Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus.

An inception cohort of patients with systemic lupus erythematosus from 14 European centres was followed for up to 5 years in order to describe the current early disease course. At inclusion patients (n = 200, 89% female, mean age 35 years, 97% Caucasian, mean SLEDAI 12.2) fulfilled a mean of 6.5 ACR classification criteria. The most prevalent criteria were antinuclear Ab presence (97%) followed by anti-dsDNA Ab (74%), arthritis (69%), leukocytopenia (54%) and malar rash (53%), antiphospholipid Ab (48%) and anti-synovial membrane Ab (21.6%). Clinical signs of lupus nephritis (LN) were present in 39% with biopsy-confirmed LN seen in 25%. Frequent additional findings were hypocomplementaemia (54%), anti-SSA Ab (49%), alopecia (26%) and Raynaud's phenomenon (31%). There were few regional differences in disease presentation and management. One and 5-year survival rates were 99% and 97% respectively. During the mean follow-up of 4.1 years 25% entered a state of early disease quiescence by global physician assessment, but the overall risk of subsequent flare was 60%. Maximum SLEDAI scores decreased over time, but 45% of patients accrued damage (SDI >or=1) for which baseline presence of proteinuria and persistent disease activity were independent predictors. The results indicate minor differences in SLE presentation and treatment within various regions of Europe and a high diagnostic reliance on anti-dsDNA Ab. Despite early reductions in disease activity and improved mortality, the risk for disease flare and damage development is, however, still substantial, especially in patients not entering an early remission.

Clinical significance of maternal anti-Ro/SS-A antibodies in children with isolated heart block.

OBJECTIVES: We studied 30 consecutive children with isolated heart block to assess the clinical impact of the presence of maternal anti-Ro/SS-A antibodies for isolated heart block. BACKGROUND: Isolated heart block in children, often associated with maternal autoimmune disease leading to anti-Ro/SS-A auto-antibody production, is an infrequent but potentially lethal disorder. METHODS: Thirty children with isolated heart block were studied with respect to medical history and electrocardiographic (ECG) analysis. The presence of anti-Ro/SS-A antibodies was determined in the maternal serum. We also examined the ECGs of all brothers and sisters of the patients for conduction abnormalities. RESULTS: Twenty-one of the 30 children had an anti-Ro/SS-A-positive mother (group A); the other 9 children had an anti-Ro/SS-A-negative mother (group B). Comparison of the clinical data from both mothers and children revealed that these two groups differed significantly with respect to the following: Prenatal diagnosis and obstetric complications occurred more often in group A, whereas progression to complete block, QRS width > 0.08 s, premature ventricular contractions and ventricular standstills > 4.5 s occurred more often in group B. In addition, mothers of children in group A reported more spontaneous abortions. All siblings of children in groups A and B had normal ECGs, excluding a subclinical form of heart block. CONCLUSIONS: Two types of heart block can be recognized: Congenital heart block is associated with maternal anti-Ro/SS-A antibodies and numerous obstetric and neonatal complications. It is diagnosed prenatally or at birth and is usually complete at onset and probably has a substantial recurrence risk. Heart block that is acquired later in life is not associated with maternal autoimmunity and has no risk for recurrence. It often presents as a partial block but progresses to complete block in time.

Dissociation studies of DNA/anti-DNA complexes in relation to anti-DNA avidity.

Antibodies to dsDNA differ in their avidity towards the antigen. The electrostatic interaction between DNA and anti-DNA is sensitive to increases in pH and/or ionic strength and therefore, elution studies employing either of these permit discrimination between anti-dsDNA populations that differ in avidity. Another way to determine anti-dsDNA avidity is the calculation of Farr/PEG ratios. These are obtained by division of the amount of anti-DNA measured with the Farr assay (which does not detect low avidity anti-dsDNA) by the amount measured with the PEG assay (which does detect low avidity anti-dsDNA). With these separate approaches, we compared the sera of 17 SLE patients with nephritis with the sera of 17 patients with central nervous system (CNS) involvement. Farr/PEG ratios and sensitivity to high pH elution of anti-dsDNA in the sera of these patients both permitted discrimination between the two groups of patients. The anti-dsDNA of patients with nephritis was found to have a significantly higher avidity towards DNA than anti-dsDNA of patients with cerebral disease. We also observed a significant correlation between Farr/PEG ratios and the salt lability of anti-dsDNA.

