Good survival rates in systemic lupus erythematosus in southern Sweden, while the mortality rate remains increased compared with the population.

OBJECTIVE: To ascertain the mortality rate and causes of death in patients with systemic lupus erythematosus (SLE) within a defined region in southern Sweden during the time period 1981-2014 and determine whether these have changed over time. METHODS: In 1981, a prospective observation study of patients with SLE was initiated in southern Sweden. All incident SLE patients within a defined geographic area were identified using previously validated methods including diagnosis and immunology registers. Patients with a confirmed SLE diagnosis were then followed prospectively at the Department of Rheumatology in Lund. Clinical data was collected at regular visits. Patients were recruited from 1981 to 2006 and followed until 2014. The patient cohort was split into two groups based on the year of diagnosis to determine secular trends. Causes of death were retrieved from medical records and from the cause of death registry at The National Board of Health and Welfare in Sweden. RESULTS: In all, 175 patients were diagnosed with SLE during the study period. A total of 60 deaths occurred during a total of 3053 years of follow-up. In the first half of the study inclusion period 46 patients died, compared with 14 in the latter. The majority of patients (51.7%) died of cardiovascular disease. Infections caused 15% of the deaths and malignancy was the cause of death in 13.3% of patients. SLE was the main cause of death for 6.7% of the patients and a contributing factor for half of the patients. Standardized mortality ratio was increased in patients by a factor of 2.5 compared with the general population. Deaths occurred at an even rate throughout the whole observation period. No significant difference in standardized mortality ratio was observed between genders but was increased in older female patients. Furthermore, secular mortality trends were not identified. CONCLUSIONS: In this long-term epidemiologic follow-up study of incident SLE, we report a substantially raised mortality rate amongst SLE patients compared with the general population. The mortality rates have not changed significantly during the observation period that spanned three decades. The main cause of death was cardiovascular disease and this finding was consistent over time.

Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus.

Objectives Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs. Methods Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Serum-mediated phagocytosis of NCs by PMNs was analysed by flow cytometry. Clinical data were recorded at time points of blood sampling. Results Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity ( p = 0.01 and p = 0.008, respectively). Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies ( p = 0.01) and glomerulonephritis before treatment ( p = 0.02). Immunosuppressive therapy was associated with a reduction of S100A8/A9 serum levels ( p = 0.002). The ability of serum to support phagocytosis of NCs by PMNs was related to increased S100A8/A9 levels ( p = 0.01). Conclusions Elevated serum levels of S100A8/A9 may be used to monitor disease activity and response to treatment in SLE patients, especially in patients with glomerulonephritis. S100A12 may be a marker of disease activity in SLE. Increased S100A8/A9 levels may reflect immune-pathological processes involving phagocytosis of immune complexes by PMNs.

An observational study of outcome in SLE patients with biopsy-verified glomerulonephritis between 1986 and 2004 in a defined area of southern Sweden: the clinical utility of the ACR renal response criteria and predictors for renal outcome.

OBJECTIVES: To test the utility of the World Health Organization (WHO) and International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria for lupus nephritis (LN) in systemic lupus erythematosus (SLE) and the American College of Rheumatology renal response criteria (ACR-RRC) for renal follow-up in an observational cohort. METHOD: All 52 biopsy-verified cases of LN during 19 years were identified, and glomerular filtration rate (GFR), serum creatinine, proteinuria, haematuria, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and complement were retrieved at diagnosis of nephritis, after 6 and 12 months, and at the latest visit. Forty-five renal biopsies were available for re-evaluation with the ISN/RPS criteria. Outcome was defined by the ACR-RRC and the final GFR. RESULTS: The mean follow-up time was 9 years; complete renal response (CRR) was achieved in 11 cases, end-stage renal disease (ESRD) in four, and nephrotic syndrome (NS) in one. The final GFR decreased with increasing age at biopsy (p < 0.01) and with interstitial manifestations added to the ISN/RPS classification (p < 0.05). The final GFR correlated with the decrease of proteinuria or casts and actual serum creatinine after 6 months of treatment (all p < 0.05). The outcome defined by ACR-RRC correlated with the nephrological components of SLEDAI-2K after 6 months of therapy (p < 0.01) and with the presence of antibodies to C1q at biopsy (p < 0.05). CONCLUSIONS: Renal outcome is correlated with the response to treatment after 6 months and with the addition of interstitial changes to the ISN/RPS classification, which might add useful information for prediction. The ACR-RRC offers a defined alternative to categorize renal response.

Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility.

The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

Systemic lupus erythematosus and cardiac risk factors: medical record documentation and patient adherence.

This study explores patients' knowledge of cardiac risk factors (CRFs), analyses how information and advice about CRFs are documented in clinical practice, and assesses patient adherence to received instructions to decrease CRFs. Systemic lupus erythematosus (SLE) patients with ≥ 4 ACR criteria participated through completing a validated cardiovascular health questionnaire (CHQ). Kappa statistics were used to compare medical records with the self-reported CHQ (agreement) and to evaluate adherence. Two hundred and eleven (72%) of the known patients with SLE participated. The mean age of the patients was 55 years. More than 70% of the SLE patients considered hypertension, obesity, smoking and hypercholesterolaemia to be very important CRFs. The agreement between medical record documentation and patients' reports was moderate for hypertension, overweight and hypercholesterolaemia (kappa 0.42-0.60) but substantial for diabetes (kappa 0.66). Patients' self-reported adherence to advice they had received regarding medication was substantial to perfect (kappa 0.65-1.0). For lifestyle changes in patients with hypertension and overweight, adherence was only fair to moderate (kappa 0.13-0.47). Swedish SLE patients' awareness of traditional CRFs was good in this study. However, the agreement between patients' self-reports and medical record documentation of CRF profiles, and patients' adherence to medical advice to CRF profiles, could be improved.

Progressive multifocal leukoencephalopathy - the importance of early diagnosis illustrated in four cases.

Progressive multifocal leukoencephalopathy (PML) is a rare, deadly demyelinating disease of the central nervous system, which is caused by a reactivation of the DNA polyomavirus JC and occurs in immunosuppressed individuals. So far, only 25 cases have been described in patients with SLE and none survived without antiviral therapy and only two cases in RA. We present four additional cases from a defined area, three in SLE, of which one survived without antiviral therapy, and one case in RA, also surviving after reduction of immunosuppressive treatment. In three of these cases, diagnosis could only be confirmed by stereotactical brain biopsy, including the two surviving cases. Thus, this article illustrates the difficulty in diagnosing progressive multifocal leukoencephalopathy, the need for brain biopsy in many cases, the importance of reduced immunosuppression as early as possible and the severe damage progressive multifocal leukoencephalopathy can cause. Furthermore, progressive multifocal leukoencephalopathy might be much more common in SLE than expected with 1 case in 800 patient-years.

Association between SLE nephritis and polymorphic variants of the CRP and FcgammaRIIIa genes.

OBJECTIVES: To study the relationship between clinical manifestations in systemic lupus erythematosus (SLE) with polymorphisms in suggested susceptibility genes encoding FcgammaRIIa, FcgammaRIIIa, FcgammaRIIIb, CRP and IL-1Ra. METHODS: Genetic polymorphisms were analysed in 323 unrelated SLE patients and 200 healthy blood donors. The genotype frequencies were compared between clinical subsets of SLE patients, as well as with healthy controls. Clinical manifestations included the ACR classification criteria. Nephritis was further classified according to WHO class on renal biopsy. RESULTS: Presence of a CRP4 A-allele was associated with SLE nephritis (P < 0.01) and inversely correlated with arthritis (P < 0.01), when comparing within the SLE group. The FcgammaRIIIa F/F genotype was also associated with nephritis (WHO class III and IV, P = 0.04 for the SLE group) and in combination with the CRP4 A-allele a stronger association was noted (P < 0.001). Furthermore, the FcgammaRIIIb NA2/NA2 genotype was associated with butterfly rash (P < 0.01). An association was found between seizures and the presence of both the FcgammaRIIa R/R and the FcgammaRIIIa F/F genotypes (P < 0.01) and an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele (P = 0.01). Furthermore, a combination of the FcgammaRIIa R/R genotype and CRP4 A-allele was associated with lymphopenia (P = 0.02) and a similar result was found for the combination of FcgammaRIIIa F/F and FcgammaRIIIb NA2/NA2 (P = 0.04). CONCLUSIONS: Polymorphic variants of the CRP and Fcgamma-receptor genes are associated with the clinical phenotype in SLE. Our findings suggest an immune complex-mediated pathogenesis in nephritis and seizures, while development of arthritis may depend on other pathogenetic pathways.

