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.

Salivary and serum interleukin 6 and basic fibroblast growth factor levels in patients with oral squamous cell carcinoma.

AIM: A role of various cytokines has been implicated in the pathogenesis of many carcinomas, and albeit the role of interleukin 6 (IL-6) and basic fibroblast growth factor (bFGF) in sera has been studied in patients with oral carcinomas, data upon salivary IL-6 and bFGF are lacking. The aim of this study was to evaluate levels of IL-6 and bFGF in the saliva and serum of patients with oral squamous cell carcinoma. METHODS: Salivary and serum IL-6 and bFGF were evaluated in a group of 33 patients (28 men, 5 women) with oral squamous cell carcinoma (OSCC), age range 40-73 years , mean 54.05 years. Control group consisted of 23 healhy participants, mean age 25 years. RESULTS: Serum IL-6 and bFGF levels were not significantly different between patients with OSCC and healthy controls. Elevated levels of salivary IL-6 and bFGF in patients with OSCC when compared to the healthy controls were found (p<0.001). CONCLUSIONS: The conclusion is drawn that higher levels of salivary IL-6 and bFGF in patients with OSCC might originate from the local production, probably from carcinoma cells.

[Hospitalization for systemic connective tissue diseases in Croatia in 1997: examples of the use of hospital morbidity registery data bases]. / Hospitalizacije zbog sistemskih bolesti vezivnoga tkiva u Hrvatskoj 1997. godine: primjer uporabe baze podataka registra bolnickog morbiditeta.

By using the explanatory analysis methods, we examined a possible model for the utilization of the Croatian Hospital Morbidity Register data for decision making in the managerial process for national health system development. To build a draft informational model, data were selected on 843 cases hospitalized in 1997 for diseases M30-M36 (ICD-10) in 45 health institutions. This was used as an index of the diagnostically/therapeutically most demanding group of rheumatic autoimmune diseases. Treatment standards were established for our health system for the patients having an M30-M36 disease by classifying Croatia's health institutions into four clusters by intensity of hospitalization, and by analyzing demographic characteristics and the length of stay by disease entity. These standards could represent a good informational base for forming consensus group panels to deal with inpatient treatment problems of patients with systemic connective tissue diseases.

Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation.

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. At this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10 y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of 1 y. Serious clinical signs or exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished.

Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT).

OBJECTIVE: Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE. METHODS: Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up. RESULTS: Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE. CONCLUSIONS: A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

[Clinical importance of laboratory tests in rheumatology]. / Klinicko znacenje laboratorijskih pretraga u reumatologiji.

Knowledge of mechanisms of rheumatic diseases has a continuing influence on the introduction of many laboratory tests to be used for establishing diagnosis or monitoring the activity of rheumatic disease. In the article presented are autoantibodies characteristic for distinct inflammatory rheumatic diseases, the role of serum complement activity, immune complexes, HLA-typing as well as other laboratory parameters needed for the diagnosis of rheumatic disease. The methods of synovial fluid analysis are described. Presented are laboratory investigations used by rheumatologists for the evaluation of activity of inflammatory rheumatic diseases and successful treatment together with investigations necessary for the evaluation of side-effects of treatment.

[Systemic lupus erythematosus]. / Sustavni eritemski lupus.

Systemic lupus erythematosus (SLE) is a multisystemic inflammatory rheumatic disease of unknown etiology. It is understood that immune complexes have dominant role in the pathogenesis of the disease with vasculitis being the basis of many clinical manifestations. SLE is considered to be the autoimmune disease because of many autoantibodies, some of them with the known pathogenetic role. Characteristic features of the disease are skin manifestations, arthritis, serositis as well as various tissue and organ lesions, particularly that of the kidney and nervous system. On the basis of disease activity and organ involvement the decision on the institution of immunosuppressive therapy is made.

Antibodies to Tamm-Horsfall protein in endemic nephropathy.