Systemic lupus erythematosus: analysis of disease activity in 55 patients with end-stage renal failure treated with hemodialysis or continuous ambulatory peritoneal dialysis. Dutch Working Party on SLE.

PURPOSE: To compare disease activity in patients with systemic lupus erythematosus (SLE) (1) before and after the onset of end-stage renal failure and (2) during hemodialysis and continuous ambulatory peritoneal dialysis (CAPD). PATIENTS AND METHODS: Records of 55 patients with SLE currently being treated with dialysis were reviewed. Disease activity was measured according to the SLE Disease Activity Index, event rates per 1,000 months' patient observation, and use of medication. RESULTS: In the majority of patients, deterioration of renal function was slowly progressive over more than 2 years. After the initiation of dialysis for end-stage renal failure, maximal extrarenal disease activity and use of medication decreased markedly, but event rates for specific nonrenal manifestations of lupus did not decrease. Overall survival with dialysis was 89% after 5 years. During dialysis no difference was found in disease activity and use of medication between treatment with either hemodialysis of CAPD. Thrombocytopenia and elevated levels of anti-double-stranded DNA, however, occurred more frequently during CAPD. CONCLUSION: Patients with SLE have excellent survival rates with dialysis; their disease activity is diminished during dialysis but not abolished. No difference in survival or disease activity was found between patients undergoing hemodialysis or CAPD.

Clinical significance of antibodies to double stranded DNA (dsDNA) for systemic lupus erythematosus (SLE).

In sera of patients with systemic lupus erythematosus (SLE) a wide variety of antibodies against nuclear antigens can be found, including antibodies to nucleic acids, histones and non-histone nuclear proteins. Among these, antibodies to double stranded DNA (dsDNA) appear to be mainly restricted to SLE. Yet, in daily practice one also finds patients that have antibodies to dsDNA during a long time ( greater than 5 years) but have not developed SLE. These anti-dsDNA positive non-SLE patients often fulfil several of the ARA criteria for SLE though one may not conclude that they form a specific clinical subset of SLE. It has often been tried to discriminate between clinical subsets of this heterogeneous disease by studying differences within the population of anti-dsDNA antibodies. Immunospecificity, complement-fixing ability, avidity, immunoglobulin (sub)class composition have all been the subject of different studies; yet, conclusions from these studies are often contradictory and more work will be necessary to elucidate this. The prognostic significance of anti-dsDNA levels in prospective studies has been proven valuable. A continuous increase in anti-dsDNA level correlates well with the appearance of an exacerbation of the disease. In other studies merely the amount of antibodies was found to be correlated with disease activity. Therapeutical consequences of these findings are still discutable. The role of anti-dsDNA antibodies in the pathogenesis of the disease is merely based on the above mentioned correlations and on the specificity of the antibodies to SLE. Questions regarding the etiology of SLE or the mere existence of anti-dsDNA antibodies in this kind of patients are unresolved.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal tubular dysfunction in primary Sjögren's syndrome: clinical studies in 27 patients.

Kidney involvement in Sjögren's syndrome (SS) including renal tubular disorders are well recognized but little is known about frequency and extent of such dysfunction in the general population of patients with primary SS, due to a lack of group studies. We studied 27 patients with primary SS and without other possible causes of tubular dysfunction. Increased urinary beta 2M excretion, due to proximal tubular dysfunction, was present in 26% of patients. Inadequate urine acidification after oral NH4 Cl, proving distal tubular dysfunction, was found in 12% of the patients studied. Concentrating ability, tested by thirst, was decreased in 44% of patients studied. Abnormal renal tubular tests correlated with presence of ANA (p = 0.05) but not with other clinical parameters. In conclusion demonstrable renal tubular dysfunctions occur in over half the patients with primary SS. Literature concerning this subject is discussed.

A comparison of assays used for the detection of antibodies to DNA.