Genetically determined mannan-binding lectin deficiency is of minor importance in determining susceptibility to severe infections and vascular organ damage in systemic lupus erythematosus.

Deficiency of mannan-binding lectin (MBL) has been reported to impact susceptibility to severe infections and atherosclerosis in systemic lupus erythematosus (SLE). In this study, MBL gene polymorphisms were analysed in 143 SLE patients and the frequency of severe infections and organ damage according to SLICC/ACR Damage Index regarding cerebrovascular accidents, angina pectoris, coronary by-pass surgery, myocardial infarction and peripheral arterial disease leading to significant tissue loss, were recorded during a mean follow-up time of 15 years from diagnosis. In a multiple logistic regression model, smoking (P = 0.001), hypertension (P = 0.030), alcohol intake (P = 0.027) and higher triglyceride concentration (P = 0.026) were associated with cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD), while the association with MBL deficiency did not reach significance (P = 0.098). Alcohol intake (>15 g/month) was inversely correlated with CPAD (OR = 0.29, 95%CI 0.096-0.87). MBL deficiency was not significantly more common in SLE patients with severe infections in a multivariate analysis (P > 0.3). In conclusion, classical risk factors such as smoking, hypertension, low alcohol intake and elevated triglyceride concentration were relatively more important for development of CPAD than MBL deficiency in SLE. Furthermore, MBL deficiency did not contribute to development of major infections in SLE.

The heterogeneity of neuropsychiatric systemic lupus erythematosus is reflected in lack of association with cerebrospinal fluid cytokine profiles.

The objective was to study the occurrence of autoantibodies and cytokines in serum and cerebrospinal fluid (CSF) in neuropsychiatric systemic lupus erythematosus (NPSLE). In total, 28 consecutive patients with NPSLE and 16 systemic lupus erythematosus (SLE) patients without neuropsychiatric involvement (non-NPSLE) were studied. IFN-alpha, IL-6, IL-10, soluble terminal complement complex (TCC), anti-ribosomal P protein antibodies (anti-P) and anti-cardiolipin antibodies (aCL) were measured in serum and CSF by immunoassays. Analyses of white blood cell differential count, CSF-albumin/serum-albumin ratio, IgG-index in CSF and isoelectric focusing in serum and CSF were also performed. CSF specimens from 23 healthy individuals were used as controls. IFN-alpha was elevated in the CSF of 5 of 28 NPSLE patients compared to three of 14 among the non-NPSLE patients. IL-6 was elevated in CSF in three of 26 NPSLE patients. Normal concentration of IL-10 was found in CSF in all 27 NPSLE-patients analysed. IFN-alpha in serum was elevated in 18 of 28 NPSLE patients. No distinct clinical phenotype was related to elevated cytokine concentration in serum or CSF. One patient with cerebral involvement complicated by progressive multifocal leukoencephalopathy displayed a very high IFN-alpha concentration in serum. High concentration of TCC was present in CSF from only one patient with systemic vasculitis and focal cerebral symptoms. In conclusion, the results of this study suggest that the diagnostic value of serum and CSF concentrations of IFN-alpha, IL-10, IL-6 and TCC is limited in unselected neuropsychiatric SLE, probably due to the heterogeneity of NPSLE pathogenesis.

Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome.

Two-hundred ninety five patients with the antiphospholipid syndrome (APS) were studied for the presence of antibodies against six anti-beta2GPI-related peptides Abs. The prevalence of a wide spectrum of clinical and laboratory parameters of APS was evaluated in all patients, and correlated with the presence of each anti-beta2GPI peptide antibody. The rates of the various antipeptides Abs ranged from 18.0 to 63.7%. Altogether, 87.1% of the patients had antibody reactivity against at least one of the six beta2GPI-related peptides. A high degree of simultaneous reactivity against several beta2GPI-peptides was found. Positive and negative correlations were found between several antipeptides Abs and the rates of thrombosis and fetal loss. Our results point to a heterogeneous activity of antiphospholipid Abs in APS patients, directed, often concurrently, against various epitopes of the beta2GPI molecule. Evaluation of APS patients for the presence of specific antipeptides Abs may be of a value in predicting the risk for future thrombotic and obstetrical complication, as well as for specific therapeutic purposes.

