Gyula Szegedi

Long-term Survival of Patients With Idiopathic Inflammatory Myopathies According to Clinical Features: A Longitudinal Study of 162 Cases

The idiopathic inflammatory myopathies are characterized by chronic muscle inflammation and involvement of internal organs, which contribute considerably to the morbidity and mortality of the disease. We conducted the current study to determine the survival data for patients with idiopathic inflammatory myopathies according to the presence of extramuscular clinical manifestations. We also determined the cumulative survival probability and the long-term prognosis and analyzed the causes of death at a single clinical immunology center.A survival analysis was performed using data for 162 patients diagnosed between 1976 and 1997 according to Bohan and Peter’s criteria. Patients were followed up for a minimum of 5 years (median, 101.5 mo) or to date of death. Cumulative survival probability was calculated by the Kaplan-Meier method. The influence of extraskeletal and extramuscular involvement was analyzed as prognostic factors for death by Cox proportional hazards survival model.Eighteen disease-specific deaths occurred; pulmonary and cardiac complications were the most frequent causes of death. Global survival rates were 95%, 92%, and 89% for 1, 5, and 10 years, respectively. Analysis for clinicopathologic subgroups revealed that cancer-associated myositis had the worst prognosis, while juvenile and overlap myositis had the best prognosis. Five- and 10-year survival rates were 94.2% and 89.4% for patients with primary polymyositis and 90.1% and 86.4% for primary dermatomyositis patients, respectively. In the whole group of patients with idiopathic inflammatory myopathy, cardiac (p < 0.01) and respiratory muscle involvement (p = 0.045) were significant prognostic factors for death. In the group of patients with primary polymyositis/dermatomyositis, cardiac involvement was the main prognostic factor for death (p < 0.01).Myositis patients described in this study have higher survival rates than reported previously worldwide. We examine the reasons for the differences between the data in the current study and the available survival data in the relevant literature.

The complex role of vitamin D in autoimmune diseases.

Vitamin D, besides having well‐known control functions of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune‐homeostasis. The immune‐regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune‐tolerance of self‐structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases. The administration of vitamin D in these animals leads to improvement of immune‐mediated symptoms. Moreover, in human autoimmune diseases, such as multiple sclerosis, or rheumatoid arthritis the pathogenic role of vitamin D has been described. The review aims at describing the complex immune‐regulatory role of vitamin D from the cellular level through autoimmune animal models and depicting the known contribution of vitamin D in the pathogenesis of human autoimmune diseases.

Association of systemic and thyroid autoimmune diseases.

Objective: There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) with systemic autoimmune diseases. Methods: One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjogren’s syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated. Results: Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90-, 160-, 220-, 556-, 176- and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively). Conclusion: Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.

Malignant lymphoma-associated autoimmune diseases – a descriptive epidemiological study

Abstract. Lymphoproliferative disorders and autoimmune diseases have some common aspects in their clinical appearance. We reviewed 940 patient charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 421 non-Hodgkins lymphoma (NHL) patients (230 males, 191 females), 32 (7.6%) had an autoimmune disease (26 females, six males, mean age 48.3 years). The most common diagnosis was Sjögrens syndrome. The other cases were autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), other musculoskeletal disorders (2), rheumatoid arthritis (1), vasculitis (1), undifferentiated collagenosis (1), colitis ulcerosa (1), autoimmune hepatitis (1), Addisons disease (1), and autoimmune hemolytic anemia (1). Of 519 Hodgkins lymphoma patients (308 males, 211 females), an associated autoimmune disease occurred in 45 (8.6%) (25 females, 20 males, mean age 39.2 years). In 31 cases, we found autoimmune thyroid disorders, then came glomerulonephritis (3), immune thrombocytopenia (3), insulin-dependent diabetes mellitus (2), autoimmune hemolytic anemia (1), seronegative spondylarthritis (1), systemic lupus erythematosus (1), mixed connective tissue disease (1), scleroderma (1), and vasculitis (1). We also analyzed histology, choice of treatment, and sequence of appearance of the disease types. We found a difference between NHL and Hodgkins lymphoma patients, since in NHL autoimmunity – mostly from Sjögrens syndrome – preceded the lymphoma diagnosis (70%), but in Hodgkins the autoimmunity developed mainly after the treatment of malignancy. The relatively high prevalence of autoimmune diseases in malignant lymphomas has several explanations. Clinicians have to consider autoimmunity when treating lymphoproliferative disorders.