In this paper we will briefly compare four assays in use in our institute for the measurement of antibodies to DNA: the anti-DNA ELISA, the PEG assay, the indirect immunofluorescence test on Crithidia luciliae and the Farr assay. Although with the use of sera from defined patients with systemic lupus erythematosus (SLE) quite good correlations were obtained between the various assays, these correlations were lost upon the use in routine screening of sera of undefined patients. It will be shown that the Farr assay has the highest specificity to systemic lupus erythematosus, whereas the ELISA and the PEG assay are the most sensitive methods. In its present form, however, the ELISA is not suited for the detection of IgM anti-DNA. Furthermore, this technique alone also detects DNA/-anti-DNA complexes present in sera or hybridoma culture supernatants.

Antibodies to DNA in patients with systemic lupus erythematosus. Their role in the diagnosis, the follow-up and the pathogenesis of the disease.

In this paper an overview of the present knowledge on antibodies against DNA will be presented. Diagnostic, prognostic and pathogenic aspects of anti-DNA will be highlighted. Detection of antibodies to DNA in the circulation of a patient by an assay selective for high avidity anti-DNA is highly diagnostic for SLE. Anti-DNA of low avidity occurs in rheumatic diseases other than SLE as well, making detection of such antibodies of less diagnostic value. Furthermore, data will be presented that show that the anti-DNA ELISA in its present form is not suited as a diagnostic tool. Not only disease features of SLE vary from patient to patient, anti-DNA avidity does so too. A relationship between anti-DNA avidity and clinical features can be found: high avidity anti-DNA is more abundant in patients with nephritis, low avidity anti-DNA in patients with CNS involvement. Prognostically, a steady increase of the level of high avidity anti-DNA generally heralds an upcoming exacerbation in a patient. Furthermore, 85% of the patients who do not have SLE at the time (high avidity) anti-DNA is detected in their serum, will develop the disease within the next few years. It is noteworthy, that patients with only low avidity anti-DNA in their circulation develop a more mild form of SLE; the (low) avidity of their anti-DNA seldomly increases during the course of their disease. The relevance of anti-DNA to the pathogenesis of SLE still is a matter of debate. On the one hand, the association of parameters of anti-DNA that determine the size of the complexes formed with DNA is in favour of the classical hypothesis, which states that SLE is primarily an immune complex disease. On the other hand, recent data on crossreactions of anti-DNA with phospholipids, glycosaminoglycans and other (poly-negative) structures plead for a role of such crossreactivities in the pathogenesis of SLE.

Increased ferritin response in adult Still's disease: specificity and relationship to outcome.

BACKGROUND: The disproportionate ferritin response encountered in some patients with adult Still's disease (ASD) may reflect a fundamental aspect in the pathophysiology of ASD. METHODS: An observational case-control study of 22 ASD patients followed for 63 months. Baseline laboratory data were compared with age- and gender-matched controls with new-onset rheumatoid arthritis (RA). Serum levels of ferritin and C-reactive protein (CRP) and the ferritin/CRP ratio were related to clinical outcome in ASD through nonparametric statistical analyses. RESULTS: Compared to RA patients, haemoglobin levels were lower (11.8 vs. 13.5 g/dL; p = 0.009) and leucocyte counts (17.1 vs. 8.6 10(9)/mL; p<0.001), erythrocyte sedimentation rate (ESR) (84 vs. 38 mm; p = 0.001), CRP (154 vs. 27 mg/L; p<0.001), aspartate aminotransferase (ASAT) (52 vs. 23 U/l; p = 0.004), serum ferritin (8750 vs. 62 microg/L; p<0.001) and ferritin/CRP ratios (9.7 vs. 1.7; p<0.001) were higher in ASD patients at baseline. Six patients (27%) achieved sustained remission (monocyclic disease), while 16 patients (73%) developed chronic disease (progressive in 27%, relapsing/remitting in 46%). The levels of ESR and CRP or other baseline variables were not associated with outcome. However, baseline serum ferritin was significantly higher in ASD patients with chronic disease (p = 0.04), while a cut-off of five times the normal upper level (NUL) was 100% sensitive and 60% specific for predicting chronic disease. CONCLUSION: An exaggerated ferritin response with levels>5 times the NUL and high ferritin/CRP ratios is useful for distinguishing between ASD and RA patients. Ferritin levels>5 times the NUL are also associated with a chronic disease course.