Malignancies during follow-up in an epidemiologically defined systemic lupus erythematosus inception cohort in southern Sweden.

The objective of this study was to identify all malignancies in an inception cohort of SLE patients in southern Sweden and compare with the observed frequencies and spectrum of malignancies in the general population. All adult incidence cases of SLE in a defined population during the period 1981-1996 were retrieved from a prospective database and the cases were followed to endpoint or through 1998. The SLE cohort registry was aggregated with the National Cancer Registry to identify all malignancies by date, type and outcome. Standardized morbidity rates (SMR) were calculated based on the sex- and age-matched general population of the region. Sixteen malignancies occurred in 13 patients out of a total of 116 SLE patients observed for 1086 patient-years. The SMR for all cancers detected was 2.24 (confidence interval 0.6-5.7) for males and 1.02 (confidence interval 0.4-2.1) for females and thus indicative of no general increase in malignancies. However, the SMR for non-Hodgkin lymphoma was 11.63 (confidence interval 1.4-42.0), for pulmonary cancer 5.55 (confidence interval 0.7-20.1) and prostatic cancer 6.41 (confidence interval 1.3-18.7) all significantly increased. The increase in prostatic carcinoma disappeared when only cases occurring after a latency period of 3y after SLE diagnosis were included. In this comprehensive inception cohort of SLE no increase in relative risk of malignancy overall was found, but the frequencies of non-Hodgkin lymphoma and pulmonary cancer were increased, possibly also the frequency of prostatic carcinoma.

Attitudes toward assisted suicide and euthanasia among physicians in Washington State.

BACKGROUND: Despite considerable public interest in legalizing physician-assisted suicide and euthanasia, little is known about physicians' attitudes toward these practices. METHODS: We sent questionnaires to 1355 randomly selected physicians in the state of Washington, including all hematologists and oncologists and a disproportionately high number of internists, family practitioners, psychiatrists, and general surgeons. To avoid ambiguity in our survey, instead of "physician-assisted suicide," we used the phrase "prescription of medication [e.g., narcotics or barbiturates] or the counseling of an ill patient so he or she may use an overdose to end his or her own life." Instead of "euthanasia," we used the phrase "deliberate administration of an overdose of medication to an ill patient at his or her request with the primary intent to end his or her life." RESULTS: Of the 1355 eligible physicians who received our questionnaire, 938 (69 percent) responded. Forty-eight percent of the respondents agreed with the statement that euthanasia is never ethically justified, and 42 percent disagreed. Fifty-four percent thought euthanasia should be legal in some situations, but only 33 percent stated that they would be willing to perform euthanasia. Thirty-nine percent of respondents agreed with the statement that physician-assisted suicide is never ethically justified, and 50 percent disagreed. Fifty-three percent thought assisted suicide should be legal in some situations, but only 40 percent stated that they would be willing to assist a patient in committing suicide. Of the groups surveyed, hematologists and oncologists were most likely to oppose euthanasia and assisted suicide, and psychiatrists were most likely to support these practices. CONCLUSIONS: The attitudes toward physician-assisted suicide and euthanasia of physicians in Washington State are polarized. A slight majority favors legalizing physician-assisted suicide and euthanasia in at least some situations, but most would be unwilling to participate in these practices themselves.

Effect of organic solvents on nervous cell membrane as measured by changes in the (Ca2+/Mg2+) ATPase activity and fluidity of synaptosomal membrane.