BACKGROUND: The aim of the study was to investigate the possible role of antibodies to Tamm-Horsfall protein (anti-THP) in the early diagnosis of endemic nephropathy (EN). METHODS: Anti-THP (IgA, IgM, IgG classes) antibodies were determined by direct ELISA in a random sample of 159 subjects from the endemic village of Kaniza who were divided into four groups according to the WHO criteria, i.e., 'diseased', 'suspect', 'at risk', and 'others'. These groups were compared to subjects from the non-endemic village of Klakar and healthy subjects from Zagreb. RESULTS: No differences for all the classes of antibody were observed among the groups of subjects from the endemic village of Kaniza (P>0.05) or between these subjects and those from the non-endemic village of Klakar (P>0.05). The values of IgM anti-THP antibodies exceeded those of the IgA and IgG classes in all groups of subjects (P<0.05). The values for all three classes of antibodies were higher in the rural than the urban population (P<0. 05). CONCLUSION: Determination of anti-THP antibodies was not found to be useful in the early diagnosis of endemic nephropathy. The results suggest that most of the anti-THP antibodies are 'natural' and/or cross reactive. The highest values observed in the rural population could probably be explained by exposure to some ubiquitous antigen or more likely they are consequences of fever.

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (

[Spondyloarthropathies]. / Spondilartropatije.

The spondyloarthropathies are a group of inflammatory joint diseases which are classified together because they share many clinical, epidemiologic and genetic features. Criteria and terminology, role of genetic factors and infection, disease mechanisms as well as the characteristics of some disease entities in diagnostic and therapeutic approach are presented.

[Intermittent intravenous cyclophosphamide application in patients with systemic lupus erythematosus]. / Intermitentna intravenska primjena ciklofosfamida u bolesnika sa sustavnim eritemskim lupusom.

The aim of this paper is retrospective analysis of data from patients in whom the indication for cyclophosphamide (CF) pulse therapy was established in our department. Indications for CF pulse treatment were lupus nephritis (LN) alone or associated with central nervous system lupus. CF was administred in the dose of 500-1000 mg/m2 intravenously once monthly for the 6 months and once every 3 months thereafter. Patients were treated with adequate dose of glucocorticoids and other symptomatic therapy. The effect of applied therapy has been analysed by monitoring proteinuria, serum creatinine concentration, creatinine clearance, ESR, ANF titer and total complement hemolytic activity. Initial therapeutic procedure has been completed in 25/30 patients. The reasons for discontinuation in 5/30 patients were as follows: end-stage renal failure in spite of therapy (1), psychosis and lost of compliance (1), recurrent pancytopenia and subsequent sepsis (1), death non related to SLE (1) and failure to show at follow-up (1). Significant improvement of all control parameters was observed in the majority of patients in whom the therapy was completely conducted. 16/25 patients continued therapy for the next 18 months and in only 1/16 patients therapy was discontinued because of end-stage renal failure. In other 15/16 patients further improvement of control parameters was observed, although not so expressed as in the first 6 months. The most frequent complications were infections (16 infections were microbiologically proved and there were probably more infections). Alopecia (2), haematuria (1) and amenorrhoea (1) were also observed. Relatively low incidence of complications may be explained by careful patient monitoring. Considering that therapeutic success is defined not only by the improvement of renal function, but by stopping of further progression of renal failure, it can be concluded that intermittent CF pulse therapy showed good effect on LN in patients with clear indication.

[Paraneoplastic autoimmune neurologic syndromes]. / Paraneoplasticki autoimuni neuroloski sindromi.

Paraneoplastic neurologic syndromes are group of distant nonmetastatic neurologic manifestations of malignant diseases. In last few decades a major advance in understanding their etiology and pathogenesis has been achieved. Larger series of patients have been reported allowing more detailed clinical research of particular syndromes. To practicing physician they can be a first clinical sign in diagnosing a neoplasm. In these conditions immunologists can test new theories in tumor immunology and autoimmunity. To the oncologists they can serve as a model in development of new modalities of treating malignant tumors. Neurologic syndromes that can be explained as autoimmune reactions initiated by the development of malignancy are presented in this paper.

[Clinical importance of antinuclear antibodies]. / Klinicko znacenje antinuklearnih protutijela.