Detection of anti-dsDNA as a diagnostic tool: a prospective study in 441 non-systemic lupus erythematosus patients with anti-dsDNA antibody (anti-dsDNA).

The diagnostic significance of anti-double-stranded deoxyribonucleic acid (anti-dsDNA) determination was evaluated in a prospective manner from 1974 to 1982 in a group of 441 patients without systemic lupus erythematosus whose sera were found to contain antibodies to dsDNA on routine screening (Farr assay). Within one year 69% (304) of these patients fulfilled the preliminary American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE). Eighty-two of the remaining 137 patients were followed up for several years. At the end of the study 52% of these patients had also developed systemic lupus erythematosus. Patients who developed systemic lupus erythematosus were characterised by the occurrence of relatively high avidity anti-dsDNA in the circulation compared with patients who did not develop systemic lupus erythematosus. It can be concluded that about 85% of patients without systemic lupus erythematosus with anti-dsDNA in the circulation will develop SLE within a few years. Taking into account the relative avidity of anti-dsDNA, as determined by calculation of Farr/polyethylene glycol (PEG) ratios, we conclude that patients with relatively high avidity anti-dsDNA are more prone to develop systemic lupus erythematosus than patients with relatively low avidity anti-dsDNA.

Systemic lupus erythematosus. VI. Analysis of the interrelationship with pregnancy.

The influence of systemic lupus erythematosus (SLE) on pregnancy and vice versa was examined during 39 pregnancies in 19 patients, and outcome was compared with 24 pregnancies in 18 other patients before SLE was established. No difference in fetal loss or premature birth rate was found, although more babies were born with low birth weight after SLE was diagnosed; there was a preponderance of female babies in both groups. Pregnancy during SLE was accompanied by disease exacerbations in up to 74% of all patients. These exacerbations concerned mostly musculoskeletal (41%) and hematological abnormalities (36%), while organ involvement occurred in 13% of all exacerbations. No differences in pregnancy outcome during SLE were found between patients with active or quiescent disease, as established by the lupus activity criteria count (LACC). The presence of antibodies to SSA in the mother was associated with the occurrence of congenital heart block; no association was found between antiphospholipid antibodies and fetal loss.

Antinuclear antibody determination: the present state of diagnostic and clinical relevance.

Determination of antinuclear antibodies (ANA) will gain in diagnostic significance if a specific type of ANA can be related to a defined clinical disorder. The past decade has brought us quite a lot of papers dedicated to this subject. Yet, with exception of the DNA/anti-DNA system, observed correlations have remained scarce or contradictory. Also, still little is known about the pathogenic role of ANA. Perhaps more recent approaches using biochemical technologies will provide us with highly purified nuclear antigens necessary to study possible correlations at a more sophisticated level.

The effect of gravity on galvanic nystagmus in rabbits.

The effect of gravity on a galvanic nystagmus provoked in rabbits was investigated. Weightlessness increased the amplitude but decreased the frequency as well as the speed of the nystagmus. During continuous galvanic stimulation the provoked nystagmus disappeared spontaneously after a period of 60-120 seconds. Weightlessness was able to arouse this nystagmus again. An explanation of this phenomenon might be that galvanic nystagmus undergoes a modifying effect from the vestibular maculae and their state of stimulation.

Renal immunofluorescence and the prediction of renal outcome in patients with proliferative lupus nephritis.

