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Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with marked disparities in prevalence and disease severity among different ethnic groups. The purpose of this study is to characterize a Latin American cohort and identify genetic risk factors for developing SLE and its end-organ manifestations in this Latin Hispanic cohort. Methods: In this cohort, SNP rs9271366 (tag SNP for HLA-DRB1*15:01) confers the highest risk for SLE among the 13 MHC gene alleles that display association with SLE (p = 8.748E-10; OR = 3.5). Among the 26 non-MHC gene alleles analyzed, SNP rs2476601 in PTPN22 gene confers the highest risk for SLE (p = 0.0001; OR = 5.6). ITGAM, TNFSF4, TNIP1, STAT4, CARD11, BLK, and TNXB gene alleles were confirmed as SLE-susceptible alleles in the DR cohort. However, IRF5 and TNFAIP3 gene alleles, established risk factors for SLE in populations of European and Asian ancestry, are not significantly associated with SLE in this cohort. We also defined a novel HLA-DRA haplotype that confers an increased risk for lupus nephritis (LN) and alleles in HLA-DRA2 and TNFSF4 genes as genetic risk factors for developing neuropsychiatric (NP) SLE. Results: In this cohort, SNP rs9271366 (tag SNP for HLA-DRB1*15:01) confers the highest risk for SLE among the 13 MHC gene alleles that display association with SLE (p = 8.748E-10; OR = 3.5). Among the 26 non-MHC gene alleles analyzed, SNP rs2476601 in PTPN22 gene confers the highest risk for SLE (p = 0.0001; OR = 5.6). ITGAM, TNFSF4, TNIP1, STAT4, CARD11, BLK, and TNXB gene alleles were confirmed as SLE-susceptible alleles in the DR cohort. However, IRF5 and TNFAIP3 gene alleles, established risk factors for SLE in populations of European and Asian ancestry, are not significantly associated with SLE in this cohort. We also defined a novel HLA-DRA haplotype that confers an increased risk for lupus nephritis (LN) and alleles in HLA-DRA2 and TNFSF4 genes as genetic risk factors for developing neuropsychiatric (NP) SLE. Conclusion: Our data suggest that the Latin American population shares some common genetic risk factors for SLE as other populations, but also has distinct risk gene alleles that contribute to SLE susceptibility and development of LN and NPSLE. This is the first study focusing on genetic risk factors for SLE in the DR, a Latin American population that has never been characterized before.

Background/objective New classification criteria for SLE have recently been developed. How these criteria affect the classification of patients with the SLE-mimicking condition UCTD is poorly understood. This study investigated the reclassification of UCTD patients using newly derived SLE criteria. Methods Patients with UCTD were identified within a single academic medical center using ICD9/10 codes. Medical record review was performed to confirm UCTD diagnosis and identify disease features present at diagnosis. The SLICC and ACR/EULAR criteria were applied, after which we compared the proportion of patients reclassified as SLE and determined which disease features were associated with reclassification. Results A total of 129 patients were included in the study. When applying the SLICC and ACR/EULAR criteria, 18 (14.0%) and 26 patients (20.2%) were reclassified as SLE. Comparison with McNemar’s test trended toward statistical significance (p = 0.057). Cohen’s kappa coefficient was 0.62 (p Conclusions Both the SLICC and ACR/EULAR criteria exhibit increased SLE classification. These newer classification criteria could be used to increase the number of SLE patients in future clinical studies.

Background Belimumab is a monoclonal antibody that reduces B lymphocyte survival by blocking the binding of soluble human B lymphocyte stimulator (BLyS) to its B cell receptors. The utility of belimumab for management of resistant systemic lupus erythematosus (SLE) skin manifestations has not been reported. We present our experience of using this novel molecule for the successful management of cutaneous lupus at our center. Methods We studied five patients with significant SLE skin manifestations. All patients met 1997 American College of Rheumatology (ACR) SLE criteria and had failed multiple medications to control their skin disease. SLE disease activity indexes (SLEDAI), Cutaneous LE disease Area and Severity Index (CLASI) and patient’s global assessment (PGA) were recorded before and 16 weeks after belimumab treatment. Belimumab was added to concomitant standard therapy. Results All five patients demonstrated marked clinical improvement subsequent to belimumab treatment. The average time to clinical improvement after treatment initiation was 8–12 weeks. SLEDAI scores (median, range) improved in all the patients ((2, 2–6) to (0, 0–4); p = 0.025). PGA scores (median, range) were better in all patients ((3, 2–3) to (1, 0–1); p = 0.039). CLASI activity scores (median, range) improved dramatically in all patients ((17, 9–31) to (3, 2–14); p = 0.043). There was no worsening of the CLASI damage scores. The mean daily prednisone dose decreased significantly from 31 mg (±18.8) at baseline to 3 mg (± 2.7) ( p = 0.042). Conclusion In this case series, the addition of belimumab to standard therapy improved the signs and symptoms of refractory cutaneous lupus. This is one of the first reports highlighting the potential utility of this medication for the treatment of severe skin involvement in SLE refractory to conventional therapies. Additional studies need to be performed to assess the use of belimumab in the treatment of cutaneous lupus.

