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.

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.

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.

Isolated hepatic perfusion in the pig with TNF-alpha with and without melphalan.

Isolated limb perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-alpha with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 microg kg(-1) TNF-alpha (n = 5), (2) 50 microg kg(-1) TNF-alpha plus 1 mg kg(-1) melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-alpha levels of 5.1 +/- 0.78 x 10(6) pg ml(-1) (+/- s.e.m). Systemic leakage of TNF-alpha from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-alpha levels was observed in groups 1 and 2 with a median peak level of 23 +/- 3 x 10(3) pg ml(-1) at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-alpha with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.

Functional analysis of synovial fluid and peripheral blood T cells from patients with rheumatoid arthritis.

Rheumatoid arthritis is a T cell-mediated autoimmune disease. The lack of knowledge of the involved target antigens severely hampers research on relevant T cells in patients. Here we describe the functional analysis of freshly isolated T cells from the peripheral blood and the site of the lesion (synovial fluid or synovial membrane) of patients with rheumatoid arthritis. Healthy donors and osteoarthritis patients served as controls. Using various polyclonal stimuli, we analyzed CD4+ T cells with respect to proliferation and their ability to produce lymphokines. Our data show that lesion-derived CD4+ T cells of patients with rheumatoid arthritis are severely defective in proliferation and lymphokine (interleukin-2, interleukin-4, tumor necrosis factor-alpha, interferon-gamma) production. This activation defect was most pronounced at lower cell densities and was present in both synovial fluid derived and synovial membrane derived CD4+ T cells of all patients tested. No difference was found between responses of synovial fluid derived CD4+ T cells from osteoarthritis patients and those observed with peripheral blood derived T cells from all groups. The observed defect in lesion-derived CD4+ T cells from rheumatoid arthritis patients was not due to the effect of inflammatory factors in the synovial fluid because preincubation with synovial fluid could not induce a similar defect in control T cells. Together, our data show a rheumatoid arthritis specific, general defect in the activation of lesion-derived CD4+ T cells.

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.

Responses of synovial fluid and peripheral blood mononuclear cells to bacterial antigens and autologous antigen presenting cells.

The specificity of T cells in the inflamed joints of patients with rheumatoid arthritis (RA) has been the subject of much study. Bacterial antigens are suspect in the aetiology of rheumatic diseases. The responsiveness of the mononuclear cell fraction of peripheral blood and synovial fluid of patients with RA and of patients with rheumatic diseases other than RA to bacterial antigens such as cell wall fragments of the anaerobic intestinal flora, cell wall fragments of Streptococcus pyogenes, intestinal flora derived peptidoglycan polysaccharide complexes, the 65 kilodalton protein of Mycobacterium tuberculosis, and muramyldipeptide was investigated. No significant difference in response was found to all these bacterial antigens in the synovial fluid of patients with RA compared with the responses in patients with other rheumatic diseases. The highest responsiveness in the synovial fluid of the patients with RA was to the streptococcal cell wall fragments and to the 65 kilodalton protein. Higher responses to several bacterial antigens in the synovial fluid of patients with RA were found compared with peripheral blood from the same patient group. The antigen presenting cell population of the synovial fluid in patients with RA and the patients with other rheumatic diseases was found to be stimulatory for autologous peripheral blood T cells even in the absence of antigen. This suggests an important role for the synovial antigen presenting cell in the aetiology of inflammatory joint diseases.

Proteolytic inactivation of alpha 1-antitrypsin and alpha 1-antichymotrypsin by neutrophils in arthritic joints.

OBJECTIVE: In vitro, activated neutrophils create a microenvironment in which proteinase inhibitors are inactivated through the coordinate action of reactive oxygen species and released elastase. We investigated whether such a mechanism may contribute to the destruction of the joint tissues in arthritis. METHODS: We analyzed the state of alpha 1-antitrypsin (alpha 1AT) and alpha 1-antichymotrypsin (alpha 1ACT), the two major inhibitors of the neutrophilic serine proteinases, in synovial fluid (SF) from patients with inflammatory arthropathies (n = 71) and osteoarthritis (OA) (n = 11), and related the results to neutrophil activation in SF. RESULTS: The ratio of functional to antigenic levels of alpha 1AT in SF of patients with inflammatory joint diseases was similar to that of alpha 1AT in normal plasma, whereas that of alpha 1ACT was significantly decreased. Patients with inflammatory arthropathies had significantly higher levels of inactivated alpha 1AT (i alpha 1AT) and inactivated alpha 1ACT (i alpha 1ACT) in SF (as determined with monoclonal antibodies specific for the inactivated [i.e., proteolytically inactivated and/or complexed] forms of these inhibitors) than patients with OA (P < 0.005). Inactivated alpha 1AT and i alpha 1ACT levels corresponded to 0.3-11% and 3-99%, respectively, of the total amount of these inhibitors in SF. Most of the i alpha 1AT in SF had a lower M(r) than that of native alpha 1AT. Inactivated alpha 1ACT in SF had an M(r) identical to that of nonfunctional alpha 1ACT in plasma treated with chymotrypsin. Levels of both i alpha 1AT and i alpha 1ACT correlated significantly with lactoferrin and elastase levels. CONCLUSION: These results suggest that alpha 1AT and alpha 1ACT in arthritic joints are inactivated in part by activated neutrophils, suggesting a role for these cells in impairment of the local balance between proteinases and their inhibitors in arthritis.

