Susan Manzi

Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus

OBJECTIVE The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAX

BACKGROUND Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci. METHODS We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden. RESULTS Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case-control series (rs13277113; odds ratio, 1.39; P=1x10(-10)) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10(-11)). CONCLUSIONS We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.

Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis

Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.

A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 × 10−8): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P≤ 1 × 10−5. A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 × 10−3) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus

OBJECTIVE To determine the prevalence of carotid atherosclerosis and associated risk factors in women with systemic lupus erythematosus (SLE). METHODS Carotid plaque and intima-media wall thickness (IMT) were measured by B-mode ultrasound in women with SLE. Risk factors associated with carotid plaque and IMT were determined at the time of the ultrasound scan and included traditional cardiovascular risk factors, SLE-specific variables, and inflammation markers. RESULTS The 175 women with SLE were predominantly white (87%), with a mean age of 44.9 years (SD 11.5). Twenty-six women (15%) had a previous arterial event (10 coronary [myocardial infarction or angina], 11 cerebrovascular [stroke or transient ischemic attack], and 5 both). The mean +/- SD IMT was 0.71 +/- 0.14 mm, and 70 women (40%) had focal plaque. Variables significantly associated with focal plaque (P < 0.05) included age, duration of lupus, systolic, diastolic, and pulse pressure, body mass index, menopausal status, levels of total and low-density lipoprotein (LDL) cholesterol, fibrinogen and C-reactive protein levels, SLE-related disease damage according to the Systemic Lupus International Collaborating Clinics (SLICC) damage index (modified to exclude cardiovascular parameters), and disease activity as determined by the Systemic Lupus Activity Measure. Women with longer duration of prednisone use and a higher cumulative dose of prednisone as well as those with prior coronary events were more likely to have plaque. In logistic regression models, independent determinants of plaque (P < 0.05) were older age, higher systolic blood pressure, higher levels of LDL cholesterol, prolonged treatment with prednisone, and a previous coronary event. Older age, a previous coronary event, and elevated systolic blood pressure were independently associated with increased severity of plaque (P < 0.01). Older age, elevated pulse pressure, a previous coronary event, and a higher SLICC disease damage score were independently related to increased IMT (P < 0.05). CONCLUSION B-mode ultrasound provides a useful noninvasive technique to assess atherosclerosis in women with SLE who are at high risk for cardiovascular disease. Potentially modifiable risk factors were found to be associated with the vascular disease detected using this method.

Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus

The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.

Vascular Stiffness in Women With Systemic Lupus Erythematosus

Large-vessel manifestations of systemic lupus erythematosus (SLE), a multisystem disease characterized by disturbances in the immune system, include higher than expected rates of hypertension and cardiovascular disease. Reductions in the elasticity of central arteries may act as a marker of early changes that predispose to the development of major vascular disease. This study evaluated risk factors associated with aortic stiffness measured by pulse wave velocity (PWV) in women with SLE. We expected SLE-specific factors, especially variables indicative of inflammation and active disease, to be associated with increasing PWV. The study population included 220 women currently enrolled in the Pittsburgh Lupus Registry. All risk factor data were collected on the day of the ultrasound examinations. PWV waveforms were collected from the right carotid and femoral arteries by Doppler probes. The mean age of the women was 45.5±10.8 years, the median SLE disease duration approximated 9 years, and the mean PWV was 6.1±1.7 m/s. Multiple regression models were stratified by menopausal status. Among postmenopausal women, PWV risk factors were primarily traditional factors and included age, systolic blood pressure, family history of vascular disease, carotid plaque, creatinine, obesity, glucose, white cell count, and cumulative SLE organ damage. Among premenopausal women, PWV risk factors consisted of a mix of SLE-related and traditional variables and included higher C3 levels, presence of ds-DNA antibodies, nonuse of hydroxychloroquine, lower leukocyte count, higher mean arterial pressure, and carotid plaque. SLE-specific variables appeared to be associated with increases in aortic PWV, indicating central artery stiffening. This was seen most clearly among premenopausal women. This finding may partially explain the higher rates of cardiovascular disease and hypertension observed in young women with SLE.

Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials

Objective To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. Methods Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) organ domain scores. Results At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA–SLEDAI, and immunological by SELENA–SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA–SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA–SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA–SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. Conclusions Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.

Inflammation-mediated rheumatic diseases and atherosclerosis

For over 20 years, premature coronary heart disease has been recognised as a major determinant of morbidity and mortality in patients with systemic lupus erythematosus (SLE).1-4 Less appreciated is the fact that the same holds true for patients with rheumatoid arthritis (RA).5-7 These two autoimmune diseases share a propensity to target women of childbearing age and a treatment armamentarium that includes corticosteroids and other immunosuppressive agents. Despite clear distinctions in pathophysiology, the immune dysfunction unique to each disease results in a chronic inflammatory state, which may have implications for the atherogenesis seen in these young patients. As we compare and contrast potential cardiovascular risk factors in these two autoimmune diseases, we may further our understanding of why these young women are at high risk for premature atherosclerosis. Women with SLE have a high incidence of coronary heart disease.1-4 Several investigators have convincingly shown that women with SLE under the age of 45 are at substantially increased risk of ischaemic heart disease.1 4 We reported that women with SLE aged 35–44 were over 50 times more likely to have a myocardial infarction than were women of similar age from a population based sample (rate ratio = 52.43, 95% CI 21.6 to 98.5).1In contrast, women with SLE in the 45–64 year age group were only two to four times more likely to have a myocardial infarction than women without SLE of the same age. We also found a small decline in the incidence rates for myocardial infarction in women with SLE aged 45–54 compared with those having the same diagnosis aged 35–44. The reasons for this are unclear. A difference in overall survival is an unlikely explanation as mortality rates from all causes were not significantly different between women in these two age strata. A plausible …

Frequency of fractures in women with systemic lupus erythematosus: Comparison with united states population data

OBJECTIVE To describe the frequency of self-reported fractures in a large population-based cohort of women with lupus, to compare the frequency of self-reported fractures between lupus patients and women of similar age in the general population by use of data from the 1994 National Health Interview Survey (NHIS), and to describe the associated risk factors for fracture in women with lupus. This study is a secondary analysis of data collected to assess cardiovascular risk in women with lupus. METHODS Fractures and associated risk factors were ascertained by self report in this retrospective cohort study of 702 living women with lupus who were followed up for 5,951 person-years. Self-reported fractures were verified in a subset of patients. A Weibull regression model was used to assess risk factors associated with time from lupus diagnosis to fracture in the univariate and multivariate analyses. Age-specific standard morbidity ratios (SMRs) were calculated to determine whether fracture occurrence was greater than expected in women with lupus. RESULTS Eighty-six (12.3%) of 702 women reported at least 1 fracture following the diagnosis of lupus. The sites of the first fracture were the leg (n = 32), foot (n = 16), arm (n = 15), spine (n = 9), rib (n = 7), hip (n = 2), pelvis (n = 2), hand (n = 1), shoulder (n = 1), and finger (n = 1). Fracture risk was increased in the lupus cohort compared with women of similar age from the United States population, using weighted data from the 1994 NHIS (SMR 4.7; 95% confidence interval 3.8, 5.8). Variables in the univariate analysis that were significantly associated (P < 0.05) with time from lupus diagnosis to fracture were older age at lupus diagnosis, longer disease duration, longer duration of corticosteroid use, less use of oral contraceptives, and menopause status. In the multivariate analysis, independent determinants of time from lupus diagnosis to fracture were older age at lupus diagnosis and longer duration of corticosteroid use. CONCLUSION Fractures occurred in 12.3% of lupus patients who were followed up for 5,951 person-years. There was nearly a 5-fold increase in fracture occurrence in the women with lupus compared with women from the US population. Older age at lupus diagnosis and longer use of corticosteroids were associated with time from lupus diagnosis to fracture. With increased life expectancy of lupus patients, fracture occurrence is a major threat to the health of these women. Prevention strategies must be directed toward minimizing the occurrence of fractures in these patients.