Antiphospholipid Antibodies are Associated with Low Levels of Complement C3 and C4 in Patients with Systemic Lupus Erythematosus.

Complement activation and low complement levels are common in systemic lupus erythematosus (SLE). Antiphospholipid antibodies (aPL) are found in about 30-40% of patients with SLE. This study aimed to investigate the association between aPL and complement levels in patients with SLE. Serum samples were collected from 269 patients with SLE enrolled in the Norwegian Systemic Connective Tissue and Vasculitis Registry (NOSVAR) during 2003-2009, and from 353 controls. All samples were analysed for anti-ß2 glycoprotein 1 (anti-ß2GP1) and anticardiolipin antibodies (aCL), C-reactive protein (CRP) and complement components C3 and C4. Median CRP level was significantly higher in cases than in controls (2.06 versus 0.90 mg/l; P < 0.0001). No significant difference in CRP was found between SLE patients with or without aPL (2.09 versus 1.89; P = 0.665). Median C3 levels were similar in cases (1.03 g/l) and controls (1.00 g/l), whereas median C4 levels were 0.16 g/l in cases versus. 0.19 in controls (P < 0.0001). However, aPL-positive SLE patients had significantly lower median C3 levels (0.92 versus. 1.07 g/l; P = 0.001) and C4 levels (0.11 versus 0.16 g/l; P < 0.0001) compared to aPL-negative patients. Lower C3 and C4 values in aPL-positive SLE patients may reflect a higher consumption of C3 and C4 due to more pronounced complement activation in aPL-positive SLE patients compared to SLE patients without aPL.

Mortality and years of potential life loss in systemic lupus erythematosus: a population-based cohort study.

Multiple sources were used to identify 325 systemic lupus erythematosus (SLE) patients within the city of Oslo during 1999-2009 who met ≥ 4 of the American College of Rheumatology (ACR) criteria. The survival, standard mortality rate (SMR), years of potential life loss before 60 years of age (YPLL60) and causes of death of these patients were examined and compared to a matched control population. Only inception cases (127) were studied in the calculation of survival. The analysis includes underlying, immediate and contributing causes of death. The five- and 10-year survival was 95% and 90%, respectively, which was significantly reduced when compared to the general population. A total of 50 SLE patients died during the study period. Overall SMR was 3.0 (95% confidence interval (CI) 2.2-3.8) with the highest SMR found for female patients aged 16-39 years old. SLE patients had a 10 times higher rate of YPLL60 compared to the control group. YPLL emphasizes active disease and reduces the importance of cancer as a cause of death in SLE. This study demonstrates that YPLL gives additional and useful information for the prognosis of SLE, supplementing traditional methods of measuring mortality.

EULAR points to consider for conducting clinical trials in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex multi-organ disease, characterised by relapses and remissions. DESIGN: ng a high-quality randomised controlled trial poses many challenges. We have developed evidenced-based recommendations for points to consider in conducting clinical trials in patients with SLE. METHODS: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Initially, the evidence for clinical trial end-points in SLE was evaluated and this has been reported separately. A consensus approach was developed by the SLE Task Force in formulating recommendations for points to consider when conducting clinical trials in SLE. RESULTS: The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not actually been validated in clinical trials, although other forms of validation have been undertaken. The final recommendations for points to consider for conducting clinical trials in SLE address the following areas: study design, eligibility criteria, outcome measures including adverse events, concomitant therapies for SLE and its complications. CONCLUSIONS: Recommendations for points to consider when conducting clinical trials in SLE were developed using an evidence-based approach followed by expert consensus. The recommendations should be disseminated, implemented and then reviewed in detail and revised using an evidence-based approach in about 5 years, by which time there will be further evidence to consider from current clinical trials.

EULAR points to consider for conducting clinical trials in systemic lupus erythematosus: literature based evidence for the selection of endpoints.

