJECTIVE: The aim of this study was to systematically review evidence regarding the association between CD40 polymorphisms and systemic lupus erythematosus and between soluble CD40 (sCD40) and CD40 ligand (sCD40L) levels and systemic lupus erythematosus. METHODS: We performed a meta-analysis on the association between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and systemic lupus erythematosus risk and sCD40/sCD40L levels in patients with systemic lupus erythematosus and controls. RESULTS: Fourteen studies were included. Ethnicity-specific meta-analysis indicated a significant association between the T allele of CD40 rs4810485 polymorphism and systemic lupus erythematosus in Europeans (odds ratio = 0.715, 95% confidence interval = 0.641-0.832, p < 0.001) and a trend toward an association between the T allele and systemic lupus erythematosus in Asians (odds ratio = 1.255, 95% confidence interval = 0.978-1.810, p = 0.074). Furthermore, a significant association was reported between systemic lupus erythematosus and the C allele of CD40 rs1883832 polymorphism (odds ratio = 1.235, 95% confidence interval = 1.087-1.405, p = 0.001) and A allele of CD40 rs3765456 polymorphism and systemic lupus erythematosus in Asians (odds ratio = 1.184, 95% confidence interval = 1.040-1.348, p = 0.011). sCD40 and sCD40L levels were significantly higher in SLE than in controls (standardized mean difference = 1.564, 95% confidence interval = 0.256-2.872, p = 0.019 and standardized mean difference = 1.499, 95% confidence interval = 1.031-1.967, p < 0.001, respectively). Stratification based on ethnicity revealed higher sCD40L levels in the systemic lupus erythematosus group among European, Asian, North American, and Arab populations. CONCLUSIONS: Our meta-analyses found associations between CD40 rs4810495, rs1883832, and rs376545 polymorphisms and systemic lupus erythematosus susceptibility and significantly higher sCD40 and sCD40L levels in patients with systemic lupus erythematosus than in controls.

Alcohol intake and risk of systemic lupus erythematosus: a Mendelian randomization study.

OBJECTIVES: This study aimed to examine whether alcohol intake is causally associated with systemic lupus erythematosus (SLE). METHODS: We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and an SLE GWAS consisting of 1311 SLE and 1783 control subjects of European descent as the outcome. RESULTS: We selected 20 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables to improve inference. The IVW method found no evidence to support a causal association between alcohol intake and SLE (beta = -0.413, SE = 0.513, p = 0.421). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.031, p = 0.582). The MR-Egger analysis found no causal association between alcohol intake and SLE (beta = -1.494, SE = 1.996, p = 0.464). Likewise, the weighted median approach also did not provide evidence of a causal association between alcohol intake and SLE (beta = -0.538, SE = 0.574, p = 0.349). The MR estimates determined using the IVW, weighted median, and MR-Egger regression methods were consistent and results from a "leave-one-out" analysis demonstrated that no single SNP was driving the IVW point estimate. CONCLUSIONS: The results of MR analysis do not support a causal inverse association between alcohol intake and SLE occurrence.

Causal association between rheumatoid arthritis and a decreased risk of Alzheimer's disease : A Mendelian randomization study.

OBJECTIVE: This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with Alzheimer's disease (AD). METHODS: We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics datasets from three-stage trans-ethnic genome-wide association studies (GWAS) meta-analyses of 29,880 RA cases and 73,758 controls as exposures and a meta-analysis of 4 GWAS datasets consisting of 17,008 AD cases and 37,154 controls of European descent as outcomes. RESULTS: We selected 80 single nucleotide polymorphisms (SNPs) from GWAS data on RA as instrumental variables (IVs), 60 of which were associated with RA on a genome-wide significance level. The IVW method showed evidence to support an inverse causal association between RA and AD (ß = -0.039, standard error [SE] = 0.017, P = 0.021). MR-Egger regression revealed that directional pleiotropy was unlikely to be a source of bias in the results (intercept = 0.002; P = 0.649). The MR-Egger analysis showed no causal association between RA and AD (ß = -0.050, SE = 0.030, P = 0.096). However, the weighted median approach showed that RA and AD were causally linked (ß = -0.078, SE = 0.024, P = 0.001). The funnel plot did not show heterogeneity between IV estimates based on the individual variants. CONCLUSIONS: The MR analysis supports that RA was causally associated with a reduced risk of AD.