The risk for endstage renal failure in patients with proliferative lupus nephritis (PLN) depends largely on the severity and reversibility of the inflammatory process as determined by light microscopy (LM). As the intrarenal formation of immune complexes is thought to initiate this inflammation, we studied whether renal immunofluorescence microscopy (IFM) provides clinical or prognostic information in addition to LM findings. Clinical data at the time of renal biopsy and during a mean follow-up of 46 months were extracted from the records of 69 SLE patients with proliferative LN (WHO class III/IV). Biopsy specimens were analyzed by LM for AI and CI, while IFM was performed on cryostat sections with the use of antisera against IgG, IgM, IgA, C3, C1q and fibrin. IFM findings were recorded in terms of the localization (glomerular, tubular or vascular) and intensity of fluorescence (score from zero to three). IFM findings were then related to clinical and LM findings and its prognostic value studied by survival analysis. Glomerular immune deposits were present in 99% of patients, tubular deposits in 38% and vascular deposits in 17%. A 'full-house' pattern (all three Ig classes) was found in 67% of biopsies and C3 and C1q deposits in 93% and 74% respectively. Median scores for AI and CI were 6 (1-18) and 3 (0-10); aside from a negative correlation between IgA deposits and CI, we found no other correlation between the amount or type of immune deposits and AI or CI. IgM deposits were associated with high serum levels of anti-dsDNA, while IgG deposits correlated with high ESR and serum creatinin levels. IFM scores were not related to steroid dose at the time of biopsy and neither type of glomerular, tubular or overall renal immune deposits had prognostic value for renal survival. Renal immunofluorescence does not reflect light microscopy findings in patients with PLN and does not contribute prognostic information in patients with PLN. Lupus (2000) 9, 504-510.

Is anticardiolipin activity a cross-reaction of anti-DNA or a separate entity?

Putative cross-reactions between anti-DNA and anticardiolipin activities were studied using sera of different patients and a panel of monoclonal antibodies to DNA. Sera were obtained from patients with systemic lupus erythematosus, from patients with syphilis, and from heroin addicts who showed a biologic false-positive result on the serologic test for syphilis. While the patients with syphilis and the heroin addicts had elevated levels of anticardiolipin antibodies in their circulation, no reactivity with DNA was observed in these sera. Sera from systemic lupus erythematosus patients often showed both anti-DNA and anticardiolipin activity. Although a correlation between anti-DNA and anticardiolipin titers was found, this did not always result from cross-reactivity of the same population of antibodies. In fact, we observed a relationship between cross-reactivity and antibody avidity. Anti-DNA of high avidity to DNA showed little cross-reactivity with cardiolipin. Anticardiolipin activity in such sera was based on the presence of specific anticardiolipin antibodies. Anti-DNA of low avidity was found to cross-react with cardiolipin. Among monoclonal antibodies to DNA, we found that cross-reactions with cardiolipin were rare: only 6 of 55 anti-DNA clones produced antibodies that also reacted with cardiolipin.

Systemic lupus erythematosus after renal transplantation: patient and graft survival and disease activity. The Dutch Working Party on Systemic Lupus Erythematosus.

OBJECTIVE: To determine the outcome of renal transplantation in patients with systemic lupus erythematosus and end-stage renal failure and to compare disease activity after transplantation with disease activity before transplantation. DESIGN: Retrospective case finding using data for an 8-year period from the central registry for renal replacement therapy in The Netherlands. SETTING: Tertiary care hospitals with facilities for renal transplantation in the Netherlands. PATIENTS: Twenty-eight patients who fulfilled at least four of the American Rheumatology Association's criteria for the classification of systemic lupus erythematosus and who received a renal transplant. MEASUREMENTS: Actuarial survival rates for grafts and patients after transplantation, maximal nonrenal scores on the Systemic Lupus Erythematosus Disease Activity Index, and time-adjusted disease exacerbation rates in all patients before and after transplantation. RESULTS: The actuarial graft survival rate at 1 year and 5 years was 68% (95% CI, 47% to 82%) and 54% (CI, 25% to 77%), respectively, whereas the actuarial patient survival rate was 87% (CI, 69% to 96%) at 1 and 5 years. High disease activity was not found to affect graft survival adversely before the start of renal replacement therapy or during dialysis. After transplantation, disease activity per patient and the overall incidence of disease exacerbations decreased. One case of recurrent lupus nephritis was seen. CONCLUSIONS: Patients with systemic lupus erythematosus and end-stage renal failure are excellent candidates for renal transplantation; disease activity after transplantation is sporadic and low, and the recurrence of lupus nephritis is rare.

Complement-fixing antibodies to dsDNA detected by the immunofluorescence technique on Crithidia luciliae. A critical appraisal.