Factor XIII of blood coagulation in human monocytes

The presence of Factor XIII subunit a was demonstrated in human monocytes by immunoperoxidase staining using specific antisera against Factor XIII and its subunits. This finding was verified by immunobiochemical techniques, as well. In an immunoblotting system after SDS polyacrylamide gel electrophoresis of denatured monocyte homogenate a protein band comigrating with Factor XIII subunit a showed positive reaction with antibodies against this subunit or whole Factor XIII. In contrast, no subunit b of Factor XIII could be detected by either of these methods in monocytes. Activity measurements were carried out by the dansylcadaverine incorporation assay in the absence and presence of anti-Factor XIII antibody with and without thrombin activation. The expression of transglutaminase activity required thrombin and was completely abolished in presence of anti- Factor XIII antibody, which clearly indicate that practically all the transglutaminase activity measured in monocytes comes from Factor XIII. Factor XIII of monocytes and macrophages might have a role in formation of focal fibrin thrombi as well as in organization of stable, fibrinolysis resistant fibrin clot at the site of inflammation or around tumor cells.

Vitamin D deficiency in undifferentiated connective tissue disease

IntroductionBoth experimental and clinical data provide evidence that vitamin D is one of those important environmental factors that can increase the prevalence of certain autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The aim of the present study was to investigate the prevalence of vitamin D insufficiency in patients with undifferentiated connective tissue disease (UCTD).MethodsPlasma 25(OH)D3 levels in 161 UCTD patients were measured in both summer and winter periods. Autoantibody profiles (antinuclear antibody, anti-U1-ribonucleoprotein, anti-SSA, anti-SSB, anti-Jo1, anti-Scl70, anti-double-stranded DNA, anti-centromere, anti-cardiolipin, rheumatoid factor, and anti-cyclic citrullinated peptide) and clinical symptoms of the patients were assessed.ResultsPlasma levels of 25(OH)D3 in UCTD patients were significantly lower compared with controls in both summer and winter periods (UCTD summer: 33 ± 13.4 ng/mL versus control: 39.9 ± 11.7 ng/mL, P = 0.01; UCTD winter: 27.8 ± 12.48 ng/mL versus control: 37.8 ± 12.3 ng/mL, P = 0.0001). The presence of dermatological symptoms (photosensitivity, erythema, and chronic discoid rash) and pleuritis was associated with low levels of vitamin D. During the average follow-up period of 2.3 years, 35 out of 161 patients (21.7%) with UCTD further developed into well-established connective tissue disease (CTD). Patients who progressed into CTDs had lower vitamin D levels than those who remained in the UCTD stage (vitamin D levels: CTD: 14.7 ± 6.45 ng/mL versus UCTD: 33.0 ± 13.4 ng/mL, P = 0.0001).ConclusionsIn patients with UCTD, a seasonal variance in levels of 25(OH)D3 was identified and showed that these levels were significantly lower than in controls during the corresponding seasons. Our results suggest that vitamin D deficiency in UCTD patients may play a role in the subsequent progression into well-defined CTDs.

Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases.