Comparative efficacy and safety of low-dose and high-dose cyclophosphamide as induction therapy for lupus nephritis: a network meta-analysis.

AIM: To assess the relative efficacy and safety of low-dose cyclophosphamide (LCYC) and high-dose CYC (HCYC) as induction therapy for lupus nephritis. METHODS: Bayesian random-effects network meta-analysis was performed to combine direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of LCYC, HCYC, and mycophenolate mofetil (MMF) for induction therapy in patients with lupus nephritis. RESULTS: Eleven RCTs (1212 patients) were included. MMF and LCYC showed similar overall response rates (OR 1.02, 95% credible interval [CrI] 0.51-2.02), and MMF showed a higher efficacy than HCYC (OR 1.48, 95% CrI 0.99-2.44). Similarly, LCYC showed a higher overall response than HCYC (OR 1.46, 95% CrI 0.83-2.86). Ranking probability based on SUCRA (surface under the cumulative ranking curve) indicated that MMF had the highest probability of being the best treatment for achieving an overall response (SUCRA = 0.7461), followed by LCYC (SUCRA = 0.6978) and HCYC (SUCRA = 0.0561). LCYC showed the highest probability of decreasing the risk of serious infections (SUCRA = 0.8513), followed by MMF (SUCRA = 0.49387) and HCYC (SUCRA = 0.1548). CONCLUSION: LCYC was an efficacious induction treatment for patients with lupus nephritis and had the highest probability of decreasing the risk of serious infections. Higher response rates and a more favorable safety profile suggest that LCYC is a good option for induction treatment in these patients.

Comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials.

OBJECTIVES: The relative efficacy and safety of tofacitinib and baricitinib were assessed in patients with rheumatoid arthritis (RA) with an inadequate response to disease-modifying anti-rheumatic drugs (DMARDs) or biologics. METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and baricitinib in combination with DMARDs in RA patients with an inadequate DMARD or biologic response. RESULTS: Twelve RCTs including 5883 patients met the inclusion criteria. There were 15 pairwise comparisons including 10 direct comparisons of 6 interventions. Tofacitinib 10 mg + methotrexate (MTX) and baricitinib 4 mg + MTX were among the most effective treatments for active RA with an inadequate DMARD or biologic response, followed by baricitinib 2 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab + MTX. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX had the highest probability of being the best treatment to achieve the ACR20 response rate (SUCRA = 0.865), followed by baricitinib 4 mg + MTX (SUCRA = 0.774), baricitinib 2 mg + MTX (SUCRA = 0.552), tofacitinib 5 mg + MTX (SUCRA = 0.512), adalimumab + MTX (SUCRA = 0.297), and placebo + MTX (SUCRA <0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, baricitinib + MTX, adalimumab + MTX, or placebo + MTX. CONCLUSIONS: In RA patients with an inadequate response to DMARDs or biologics, tofacitinib 10 mg + MTX and baricitinib 4 mg + MTX were the most efficacious interventions and were not associated with a significant risk of serious adverse events.

Alcohol intake and risk of rheumatoid arthritis: a Mendelian randomization study.

OBJECTIVE: To examine whether alcohol intake is causally associated with rheumatoid arthritis (RA). METHODS: We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and a GWAS meta-analysis of 5539 autoantibody-positive RA patients and 20,169 controls as the outcome. RESULTS: We selected 24 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables (IVs) to improve inference, 16 of which were inversely associated with RA. The IVW method showed no evidence of a causal association between alcohol intake and RA (beta = 0.218, SE = 0.213, p = 0.306). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.027, p = 0.292). The MR-Egger analysis and the weighted median approach showed no causal association between alcohol intake and RA (beta = -0.778, SE = 0.947, p = 0.420 and beta = -0.286, SE = 0.302, p = 0.344, respectively). Cochran's Q test did not indicate heterogeneity between IV estimates based on the individual variants, and results from a "leave-one-out" analysis demonstrated that no single SNP was driving the IVW point estimate. CONCLUSION: The MR analysis does not support a causal inverse association between alcohol intake and RA occurrence.