Livedoid vasculopathy (LV) is a small vessel occlusive disease that can present with a painful purpuric eruption. Predominantly affecting young women, LV has been associated with hypercoagulable states and antiphospholipid syndrome. We present an unusual case of LV occurring in the setting of acute kidney injury secondary to lupus nephritis. It is important to differentiate LV from vasculitis as the treatment recommendation centers on anticoagulation therapy rather than immunosuppression. Additionally, antiphospholipid syndrome should be ruled out in cases of systemic lupus erythematosus with LV due to risk of thrombotic events.

Objective To compare anti-malondialdehyde–acetaldehyde (MAA) antibody concentrations between rheumatoid arthritis (RA) patients and healthy and rheumatic disease controls. Methods Anti-MAA antibody (IgA, IgM, IgG) was measured using ELISA and banked serum from patients with RA (n = 284), osteoarthritis (OA, n = 330), spondyloarthropathy (SpA, n = 50), and systemic lupus erythematosus (SLE, n = 88) as well as healthy controls (n = 82). Anti-MAA antibody concentrations and the frequency of positivity were compared across groups. Multivariable linear regression analysis limited to RA and OA patients (due to sample size and data availability) was used to identify factors associated with anti-MAA antibody concentrations. Results Although RA patients demonstrated among the highest circulating concentrations across isotypes, only IgA anti-MAA antibody was significantly higher than all other groups (p ≤ 0.02). Proportions (7% to 74%) of OA and SLE (less so for SpA) samples were positive for anti-MAA antibody, limiting the discriminatory capacity of anti-MAA antibody in RA (positive in 18% to 80%). In analyses limited to those with RA or OA, factors associated with higher anti-MAA antibody concentrations included RA case status, younger age (IgM), male sex (IgG), African American race (IgA, IgG) and current smoking (IgA). C-reactive protein levels and comorbidities were not associated with anti-MAA antibody concentrations. Conclusion With the possible exception of the IgA isotype, serum anti-MAA antibodies measured with currently available assays do not appear to adequately discriminate RA from other rheumatic conditions. With the identification of specific proteins that are MAA-modified in diseased tissues and requisite assay refinement, anti-MAA antibody holds potential promise as a biomarker in RA.

Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils. Recent studies suggest that NETs play an active role in driving autoimmunity and tissue injury in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The purpose of this study was to investigate if celastrol, a triterpenoid compound, can inhibit NET formation induced by inflammatory stimuli associated with RA and SLE. We found that celastrol can completely inhibit neutrophil oxidative burst and NET formation induced by tumor necrosis factor alpha (TNFα) with an IC50 of 0.34 µM and by ovalbumin:anti-ovalbumin immune complexes (Ova IC) with an IC50 of 1.53 µM. Celastrol also completely inhibited neutrophil oxidative burst and NET formation induced by immunoglobulin G (IgG) purified from RA and SLE patient sera. Further investigating into the mechanisms, we found that celastrol treatment downregulated the activation of spleen tyrosine kinase (SYK) and the concomitant phosphorylation of mitogen-activated protein kinase kinase (MAPKK/MEK), extracellular-signal-regulated kinase (ERK), and NFκB inhibitor alpha (IκBα), as well as citrullination of histones. Our data reveals that celastrol potently inhibits neutrophil oxidative burst and NET formation induced by different inflammatory stimuli, possibly through downregulating the SYK-MEK-ERK-NFκB signaling cascade. These results suggest that celastrol may have therapeutic potentials for the treatment of inflammatory and autoimmune diseases involving neutrophils and NETs.