Studies using an adapted immunofluorescence technique (IFT) on Crithidia luciliae to determine the complement fixing ability of antibodies to dsDNA in relation to disease manifestations, i.e., nephritis, have yielded conflicting results. To establish the relevance of these determinations, we studied sera containing antibodies to dsDNA from 64 patients with systemic lupus erythematosus (SLE), and found that anti-dsDNA of 52% of these sera had the ability to fix complement. SLE patients with nephritis demonstrated a much higher incidence of complement fixing anti-dsDNA (83%) than patients without nephritis (17%, p less than 0.01). On the other hand, patients with nephritis also had higher titers of anti-dsDNA (mean 1:400) than patients without nephritis (mean titer 1:75; p less than 0.01). A clearcut correlation between anti-dsDNA titer and complement fixing anti-dsDNA titer (p less than 0.01) was observed which obviously disturbs the correlation between nephritis and complement fixing anti-dsDNA. Comparing matched sera from patients with nephritis and patients without nephritis with the same antidsDNA titer, we found no difference in complement fixing anti-dsDNA. In the IFT used to measure complement fixing anti-dsDNA, incubation of the Crithidia slides with patients' serum was followed by an incubation with fresh normal serum which served as a source of complement. We observed that this incubation with fresh normal serum resulted in elution of anti-dsDNA antibodies from kinetoplast DNA. This elution was caused by IgG present in normal serum.

Specificity in systemic lupus erythematosus of antibodies to double-stranded DNA measured with the polyethylene glycol precipitation assay.

Recently, a new radioimmunoassay--the polyethylene glycol (PEG) assay--was introduced to measure antibodies to double-stranded (ds) DNA. In this method, polyethylene glycol precipitation of formed 3H-DNA/antiDNA complexes is used instead of the ammonium sulfate precipitation used in the Farr assay. In contrast to the Farr assay, with which only high-avidity antibodies to dsDNA are detected, the PEG assay also reportedly measures anti-dsDNA of relatively low avidity. We studied whether this gain in antibody measurement results in loss of specificity for systemic lupus erythematosus. When the PEG assay was applied to a selected panel of 440 sera from patients with various well-defined autoimmune diseases and to a group of 197 normal human control sera, matched sex and age to the patients, the method was found to be fairly specific for systemic lupus erythematosus, although the sera from some patients with myasthenia gravis and some with autoimmune liver disease were also found positive. Screening of 352 additional serum specimens, sent to our laboratory for diagnostic reasons, revealed that, with the PEG assay, an extra population of relatively low-avidity antibodies to dsDNA--missed by the Farr assay--was detected. Upon clinical evaluation, we found that the patients in whom such antibodies were detected generally fulfilled a number of the preliminary criteria of the American Rheumatism Association for systemic lupus erythematosus, but that this diagnosis often was not made. We claim that the presence of low-avidity antiDNA characterizes a milder form of the disease in which patients often show only a single clinical feature of the disease. We conclude that results of the PEG assay add valuable diagnostic and clinical information to results obtained by the Farr assay.

Low molecular weight C1q in systemic lupus erythematosus.

In sera of patients suffering from an exacerbation of systemic lupus erythematosus (SLE), increased amounts of abnormal C1q were detected, contrasting with decreased or even undetectable levels of normal C1q in these sera. When analyzed immunochemically by double immunodiffusion, this low m.w. C1q (LMW-C1q) appeared to be identical with the defective C1q in serum of individuals with an inherited, homozygous inability to produce functional plasma C1q. These persons show a tendency to develop SLE-like syndromes. Like the genetically defective C1q, the abnormal C1q molecule in SLE sera was hemolytically inactive, did not incorporate in C1, was found in the supernatant of euglobulin-precipitated serum, and appeared in the break-through fraction of a cation-exchange column. Sucrose gradients and gel filtration analyses supported the putative identity of the molecules. SDS-PAGE and immunoblots revealed the presence of subunits that reacted with antibodies against C1q and confirmed the C1q-like nature of LMW-C1q. Low levels of LMW-C1q were also detected in serum and plasma of normal individuals. A radial immunodiffusion technique was used to measure LMW-C1q in the serum of 54 patients. Although these patients were not selected for parameters of disease activity, their levels of LMW-C1q were significantly higher than those of normal individuals and children with decreased C3 levels due to acute glomerulonephritis.