Outcomes of multitarget therapy using mycophenolate mofetil and tacrolimus for refractory or relapsing lupus nephritis.

Objectives Outcomes of systemic lupus erythematosus (SLE) have significantly improved over the years. However, when there is major organ involvement, the outcomes can still be unfavorable. Outcomes of multitarget therapy using mycophenolate mofetil (MMF) and tacrolimus in patients with SLE who were refractory to standard therapy were assessed. Methods We retrospectively reviewed the Hanyang BAE lupus cohort to identify patients with biopsy-confirmed lupus nephritis (classes III, IV, or V) who failed to either achieve complete response with standard induction therapy or those who had a lupus flare after achieving a complete response with conventional induction therapy and subsequently were switched to multitarget combination therapy with MMF and tacrolimus. Outcomes, including renal response, proteinuria, glomerular filtration rate, serum albumin, anti-dsDNA antibody level, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and complements, were assessed at six and 12 months. Results Twenty-nine patients, including 12 who failed to achieve a complete response at 12 months after initial conventional induction therapy and 17 with lupus flare after achieving a complete response at 12 months and treated with multitarget therapy, were included in the analysis. At six months, 53.9% of the patients showed a response, with 15.4% of patients showing a complete response and 38.5% of patients showing a partial response. At 12 months, 55.5% of patients exhibited a response (with complete and partial response in 25.9% and 29.6%, respectively). The dosage of steroids was significantly decreased at six months compared with baseline and was maintained at 12 months. Proteinuria, anti-double-stranded DNA antibody positivity, as well as C3 and C4 levels improved after treatment and persisted until 12 months, but were not significant. SLEDAI also improved. Outcomes were significantly better in patients who had a complete response but later had a flare, resulting in the use of multitarget therapy and achieving a subsequent complete response. Conclusions Multitarget therapy with MMF and tacrolimus can be a reasonable option in refractory lupus nephritis patients who failed to show adequate response to conventional induction therapy or who had flares during maintenance therapy. This treatment can help patients achieve a renal response and reduce the use of steroids.

Late-onset systemic lupus erythematosus: Is it "mild lupus"?

Objective The objective of this paper is to investigate the clinical characteristics and prognosis of patients with late-onset systemic lupus erythematosus (SLE) using a prospective observational cohort. Methods Late-onset SLE (≥50 years old) was compared with adult-onset SLE (≥18 and <50 years old) using 1997 ACR classification criteria for SLE, autoantibodies, disease activity measured by Adjusted Mean SLE Disease Activity Index (AMS), and damage measured by Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI). The standardized mortality ratio (SMR) was calculated. Results A total of 917 patients with SLE were enrolled. The mean number of cumulative ACR criteria in late-onset SLE ( n = 32, 3.5%) was lower than that in adult-onset SLE (4.6 ± 1.2 vs. 5.5 ± 1.4, p < 0.05). The percentage of patients with low complement was lower in late-onset SLE than adult-onset SLE ( p < 0.05). AMS was also lower in late-onset SLE (2.7 ± 2.1 vs. 4.3 ± 2.6, p < 0.01), but SDI was similar between the two groups (50% vs. 43.4%, p = 0.58). The SMR of late-onset SLE was 1.58 (95% CI 0.58-3.43), while the SMR of adult-onset SLE was 3.34 (2.34-4.63). Conclusion Compared with adult-onset SLE, late-onset SLE has a lower number of ACR criteria and lower disease activity. Organ damage is not different, but prognosis and mortality are more favorable.

Factors associated with development and mortality of pulmonary hypertension in systemic lupus erythematosus patients.

Objectives This study aims to identify the factors associated with the development and mortality of pulmonary hypertension (PH) in systemic lupus erythematosus (SLE) patients. Methods We conducted a prospective study of SLE patients in a single tertiary center. PH was defined as a systolic pulmonary arterial pressure ≥30 mmHg on transthoracic echocardiography. We assessed potential associated factors contributing to the development and mortality of PH in SLE patients. Results Of 1110 patients with SLE, 48 patients were identified to have PH. Multivariable analysis indicated that pleuritis or pericarditis (odds ratio (OR) = 4.62), anti-RNP antibody (OR = 2.42), interstitial lung disease (ILD) (OR = 8.34) and cerebro-cardiovascular disease (OR = 13.37) were independently associated with the development of PH in SLE. Subgroup analysis among patients with PH demonstrated that there were no statistically significant factors associated with PH mortality in SLE. Conclusions The prevalence of PH was 4.3% in our cohort. There were significant associations with pleuritis or pericarditis, anti-RNP antibody, ILD, and cerebro-cardiovascular disease in SLE, which may contribute to the development of PH. However, there were no statistically significant factors associated with PH mortality in SLE.