OBJECTIVE: To assess available evidence on the use of end-points (outcome measures) in clinical trials in systemic lupus erythematosus (SLE), as a part of the development of evidence-based recommendations for points to consider in clinical trials in SLE. METHODS: The European League Against Rheumatism (EULAR) Task Force on SLE comprised 19 specialists, a clinical epidemiologist and a research fellow. Key questions addressing the evidence for clinical trial end-points in SLE were compiled using the Delphi technique. A systematic search of the PubMed and Cochrane Library databases was performed using McMaster/Hedges clinical query strategies and an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence and agreement on the statements was measured across the 19 specialists. RESULTS: Eight questions were generated regarding end-points for clinical trials. The evidence to support each proposition was evaluated. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not been formally validated in clinical trials, although some indirect validation has been undertaken. CONCLUSION: This systematic literature review forms the evidence base considered in the development of the EULAR recommendations for end-points in clinical trials in SLE.

Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity.

BACKGROUND: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients. METHODS: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables. RESULTS: Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants. CONCLUSIONS: Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4. The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.

EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE. METHODS: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists. RESULTS: Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10. CONCLUSION: Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.

Systemic lupus erythematosus and the extended major histocompatibility complex--evidence for several predisposing loci.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease reported to be associated with several alleles in the HLA complex. The purpose of this study was to systematically examine the extended HLA complex (xMHC) in order to get an overview of the primary predisposing genetic factors. MATERIALS AND METHODS: One hundred and sixty-four SLE patients and 254 healthy, unrelated controls were genotyped for HLA-DRB1, -B and -A alleles, as well as 13 microsatellites markers covering the xMHC. Moreover, we selected 335 additional controls matched with the patients for the HLA haplotypes showing the strongest associations, in order to look for additional predisposing loci. RESULTS: Two regions of the xMHC showed associations: the region covering DRB1 to B, and the extended class I region. Explicitly, DRB1*03 and B*08 displayed strong associations with SLE, which seem to be independent of each other. Furthermore, associations were seen with alleles at microsatellites D6S2225 and D6S2223, located about 3.6 Mb telomeric of HLA-B, and these were not secondary to the associations found with DRB1*03 and B*08. CONCLUSION: Both the DRB1*03 and the B*08 alleles display disease association, either implicating involvement of both alleles or caused by another yet unidentified gene(s) in linkage disequilibrium. The associations found in the extended class I region could be markers for a 'novel' predisposing locus (loci) in SLE, adding to the risk conferred by DRB1*03 and B*08. Interestingly, this region has been shown to also be associated with other autoimmune diseases, hence the gene(s) might confer a general propensity for autoimmunity.

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases.

A functional single nucleotide polymorphism, 1858C>T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR=1.41; P=0.04), not previously reported, and a tendency for an association with coeliac disease (OR=1.35; P=0.08). In primary sclerosing cholangitis, no association was observed (OR=0.95; P=0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR=1.58; P=0.001), but could not find support for an association with systemic lupus erythematosus (OR=0.94; P=0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C>T polymorphism in PTPN22.

Sicca symptoms and secondary Sjögren's syndrome in systemic lupus erythematosus: comparison with rheumatoid arthritis and correlation with disease variables.

