Current causes of death in systemic lupus erythematosus in Europe, 2000--2004: relation to disease activity and damage accrual.

Current therapeutic and diagnostic resources have turned systemic lupus erythematosus (SLE) into a chronic disease by reducing mortality rates. The exact contribution of disease activity and disease related damage to mortality is not well studied. The aim of this study was to describe the current causes of death (COD) in a multinational European cohort of patients with SLE in relation to quantified measures of disease activity and damage. Prospective five-year observational study of case fatalities in SLE patients at 12 European centres was performed. Demographics, disease manifestations, interventions and quantified disease activity (by ECLAM and SLEDAI) and damage (by SLICC-DI) at the time of death were related to the various COD. Ninety-one case fatalities (89% females) occurred after median disease duration of 10.2 years (range 0.2-40) corresponding to a annual case fatality of one for each of the participating cohorts. Cumulative mortality correlated linearly with disease duration with nearly 10% of fatalities occurring in the first year and 40% after more than 10 years of disease. Death occurred during SLE remission in one third of cases. In the remaining cases a mixture of disease activity (median ECLAM 5.5, median SLEDAI 15) and accrued damage (median SLICC-DI 5.0) with opposing relationships to disease duration contributed to death. Infections and cardiovascular events were the most frequent COD in both early and late fatalities with no gender differences for type of COD, disease activity, damage or comorbidity. In Europe, case fatalities have become uncommon events in dedicated SLE cohorts. The bimodal mortality curve has flattened out and deaths now occur evenly throughout the disease course with infectious and cardiovascular complications as the main direct COD in both early and late fatalities. Accrued damage supplants disease activity over time as the main SLE specific contributor to death over time.

Fibronectin, Cryoglobulinemia and Immune Complexes in Sjogren's Syndrome Patients.

The problem of proper diagnosis, patient's status and disease progression is very actual for autoimmune diseases. Still the diagnosis of Sjogren's syndrome is more state of art than of science. Our preliminary investigations showed that serum fibronectin of elevated molecular weight may be probably considered as one of the diagnostic criteria in Sjogren's syndrome patients. The increase of molecular weight of FN chains from 220 kDa to 250 kDa derives from relative and absolute elevation in a content of N-acetylglucosamine in FN carbohydrate chains. The present results concern the presence of FN in cryoprecipitates and circulating immune complexes in Sjogren's syndrome patients and as it has been demonstrated this parameter may be used as a prognostic sign.

Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus.

We investigated a possible association between markers of immune activation and disease activity in 52 patients with systemic lupus erythematosus (SLE). Serum concentrations of neopterin, beta-2-microglobulin, 55 kD-type soluble tumor necrosis factor receptor, soluble interleukin-2 receptor and soluble CD8 were compared to the Index of European Consensus Lupus Activity Measurement (ECLAM). All markers of immune activation, except sCD8, significantly correlated with ECLAM. Stepwise multiple linear regression analysis revealed erythrocyte sedimentation rate and neopterin to correlate best with ECLAM (multiple correlation coefficient = 0.74, P < 0.001). The study shows that serum neopterin concentrations are a useful independent index for disease activity in SLE. The finding of enhanced concentrations of various parameters of immune activation in patients confirm a role of the T cell and macrophage activation in the pathogenesis of SLE.

Serum-soluble receptors for tumor necrosis factor-alpha and interleukin-2, and neopterin in acute rheumatic fever.

Immune activation may play an important role in the pathogenesis of acute rheumatic fever (ARF). The objective of the present study was to investigate serum concentrations of various markers of immune activation in ARF patients. Sera of 32 patients with ARF were investigated, 20 of them in follow-up. Radioimmunoassay was used to quantify neopterin and ELISA for the measurement of 55-kDa-type soluble tumor necrosis factor receptor (sTNF-R) and soluble interleukin-2 receptor (sIL2-R). Markers of immune activation were found to be raised in 48% (sTNF-R), 28% (sIL2-R), and 78% (neopterin) of patients at the onset of ARF. There were significant correlations between the concentrations of neopterin and sTNF-R (rs = 0.60, P < 0.001) or sIL2-R (rs = 0.35, P < 0.05). Higher neopterin concentrations were found in patients with combined aortic and mitral insufficiency than in patients with mitral valve lesions alone (U = 2.67, P < 0.05) or without valve lesion (U = 2.36, P < 0.05). Increased concentrations of neopterin, sTNF-R, and sIL2-R demonstrate activation of the cellular immune system in patients with ARF. Higher serum neopterin concentrations are associated with development of combined aortic and mitral insufficiency during the first episode of ARF.

Can observational studies replace or complement experiment?