Prevalence, risk factors, and impact on mortality of neuropsychiatric lupus: a prospective, single-center study.

Objective The objective of this paper is to identify the prevalence, risk factors, and impact on mortality of neuropsychiatric systemic lupus erythematosus (NPSLE). Methods Patients from the Hanyang BAE lupus cohort were registered and followed from 1998 to 2015. NPSLE was defined using American College of Rheumatology (ACR) case definitions and Ainiala criteria. Demographics, autoantibodies, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and Systemic Lupus International Collaborating Clinic (SLICC)/ACR Damage Index were collected at baseline and then annually. Mortality data were derived by linking data from the Korean National Statistics Office. Multivariable logistic regression and Cox regression analysis were conducted in the inception cohort to assess the risk factors and mortality impact of NPSLE. Results Of 1121 registered patients, 429 (38.3%) had NPSLE manifestations according to ACR criteria and 216 (19.3%) by Ainiala criteria. In multivariable logistic regression analysis, higher SLEDAI (OR 1.08, CI 1.01-1.16, p = 0.02) and antiphospholipid antibody positivity (OR 1.72, CI 1.03-2.87, p = 0.04) at SLE diagnosis increased NPSLE risk, while elevated anti-dsDNA antibodies (OR 0.43, CI 0.24-0.78, p < 0.01) and greater education duration (OR 0.92, CI 0.85-1.00, p = 0.04) showed reduced risk of NPSLE. Cox proportional hazard models demonstrated that presence of NPSLE had a three-fold increased risk of mortality (HR 3.09, CI 1.03-9.21, p = 0.04), especially in patients with focal CNS NPSLE (HR = 7.83, CI 2.12-28.96, p < 0.01). Conclusion Higher SLEDAI, antiphospholipid antibody positivity, absence of anti-dsDNA antibody at SLE diagnosis, and fewer years of education are risk factors for development of NPSLE. Presence of NPSLE, especially focal CNS NPSLE, increased the risk of mortality in SLE patients.

Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus.

Objectives Avascular necrosis (AVN) is one of the most common causes of organ damage in patients with systemic lupus erythematosus (SLE) and often causes serious physical disability. The aims of this study were to investigate clinical risk factors associated with symptomatic AVN and to analyze their synergistic effects in a large SLE cohort in Korea. Methods Patients with SLE were enrolled and followed from 1998 to 2014 in the Hanyang BAE Lupus cohort, and damage was measured annually according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). AVN was confirmed by imaging study if patients had symptoms. To determine risk factors for AVN, clinical, laboratory and therapeutic variables were analyzed by logistic regression. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) were calculated to measure interactions between significant variables. Results Among 1219 SLE patients, symptomatic AVN was the most common type of musculoskeletal damage (10.8%, n = 132). SLE patients with AVN showed an earlier onset age, demonstrated AVN more commonly in conjunction with certain other clinical manifestations such as renal and neuropsychiatric disorders, and received significantly higher total cumulative corticosteroid dose and immunosuppressive agents than did patients without AVN. However, in multivariable analysis, only two variables including use of a cumulative corticosteroid dose greater than 20 g (odds ratio (OR) 3.62, p = 0.015) and use of immunosuppressants including cyclophosphamide or mycophenolate mofetil (OR 4.51, p < 0.001) remained as significant risk factors for AVN. Patients with cumulative corticosteroid dose > 20 g and immunosuppressant use had a 15.44-fold increased risk for AVN, compared with patients without these risk factors ( p < 0.001). RERI, AP and S, which define the strength of interactions between two risk factors, were 9.01 (95% confidence interval (CI) 1.30-16.73), 0.58 (95% CI 0.36-0.81) and 2.66 (95% CI 1.42-4.99), respectively, supporting the presence of synergistic interactions in the development of symptomatic AVN in our Korean lupus cohort. Conclusions An individual risk assessment for AVN development should be made prior to and during treatment for SLE, especially in patients with high-dose corticosteroid and immunosuppressant use regardless of clinical manifestations and disease activity.