OBJECTIVE: Firstly, to study the prevalence of ocular and oral sicca symptoms, reduced tear and saliva production, and the minimum frequency of secondary Sjögren's syndrome (sSS) in systemic lupus erythematosus (SLE). Secondly, to compare sicca symptoms and findings with those of matched patients with rheumatoid arthritis (RA), and sicca symptoms with those in healthy controls. Finally, to study possible associations of clinical variables with sicca symptoms and sSS in SLE. METHODS: Self reported sicca symptoms were recorded in 81 patients with SLE aged < or =70, 81 matched patients with RA, and 81 matched healthy controls. Other study variables included Schirmer-I test (S1T), unstimulated whole saliva, health status measures (in SLE and RA), disease activity, accumulated organ damage, and serological markers (in SLE). RESULTS: A significantly higher proportion of patients with SLE reported sicca symptoms than healthy controls. Further, a significantly higher proportion reported ocular sicca symptoms (43 and 21%, respectively) and had pathologically reduced S1T compared with RA (46 and 21%, respectively). No difference was seen in oral sicca symptoms and saliva production. In SLE, sicca symptoms were associated with fatigue, and sSS with anti-SSB or anti-SSA antibodies, or both. CONCLUSIONS: An increased prevalence of sicca symptoms was found in patients with SLE compared with controls, and a higher prevalence of ocular sicca symptoms and reduced tear production in SLE compared with RA. Sicca problems should be considered in the care of patients with SLE, especially those with anti-SSB and/or anti-SSA antibodies who have sicca symptoms and fatigue.

Disease course in systemic lupus erythematosus: changes in health status, disease activity, and organ damage after 2 years.

OBJECTIVE: To examine changes in health status, disease activity, and organ damage after 2 years and to study possible disease variables predicting change in health status, disease activity, and organ damage at followup in systemic lupus erythematosus (SLE). Second, to compare changes in health status in patients with SLE to that of matched patients with rheumatoid arthritis (RA) and matched healthy controls. METHODS: A 2 year longitudinal observational study, measuring health status (Short-Form 36. visual analog scale for pain and fatigue, modified Health Assessment Questionnaire, patient global assessment of disease activity), disease activity, and organ damage in 87 patients with SLE. Health status measures in SLE were compared to 65 matched RA patients selected from the Oslo RA register and to 77 matched healthy controls from the population register. RESULTS: On a group level the SLE patients showed stable health status measures and disease activity scores 2 years after baseline, but organ damage scores increased significantly. Increase in organ damage was significantly and independently predicted by baseline scores of disease activity and organ damage, health status, and disease activity by the respective baseline scores. Changes in health status measures over 2 years were similar in SLE, RA, and healthy controls. CONCLUSION: Our 2 year longitudinal observational SLE study showed a stable course of health status and disease activity, whereas organ damage increased. Disease activity and organ damage at baseline predicted the latter. Our results indicate the value of careful monitoring of disease activity over time in SLE and individually tailored treatment guided by the predictors of course and outcome.

Bone mineral density in systemic lupus erythematosus: comparison with rheumatoid arthritis and healthy controls.

OBJECTIVES: To examine bone mineral density (BMD) frequency of osteoporosis and reduced bone mass in systemic lupus erythematosus (SLE), and compare the data of the SLE patients with matched rheumatoid arthritis (RA) patients and healthy controls. Secondly, to study possible correlations between BMD, demographic and disease variables in the SLE patients. METHODS: Measures of BMD assessed by dual energy x ray absorptiometry were obtained from 75 SLE patients aged

Health status in systemic lupus erythematosus compared to rheumatoid arthritis and healthy controls.

OBJECTIVE: To examine health status in systemic lupus erythematosus (SLE), using both generic and arthritis-specific instruments, and compare the health status in patients with SLE to matched patients with rheumatoid arthritis (RA) and matched healthy controls. As well, to study possible correlations between health status measures and demographic and disease variables in the patients with SLE. METHODS: Patients were recruited from the Oslo county registers of patients with SLE and RA, and the healthy controls from the county population register. Measures of health status (Medical Outcome Survey SF-36, joint pain and fatigue on visual analog scale, Modified Health Assessment Questionnaire) were obtained from 82 SLE and 82 RA patients matched for age, sex, and disease duration, and from 74 age and sex matched healthy controls. Disease activity and organ damage were assessed in the patients with SLE. RESULTS: Patients with SLE were significantly more affected in all dimensions of health status compared to controls, except in the SF-36 category role-emotional. Further, patients with SLE were significantly less affected than patients with RA with regard to physical function and joint pain, but scores were similar in all other dimensions of health status. Scores of health status correlated more strongly to the damage index than to disease activity, indicating that health status measures capture some of the same concept as the damage index, namely the consequence of the disease over time. CONCLUSION: Our study showed that patients with SLE and RA have a multidimensional involvement of health status compared to healthy controls. The findings call for a biopsychosocial approach in the management of SLE.