The therapeutic effects of interventions in patients with rheumatoid arthritis (RA) are frequently modest. In the assessment of treatments effects, variability due to a variety of sources causes problems that are best controlled by randomized clinical trials. Currently most trials give only a short term picture of RA, a chronic disease whose outcome is multidimensional. Inclusion criteria of clinical trials are frequently very strict, raising concern about the external validity of the results. More longterm data is needed to guide clinical practice. Observational studies may contribute to the body of evidence, but have inherent shortcomings. They are liable to bias and supply weaker evidence. There must be creative development of trial designs suitable for evaluating longterm outcomes. Such trials may include many of the positive features of observational studies, but should not omit the principles of randomization and controlled comparison.

Serum viscosity is a sensitive test for monitoring primary Sjögren syndrome.

Primary Sjögren's syndrome (pSS) is characterized by chronic inflammation, resulting in secondary changes in serum protein content. In an attempt to evaluate disease activity we have measured serum viscosity (SV) in 41 patients with pSS and compared SV with laboratory findings such as: total proteins, gamma-globulin concentrations, titre of rheumatoid factor (RF) and level of circulating immune complexes. SV was found to correlate with these laboratory parameters. The pSS patients with low serum viscosity had worse clinical abnormalities than those with the high SV. Thus SV affords a useful monitoring test for pSS patients.

Markers of collagen and basement membrane metabolism in sera of patients with progressive systemic sclerosis.

The concentrations of the amino terminal propeptide of type III procollagen, the 7S domain of type IV collagen, and the fragment P1 of laminin (PIIINP, 7S, and P1 respectively) and the activity of galactosylhydroxylysyl glucosyltransferase (GGT) in serum were evaluated as indicators of disease activity in a cross sectional study of 84 patients with progressive systemic sclerosis. The mean values of PIIINP, P1, and GGT were raised in progressive systemic sclerosis, 19-32% of patients having abnormal values of the various tests. PIIINP, measured with two different assays, and P1 were associated with active, acute, or subacute disease. GGT also correlated positively with some acute phase proteins in the whole group, without a clear association with the course of the disease. Arthritis was associated with increased PIIINP concentrations as well as with an increased activity of GGT. Kidney disease led to raised concentrations of the degradation products of PIIINP. Raynaud's phenomenon in the hands was related to increased PIIINP concentrations.

Seronegative rheumatoid arthritis: a clinical study with HLA typing.

We examined both clinically and by determining HLA-A, -B, -C and -DR antigens 50 patients thought to have seronegative erosive polyarticular rheumatoid arthritis (RA) in Finland and the USSR. All the patients fulfilled at least 4 of the 1987 ARA criteria for RA. According to HLA typing and clinical findings, of which a part was collected by followup, the patients fell into 5 groups: HLA-B27 related diseases, putative psoriatic arthritis, putative juvenile chronic polyarthritis, and seropositive and seronegative RA. Our results indicate that most of the patients with seronegative RA had some other disease. In the remaining cases the presence of rheumatoid factors had not been examined adequately, especially at the early phase of disease. The classification of erosive seronegative polyarticular patients is discussed.

Eosinophilic fasciitis. Review and report of six cases.

Six patients with eosinophilic fasciitis are presented. This syndrome is characterized by indurative swellings of arms and legs, with rapidly progressing difficulties in extending elbows, wrists, and fingers, and often limited motion of shoulders and ankle joints. Pain when contracting muscles, and weakness of proximal muscles and hand grip are common features. The frequent occurrence of localized skin lesions has presented differential diagnostic difficulties to systemic sclerosis and to polymyositis. Visceral involvement and Raynaud's phenomena, however, are absent or mild. Blood eosinophilia, hypergammaglobulinemia, and unspecific signs of inflammation are found. Biopsy of muscle fascia gives characteristic histopathological findings of cell infiltrations (mostly mononuclear cells, frequently eosinophils) and vascular proliferation, in the middle layer of a thickened fascia. Skin changes are prevalent, but not conclusive for the diagnosis, and myositis in some patients might be difficult to distinguish from polymyositis. The importance of the clinical recognition of eosinophilic fasciitis and the inclusion of fascia in diagnostic muscle biopsies, is underlined.

Comparative studies of antilymphocyte, antipolynucleotide, and antiviral antibodies among families of patients with systemic lupus erythematosus.

Antilymphocyte, antipolynucleotide, and antiviral antibodies in 15 Soviet systemic lupus erythematosus (SLE) probands and their 41 relatives were compared with those in 57 members of 15 control Russian families. Seventy-eight and three-tenths percent of SLE relatives were positive for antilymphocyte antibody versus 26.3% positive reactions in controls. Antipolynucleotide antibody closely paralleled antilymphocyte antibody in both groups. Antiviral antibody was significantly increased in SLE relatives as compared to control family members. No correlation was noted between quantitative IgG, IgA, or IgM levels and various antibodies studied.