CXCR3-deficient mesenchymal stem cells fail to infiltrate into the nephritic kidney and do not ameliorate lupus symptoms in MRL. Faslpr mice.

Mesenchymal stem cell therapy is a promising candidate for the treatment of systemic lupus erythematosus (SLE). To exert their efficacy fully, mesenchymal stem cells must infiltrate efficiently into the lesion sites. Here, we examined the role of CXCR3 in mesenchymal stem cell infiltration into the kidney of MRL. Faslpr mice, which highly expressed CXCL10. The phenotypes, production of immunosuppressive mediators, and capacity to inhibit T and B cells of CXCR3-deficient mesenchymal stem cells were similar to those of wild-type mesenchymal stem cells. However, they showed less infiltration into the nephritic kidney, less conjugation with endothelial cells and weaker MMP-9 expression than did wild-type mesenchymal stem cells. Consequently, CXCR3-deficient mesenchymal stem cells did not ameliorate lupus symptoms in MRL. Faslpr mice in comparison with wild-type mesenchymal stem cells. In summary, our data suggest that upregulation of CXCR3 in mesenchymal stem cells will be a good strategy to increase their infiltration into the kidney, which will improve therapeutic outcomes in SLE.

Breast cancer in systemic lupus erythematosus (SLE): receptor status and treatment.

Objective There is a decreased risk of breast cancer in systemic lupus erythematosus (SLE) versus the general population; little is known regarding the receptor status of breast cancers in SLE, or treatment. Methods Breast cancer cases occurring after SLE diagnosis were ascertained through linkage with tumor registries. We determined breast cancer positivity for estrogen receptors (ER), progesterone receptors (PR), and/or Human Epidermal Growth Factor Receptor 2 (HER2), as well as cancer treatment. Results We obtained information on ER, PR, and/or HER2 status for 63 SLE patients with breast cancer. Fifty-three had information on ER and/or PR status; 36 of these (69%) were ER positive. Thirty-six of the 63 had information on HER2 status; of these, 26 had complete information on all three receptors. Twenty-one of these 26 (81%) were HER2 negative; seven of 26(27%) were triple negative. All but one patient underwent surgery; 11.5% received both non-tamoxifen chemotherapy and radiotherapy, 16.4% radiotherapy without non-tamoxifen chemotherapy, and 14.7% received non-tamoxifen chemotherapy without radiotherapy. Conclusion ER positivity was similar to historical general population figures, with a trend toward a higher proportion of triple-negative breast cancers in SLE (possibly reflecting the relatively young age of our SLE patients).

Association between anti-Porphyromonas gingivalis antibody, anti-citrullinated protein antibodies, and rheumatoid arthritis : A meta-analysis.

OBJECTIVE: The aim of this study was to determine the relationship between anti-Porphyromonas gingivalis (anti-P. gingivalis) antibody levels and rheumatoid arthritis (RA) and its correlation with anti-citrullinated protein antibodies (ACPA). METHODS: We performed a meta-analysis of studies comparing (a) anti-P. gingivalis antibody levels in RA patients and healthy controls and (b) the correlation coefficients between the anti-P. gingivalis antibody levels and ACPA in RA patients. RESULTS: The study included 14 articles with 3829 RA patients and 1239 controls. Our meta-analysis showed that anti-P. gingivalis antibody levels were significantly higher in the RA group than in the control group (standardized mean difference [SMD] = 0.630, 95% CI = 0.272-0.989, p = 0.001). Subgroup analysis revealed that RA patients had significantly elevated anti-P. gingivalis antibody levels compared with healthy controls, but not compared with the non-RA control group and also not between different sample sizes. Anti-P. gingivalis antibody levels were significantly higher in the RA group than in the control group in the age-/sex-matched population, but not in the unmatched population. Anti-P. gingivalis antibody levels were significantly higher in the ACPA-positive group than in the ACPA-negative group (SMD = 0.322, 95% CI = 0.164-0.480, p = 6.4 × 10-5). Meta-analysis of the correlation coefficients showed a significant positive correlation between anti-P. gingivalis antibody levels and ACPA (correlation coefficient = 0.147, 95% CI = 0.033-0.258, p = 0.012). CONCLUSION: Our meta-analysis demonstrated that anti-P. gingivalis antibody levels were significantly higher in patients with RA and they were positively correlated with ACPA.