Angiogenesis, the formation of new vessels, is important in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. Chemotactic cytokines termed chemokines mediate the ingress of leukocytes, including neutrophils and monocytes into the inflamed synovium. In this review, authors discuss the role of the most important angiogenic factors and angiogenesis inhibitors, as well as relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. RA was chosen as a prototype to discuss these issues, as the majority of studies on the role of angiogenesis and chemokines in inflammatory diseases were carried out in arthritis. However, other systemic inflammatory (autoimmune) diseases including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögrens syndrome (SS), mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM) and systemic vasculites are also discussed in this context. As a number of chemokines may also play a role in neovascularizaton, this issue is also described here. Apart from discussing the pathogenic role of angiogenesis and chemokines, authors also review the regulation of angiogenesis and chemokine production by other inflammatory meditors, as well as the important relevance of neovascularization and chemokines for antirheumatic intervention.

Accelerated Atherosclerosis in Rheumatoid Arthritis

Abstract:  Cardiovascular disease is a leading cause of mortality in rheumatoid arthritis (RA). Endothelial dysfunction often precedes manifest atherosclerosis. Both traditional, Framingham risk factors and inflammation‐associated factors are involved in RA‐associated atherosclerosis. Among imaging techniques, the early determination of common carotid intima‐media thickness (ccIMT), flow‐mediated vasodilation (FMD), and nitroglycerine‐mediated vasodilation (NMD) may be useful to determine atherosclerosis and endothelial dysfunction. We and others found increased ccIMT and impaired FMD in RA patients. Among immunological and metabolic laboratory markers, anticyclic citrullinated peptide (anti‐CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, pro‐inflammatory cytokines including tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6), Th0/Th1 T cells, homocysteine, dyslipidemia, decreased folate and vitamin B12 production, and impaired paraoxonase activity may all be involved in the development of vascular disease in RA. The early diagnosis of endothelial dysfunction and atherosclerosis, active immunosuppressive treatment, the use of drugs that control atherosclerosis, changes in sedentary lifestyle, and the close follow‐up of RA patients may help to minimize cardiovascular risk in these individuals.

Evaluation of clinical and laboratory features of antiphospholipid syndrome: a retrospective study of 637 patients

We retrospectively analysed the data of 1519 antiphospholipid antibody (APLA) positive patients between 1986 and 1999. Among them 637 were considered to have antiphospholipid syndrome (APS) based on the 1999 preliminary classification criteria, while 704 patients had no clinical signs of the syndrome. Our aim was to compare the autoantibody profile and clinical characteristics of primary and secondary APS, moreover to evaluate the associations between different APLA and specific symptoms attributable to APS. In our results, the APLA profiles for primary and SLE-associated secondary APS were similar. Among the evaluated clinical symptoms, cerebrovascular thrombosis was found to be more frequent in the SLE-associated, than in the primary APS group (P = 0.04). We identified important differences in the clinical profile of patient populations with various types of APLA. Venous thrombosis occurred more frequently in subjects with lupus anticoagulant (LA), than in those with IgG or IgM type ACLA (P < 0.0001), while coronary, carotid and peripheral artery thrombosis occurred more often in subjects with IgG or IgM ACLA (P < 0.0001). These findings may support the role of antibodies to cardiolipin or its cofactor, b2glycoprotein I (b2-GPI) in the initiation and progression of atherosclerosis. Cerebrovascular thrombosis was detected in larger proportion of LA or IgG ACLA-positive patients compared with to IgM ACLA-positive subjects, while the occurrence of foetal loss was similar in all three groups.

Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment.

Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to increased cardio- and cerebrovascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated atherosclerosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or spondyloarthropathies (SpA), obliterative vasculopathy may rather be characteristic for systemic sclerosis (SSc) or mixed connective tissue disease (MCTD). Antiphospholipid antibodies have been implicated in vasculopathies underlying SLE, antiphospholipid syndrome (APS), RA and MCTD. There is also heterogeneity with respect to inflammatory risk factors. Cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) and immune complexes are primarily involved in arthritides, such as RA, SpA, as well as in SLE. On the other hand, autoantibodies including anti-oxLDL anti-cardiolipin and anti-β2GPI are rather involved in SLE- and APS-associated vasculopathies. Regarding the non-invasive assessment of vascular function, endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have just been published, and similar recommendations in connective tissue diseases are to be developed soon.