Determination of antinuclear antibodies in the sera of patients with multisystem connective tissue disease has a long clinical application. In the review article authors report on their clinical significance and describe the types of antinuclear antibodies; anti-DNA antibodies, antihistone antibodies, anti-RNA-protein complexes and other antinuclear antibodies. The methods of laboratory determination of antibody types are discussed as well as their application in the diagnosis of autoimmune and multisystem-rheumatic diseases.

Antibodies to Tamm-Horsfall protein in patients treated with extracorporeal shock wave lithotripsy (ESWL).

The aim of this study was to determine antibodies to Tamm-Horsfall protein in patients with nephrolithiasis treated with extracorporeal shock wave lithotripsy (ESWL). The values of antibodies to Tamm-Horsfall protein were determined by direct enzyme immunoassay. No statistically significant differences (P > 0.05) were observed for the IgG and IgM classes of antibodies between the groups of healthy subjects and patients with nephrolithiasis before, and 30 and 60 days after ESWL. The values of IgA class determined 30 days after treatment were significantly higher (P < 0.05) in patients, which could be due to the stimulation of the immune system. The highest values of antibodies to Tamm-Horsfall protein were obtained in both groups in the test with secondary antibodies directed toward IgM class, implicated at the presence of cross-reactive antibodies. Determination of antibodies to THP subunits isolated form urine of patients with nephrolithiasis should be performed.

Antibodies to Tamm-Horsfall protein subunits prepared in vitro, in patients with acute pyelonephritis.

The aim of this study was to determine antibodies to Tamm-Horsfall protein subunits in patients with acute pyelonephritis. The protein subunits used in this determination were prepared by chemical treatment of Tamm-Horsfall protein isolated from the urine of healthy individuals. Values for IgG and IgA were significantly higher (p < 0.05 and p < 0.01 respectively) in patients than in healthy persons, while IgM class antibodies were significantly higher only in the test performed with subunits obtained with 8.3 mol/l acetic acid (THP-A) (p < 0.05). Values for all three classes determined in the test with THP-A were significantly higher in patients with vesicoureteral reflux than in patients with normal radiological findings (p < 0.05). Antibodies to Tamm-Horsfall protein subunits isolated from the urine of patients with acute pyelonephritis should also be determined.

Binding of anti-double stranded (ds) DNA-positive sera to denatured (d) DNA and synthetic poly[dA-dT] x poly[dA-dT] double stranded copolymer in an ELISA format.

Using an ELISA assay anti-nuclear antibody-positive sera from 300 patients with various immune-related diseases and 64 anti-nuclear antibody-negative sera were analysed for binding to S1-nuclease-treated double stranded (ds) DNA. In addition, the pattern of reactivity of 50 selected anti-dsDNA-positive sera was established using denatured (d) DNA and poly[dA-dT] X poly[dA-dT] double-stranded alternating copolymer (dAT) as additional DNA antigens. None of the 64 anti-nuclear antibody-negative sera and 76 of the 300 anti-nuclear antibody-positive sera (25%) were anti-dsDNA-positive. Of the anti-nuclear antibody-positive and anti-dsDNA-positive sera, 48 (63%) were from systemic lupus erythematosus patients, and 7 (9%) from rheumatoid arthritis patients, whereas 21 patients (27.6%) suffered from various immune and non-immune related diseases. Anti-dsDNA-positive reactivity was highly correlated with dDNA and dAT reactivity (r = 0.906, p < 0.0001 and r = 0.93, p < 0.0001, respectively). Although the majority of the 50 selected (37 systemic lupus erythematosus and 13 non-systemic lupus erythematosus) anti-dsDNA-positive sera concomitantly bound to both additional antigens, 7 of these (14%) did not bind to dAT, and 2 (4%) did not bind to dDNA. Anti-dsDNA-positive sera (n = 37) showed a similar pattern, in which 8.1% and 2.7% of sera did not bind to dAT and to dDNA, respectively. In contrast, anti-dsDNA-negative sera from various immune-related diseases bound either ssDNA (12.5%) or dDNA and dAT (12.5%). These data suggest that dsDNA and dAT-based assays detect similar but not identical specificities in the sera of patients suffering from systemic lupus erythematosus and in a proportion of non-systemic lupus erythematosus patients.