The Oral Contraceptives part of the Safety of Estrogens in Lupus Erythematosus National Assessment (OC-SELENA) study was a prospective, randomized, double-blind trial carried out at 15 U.S. centers that examined the effects of oral contraceptives on disease activity in 183 premenopausal women with systemic lupus erythematosus. Initially, disease was inactive in 76% of participants and active but stable in the remaining 24%. Participants were assigned to receive 35 μg triphasic ethinyl estradiol plus 0.5, 0.75, or 1 mg norethindrone, or placebo, for 12 28-day cycles. None of the subjects had moderate to high titers of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. Just over one third of patients in each group failed to comply throughout the 12-month study. Only seven of 91 women given oral contraceptives and seven of 92 placebo recipients had a severe flare of disease during the study. Two flares in the active treatment group occurred when the study drug was omitted. On Cox proportional-hazards analysis, the relative risk (RR) of a severe flare occurring during OC treatment, compared with placebo, was 0.93 (95% confidence interval [CI], 0.33-2.65). The estimated difference was less than the maximum clinically acceptable difference. Participants in both groups who had active disease at the outset were likelier than those whose disease was inactive to have a severe flare. The estimated RR, adjusted for treatment, was 3.5 (95% CI, 1.23-9.99). Rates of moderate or mild flares were similar in the treatment and placebo groups. The likelihood of having at least one flare of any degree during 12 months of follow up was 76% for actively treated patients and 69% for those in the placebo group (RR, 1.09; 95% CI, 0.76-1.55). One OC-treated patient had deep venous thrombosis (DVT) and one had a clotted graft. In the placebo group, there was one case each of DVT, ocular thrombosis, and superficial thrombophlebitis, and one woman died after the trial ended. These findings endorse the use of oral contraceptives, including estrogen, as a birth control measure by women having inactive or active but stable systemic lupus erythematosus. These patients are at relatively low risk of developing thrombosis.

Hepatitis C virus (HCV) infection is associated with various autoimmune disorders and can mimic systemic lupus erythematosus (SLE) clinically and serologically. There are few reports of prevalence of HCV infection in patients with SLE. The aim of this study was to determine the prevalence of HCV viremia by polymerase chain reaction (PCR) in patients with SLE.We tested sera from 40 consecutive patients with SLE collected from 1993 to 2000. All of the patients had HCV viral load measured by PCR. The results were compared with the prevalence of HCV viremia in a control group of blood donors in our geographic area as well as in United States general population.HCV was detected in 4 of 40 patients (10%). The prevalence of HCV in our area blood donors is 130 cases per 100,000 persons (0.13%; P0.0001). The prevalence of HCV infection in the United States general population, screened by PCR, is 1330 cases per 100,000 people (1.33%; P=0.002). The prevalence of HCV infection was significantly higher in our SLE patients than in our area blood donors. The frequency of HCV infection was also higher than that of the United States general population.Our observations support those of other investigators who have reported an increased prevalence of HCV infection in SLE patients. Further detailed investigation of this association may help in understanding the pathogenesis of SLE. HCV infection should be tested when the diagnosis of SLE is considered.

• Objective. —To describe a case of autoimmune exocrinopathy in a child at the age of 3 months who presented with the origianl diagnosis of recurrent parotitis. Design. —This a case report of a 9-year-old girl with recurrent parotitis who was later found to have Sjogren's syndrome. The literature relating to primary Sjogren's syndrome in the pediatric population is reviewed. Setting. —The patient was seen in the rheumatology and otolaryngology clinics at a university medical center. Interventions. —This study did not address therapy. Main Outcome Measure. —Diagnosis of Sjogren's syndrome. Results. —The patient had xerostomia, an abnormal result of a salivary gland biopsy, SSA and SSB antibodies, and the histocompatibility antigens HLA-B8 and HLA-DR3 that are associated with Sjogren's syndrome. Conclusions. —Primary Sjogren's syndrome should be considered in cases of recurrent parotitis of childhood. More studies are needed to assess the natural history of autoimmune exocrinopathy in children. ( Arch Otolaryngol Head Neck Surg. 1993;119:347-349)

Systemic lupus erythematosus (SLE) is characterized by the over-production of high affinity autoantibodies. However, it is not clear how these autoantibodies are generated and selected. VH replacement is originally considered as a receptor editing process to change unwanted non-functional immunoglobulin heavy chain (IgH) genes or IgH genes encoding self reactive BCRs. Our sequence analysis shows that VH replacement products are highly enriched in IgH genes derived from different autoimmune diseases, including SLE. In this study, we performed single cell RT-PCR to study the functional antibody repertoires in active SLE patients. Analysis of 180 recombinant antibodies derived from SLE patients showed that 19.0% of the antibodies derived from naïve B cells and 56.9% of the antibodies derived from plasmablasts are autoreactive. In contrast, only 7.7% and 17.4% of the antibodies derived from naïve B cells and plasmablast B cells are autoreactive in healthy donors. The VH replacement products are significantly increased in IgH genes obtained from SLE patients (20%) compared to that in healthy controls (10%). Importantly, the accumulated VH replacement products in SLE patients have long CDR3 regions enriched with positively charged amino acids; 74% of them directly encode anti-nuclear antigen or polyreactive antibodies. Based on these results, we conclude that the accumulated VH replacement products in SLE patients contribute to the generation of auto/polyreactive antibodies in SLE.

There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE).To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE.Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002.16 university-affiliated rheumatology clinics or practices in 11 U.S. states.351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE.12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group.The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite.Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis.Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis.Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.