Analysis of intraarticular fibrinolytic pathways in patients with inflammatory and noninflammatory joint diseases.

OBJECTIVE: Intraarticular activation of the fibrinolytic system has been suspected to occur in patients with arthritis. We undertook the present study to investigate the relation of this activation to clinical symptoms, and the molecular pathways involved. METHODS: We quantitatively assessed levels of plasmin-alpha 2-antiplasmin (PAP) complexes in synovial fluid (SF) from 25 patients with rheumatoid arthritis (RA), 7 with seronegative spondylarthropathy (SSA), and 10 with osteoarthritis (OA), and conducted an analysis to determine the plasminogen-activating pathway via which these complexes were generated. In addition, we studied the relationship of intraarticular fibrinolysis to clinical and biochemical parameters. RESULTS: All patients studied had increased SF levels of PAP complexes. Levels in patients with RA and SSA were slightly higher than those in patients with OA. These complexes were probably formed by activation of urokinase-type plasminogen activator (u-PA), and not tissue-type plasminogen activator (t-PA), since SF levels of both u-PA antigen and u-PA-plasminogen activator inhibitor (PAI) complexes were increased in 27 of the 42 patients. Conversely, SF levels of t-PA were below normal in all but 1 patient. In some patients, activation of factor XII presumably also contributed to plasminogen activation in SF, since levels of factor XIIa-C1 inhibitor in SF were increased in 8 of the 42 patients and correlated, as did u-PA-PAI levels, with levels of PAP complexes. Several of the parameters of fibrinolysis in SF, particularly u-PA antigen and u-PA-PAI-1 complexes, were found to correlate with clinical and biochemical parameters. CONCLUSION: Our results suggest that plasminogen is frequently activated in the joints of patients with inflammatory or noninflammatory arthropathy and that this activation mainly occurs via a u-PA-, and in some cases also via a factor XII-, dependent pathway. The possible relation of this activation process to stimulation of synovial cells by cytokines is discussed.

Diagnostic value of antibodies against ribosomal phosphoproteins. A cross sectional and longitudinal study.

Antibodies against ribosomal phosphoproteins (anti-P antibodies) are found in about 10% of patients with systemic lupus erythematosus (SLE). Using an ELISA with a synthetic peptide for screening and an immunoblotting technique as a confirmation test for detection of these antibodies, we found 16 positive patients among 946 sera sent to our reference laboratory for anti-DNA determination. All 12 patients on which we could obtain clinical data had clearcut SLE, fulfilling 6 ARA criteria on average. Skin symptoms were observed more frequently in anti-P positive than in anti-P negative patients with SLE. We also tested 56 sera from 54 patients with well defined SLE during monosymptomatic exacerbations and found an identical frequency of about 10% of anti-P antibodies in groups of patients with different types of exacerbation, including psychosis. A retrospective analysis of 9 patients followed 3-10 years showed that they all were already positive for anti-P at the onset of disease. In total these patients showed 15 major peaks in anti-P levels (defined as at least a 4-fold rise in titer in a period of 3 months). Five of the fluctuations in anti-P levels were paralleled by fluctuations in anti-DNA levels. In 6/15 cases, peaks of anti-P levels were accompanied by an exacerbation of SLE, but only 2 peaks of anti-P levels were already detectable before the onset of the exacerbation. In addition, 6 other exacerbations occurred in the absence of major anti-P rises in the preceding 3 months. Therefore, quantitative determinations of anti-P have at most a limited practical value in the followup of patients with SLE.

Sjögren syndrome: comparative studies in local ocular and serum immunoglobulin concentrations with special reference to secretory IgA.

The objective of the present study was to examine Secretory IgA in tears and serum of Sjögren patients (34 patients and 23 controls). The test was performed in a parallel study using a polyclonal and a monoclonal method (Inter-Assay variation 9.1/Intra-Assay variation 5.5). No differences in the levels of tear secretory IgA were found between patients and controls. In serum however, secretory IgA, total IgA, IgM and IgG showed a significant increase in the Sjögren patients. The fact that secretory IgA levels remain normal in the ocular mucosa of these patients may explain that, despite the autoimmune destruction of the lacrimal gland, humoral defense factors are normally present on the surface of the eye to combat infections.

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.

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.

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.

Contribution of renal biopsy data in predicting outcome in lupus nephritis. Analysis of 116 patients.

We reassessed renal biopsy specimens from 116 patients with systemic lupus erythematosus and clinical manifestations of lupus nephritis to determine the contributions of the World Health Organization classification system, the activity and chronicity indexes of the National Institutes of Health scoring system, and various clinical parameters at the time of biopsy to predicting disease outcome. Multivariate analysis showed that only a chronicity index greater than 3 was predictive for decreased renal survival, while age greater than 31 years at biopsy and a chronicity index greater than 3 were associated with decreased patient survival. Clinical tests of renal function were not reliable in discriminating between active lesions and chronic renal damage.

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.

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.