Oral and ocular sicca symptoms and findings are prevalent in systemic lupus erythematosus.

The aims of this study were 1) to examine the frequency of oral and ocular sicca symptoms in patients with systemic lupus erythematosus (SLE); 2) to compare saliva and tear volume, salivary proteins, and features of the oral microflora and mucosa to a matched healthy control group; and 3) to relate the findings to disease parameters. Median disease duration was 5.5 (0.5-28) years, disease activity 5 (2-20), damage score 1 (0-7), and Schirmer I test 7.5 (0-30 mm). Seventeen and twelve patients complained of oral and ocular dryness, respectively. Unstimulated whole saliva and proline-rich proteins in submandibular saliva were significantly reduced in SLE. Oral microbial counts were generally higher in the patients than controls, and the number of oral mucosal changes was increased. The results show that sicca symptoms, although frequent, were not correlated to secretory rates of saliva or tears, but to oral microbial counts. There was no obvious correlation to patient's age, disease activity or duration.

Application of the 1982 revised criteria for the classification of systemic lupus erythematosus on a cohort of 346 Norwegian patients with connective tissue disease.

By reviewing patient's records, we evaluated the sensitivity and specificity of the 1982 revised classification criteria for systemic lupus erythematosus on a cohort of 346 Norwegian patients with connective tissue disease, seen at a rheumatology referral center in the period 1986-95. The patients with CTD other than SLE were used as controls. The number of the 1982 revised classification criteria for SLE fulfilled by each individual patient was calculated. Fifty-five of the 76 SLE patients (72%) met four or more criteria for SLE, giving a low sensitivity of 72%. Twenty-three of the 270 patients with CTD other than SLE (9%) met four or more criteria for SLE, giving an acceptable specificity of 91%. Applying the "revised/revised 1997 ACR criteria for SLE" the sensitivity would have increased to 78% and the specificity reduced to 89%. The sample of SLE patients was characterized by mild disease with a low proportion of severe internal manifestations.

Conversion of patients with rheumatoid arthritis from the conventional to a microemulsion formulation of cyclosporine: a double blind comparison to screen for differences in safety, efficacy, and pharmacokinetics.

OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclosporin A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with maintenance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetics between formulations. METHODS: In this double blind, multicenter, parallel group study, 51 patients receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measured before and at intervals after conversion. CyA steady-state area under the curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. RESULTS: Initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulation was 23% higher than from conventional CyA. Replicate assessments indicated a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs and laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional to microemulsion CyA. CONCLUSION: Existing CyA dosing guidelines, formulated for conventional CyA, are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation.

Nutrient intake and nutritional status in children with juvenile chronic arthritis.

Nutrient intake and nutritional status were assessed in 15 children with juvenile chronic arthritis (JCA) and in 17 healthy controls. Anthropometric measurements were similar in children with pauciarticular JCA and in controls, whereas weight (p = 0.05) and upper arm muscle area (UAMA) (p less than 0.01) were reduced in children with polyarticular JCA. Compared with healthy controls the concentrations of hemoglobin, serum iron and serum zinc were reduced in the children with polyarticular JCA (p less than 0.01) and serum copper was increased (p less than 0.01). In the patients the concentrations of hemoglobin, serum iron and serum zinc correlated negatively with erythrocyte sedimentation rate (ESR), whereas serum copper correlated positively. Impaired nutritional status was found in the children with polyarticular JCA in spite of increased energy and protein intake. In this group of patients the dietary intake of calcium was also found to be reduced.