The effect of various solvents on the central nervous system was studied by using rat brain synaptosomal membranes as an in vitro model. The activity of (Ca2+/Mg2+) ATPase and the membrane fluidity was determined. The alteration of the ATPase activity depended on the physio-chemical characteristics of the solvent in question. Incubation with aliphatic alkanes caused a stimulation of the ATPase activity whereas mixed hydrocarbons as kerosene, white spirit and gasoline inhibited the enzyme. Incubation with chlorinated hydrocarbons caused a biphasic response dependent on the concentration. Oxygen-containing hydrocarbons exhibited various effects as found after incubation with hydrocarbons. The different effects of the solvents on the ATPase activity suggest that the lipophilicity of the solvents is one of more parameters affecting the membrane. Furthermore, the biphasic response following the incubation with chlorinated hydrocarbons indicates that more mechanisms are involved in the enzyme effect. The membrane fluidity is increased with higher concentrations of the solvents. From the results it is concluded that the ATPase activity depends not only on the membrane fluidity and volume, but also on the hydrophilic vicinity of the enzyme molecule.

Effects of simultaneous ethanol and toluene exposure on nerve cells measured by changes in synaptosomal calcium uptake and (Ca2+/Mg2+)-ATPase activity.

The effect of simultaneous exposure of rats to toluene and ethanol on synaptosomal calcium uptake and (Ca2+/Mg2+)-ATPase activity was studied. Rats were exposed to 500 p.p.m. toluene by inhalation for 12 hr a day during four weeks. During the exposure period, the rats had access to 5% sucrose solution containing 20% ethanol or to 5% sucrose solution alone. Rats drinking ethanol exhibited a smaller weight gain than rats drinking water alone. Furthermore, rats exposed simultaneously to toluene and ethanol had a higher ethanol intake than unexposed rats. The toluene exposure caused a higher synaptosomal calcium uptake in vitro. Ethanol intake did not change the synaptosomal calcium uptake in vitro. The synaptosomal calcium uptake in rats exposed to toluene and ethanol was nearly identical to that measured in control rats. In vivo exposure to toluene, or ethanol, or toluene/ethanol simultaneously did not affect the (Ca2+/Mg2+)-ATPase activity in vitro. Incubation with toluene in vitro decreased the (Ca2+/Mg2+)-ATPase activity in a concentration dependent manner. Ethanol had only a slight effect on the enzyme. Simultaneous incubation with toluene and ethanol showed an antagonistic effect of ethanol on the toluene inhibition of the ATPase activity.

The effects of alcohols in vitro on the nervous cell membrane measured by changes in the (Ca2+/Mg2+) ATPase activity and fluidity of the synaptosomal membrane.

The effect of various alkanols on the central nervous system was studied by using rat brain synaptosomal membranes as an in vitro model. The activity of (Ca2+/Mg2+)ATPase and the membrane fluidity were determined. The n-alkanols exhibited an increased molar inhibition of the ATPase activity with an increase in the carbon chain length up to 1-octanol. 1-octanol and 1-decanol caused a biphasic effect on the ATPase activity depending on the alkanol concentration, whereas 1-dodecanol caused a stimulation of the ATPase activity. All alkanols studied caused an increased fluidity of the membrane. Our results indicate that the effect of alkanols on the ATPase activity depends on changes in the border layer between the membrane and the surrounding medium and on a binding of the alkanols to the enzyme molecule. Furthermore, the two-way effect of 1-octanol and 1-decanol and the stimulatory effect of 1-dodecanol indicate that more mechanisms are involved. In addition, the results indicate that changes in the membrane fluidity do not seem to be a prerequisite of the ATPase inhibition.

The effect of toluene exposure for up to 18 months (78 weeks) on the (Ca2+/Mg2+)ATPase and fluidity of synaptosomal membranes isolated from rat brain.

The effect of toluene on the central nerve system was studied by using rat brain synaptosomal membranes as in vitro and in vivo models. The activity of Ca2+/Mg2+ ATPase and the membrane fluidity were determined. Short-term exposure in vivo to 500 p.p.m. of toluene had an inhibitory effect on the enzyme studied whereas long-term exposure to toluene caused an increased activity. Exposure to toluene had no effect at all on the membrane fluidity. The in vitro experiment showed an effect of toluene on both parameters. The alteration in the enzyme activity and membrane fluidity was parallel in the exposed animals as well as those of control. Our results show that long-term exposure to toluene affects nerve cell membranes by other mechanisms than those observed under in vitro conditions.