Comparative efficacy and tolerability of sarilumab 150 and 200 mg in patients with active rheumatoid arthritis : A Bayesian network meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to assess the relative efficacy and tolerability of every other week (q2w) dosing of sarilumab 150 and 200 mg in patients with active rheumatoid arthritis (RA). METHODS: In this network meta-analysis, randomized controlled trials (RCTs) examining the efficacy and tolerability of sarilumab in patients with active RA were included. A Bayesian network meta-analysis was conducted to combine the direct and indirect evidence from the RCTs. RESULTS: Four RCTs, involving 2667 patients, met the inclusion criteria. The American College of Rheumatology (ACR)50 response rate was significantly higher in the sarilumab 200 mg and sarilumab 200 mg + methotrexate (MTX) groups than in the placebo + MTX group (odds ratio, OR, of 4.05, 95% credible interval, CrI, of 2.04-8.33 and OR of 3.75, 95% CrI of 2.37-5.72, respectively). Compared to the placebo + MTX group, the sarilumab 150 mg + MTX and adalimumab 40 mg groups showed a significantly higher ACR50 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that sarilumab 200 mg was likely to achieve the best ACR50 response rate (SUCRA = 0.8518), followed by sarilumab 200 mg + MTX (SUCRA = 0.8225), sarilumab 150 mg + MTX (SUCRA = 0.5112), adalimumab 40 mg (SUCRA = 0.3072), and placebo + MTX (SUCRA = 0.0072). The ACR50 and ACR70 response rate distributions were comparable, except that sarilumab 200 mg + MTX was likely to achieve the best ACR70 response rate. The tolerability based on the number of patient withdrawals due to adverse events (AEs) did not differ significantly between the treatments, except that placebo + MTX was likely to be the best tolerated. CONCLUSION: Sarilumab 150 and 200 mg are efficacious treatments for active RA and are well tolerated.

Association between shortened telomere length and rheumatoid arthritis : A meta-analysis.

OBJECTIVE: This study aimed to evaluate the relationship between telomere length and rheumatoid arthritis (RA). METHODS: We performed a meta-analysis of studies comparing the telomere length in RA patients and healthy controls, and conducted subgroup analysis based on ethnicity, age-matched status, study quality, sample type, assay method, subject number, and shared epitope (SE) status. RESULTS: Nine studies from seven articles, with 388 RA patients and 362 controls, were included. Meta-analysis showed that the telomere length was significantly shorter in all individuals of the RA group than in those of the control group (SMD = -0.833, 95 % CI = -1.332 to -0.334, p = 0.001). Stratification by ethnicity showed significantly shortened telomere lengths in both mixed and age-matched Caucasian populations with RA (SMD = -1.415, 95 % CI = -1.709 to -1.120, p < 1.0 × 10-8; SMD = -0.658, 95 % CI = -1.187 to -0.0.128, p = 0.015). The telomere length was significantly shorter in the RA group than in the age-matched control group; however, this was not the case in the RA group that was not age-matched (SMD = -1.070, 95 % CI = -1.489 to -0.650, p = 5.7 × 10-7; SMD = 0.155, 95 % CI = -0.119 to 0.429, p = 0.267). Stratification by SE status revealed a significantly shortened telomere length in the SE-positive group, but not in the SE-negative group (SMD = -1.033, 95 % CI = -1.398 to -0.768, p < 1.0 × 10-8; SMD = -0.967, 95 % CI = -2.382 to 0.449, p = 0.181). In addition, the telomere length was significantly shorter in the SE-positive RA group than in the SE-negative RA group (SMD = -0.415, 95 % CI = -0.699 to -0.131, p = 0.004). CONCLUSIONS: Our meta-analysis demonstrated that the telomere length was significantly shorter in patients with RA, and was significantly more so in the SE-positive group than in the SE-negative group.