Rheumatoid Arthritis: Yugoslavia

Stojanovich L, Marisavljevich D. · Bezhanijska Kosa University Medical Center, Belgrade University, Serbia. · Autoimmun Rev. · Pubmed #18190880 No free full text.

Abstract: The etiology of autoimmune diseases is multifactorial: genetic, environmental, hormonal, and immunological factors are all considered important in their development. Nevertheless, the onset of at least 50% of autoimmune disorders has been attributed to "unknown trigger factors". Physical and psychological stress has been implicated in the development of autoimmune disease, since numerous animal and human studies demonstrated the effect of sundry stressors on immune function. Moreover, many retrospective studies found that a high proportion (up to 80%) of patients reported uncommon emotional stress before disease onset. Unfortunately, not only does stress cause disease, but the disease itself also causes significant stress in the patients, creating a vicious cycle. Recent reviews discuss the possible role of psychological stress, and of the major stress-related hormones, in the pathogenesis of autoimmune disease. It is presumed that the stress-triggered neuroendocrine hormones lead to immune dysregulation, which ultimately results in autoimmune disease, by altering or amplifying cytokine production. The treatment of autoimmune disease should thus include stress management and behavioral intervention to prevent stress-related immune imbalance. Different stress reactions should be discussed with autoimmune patients, and obligatory questionnaires about trigger factors should include psychological stress in addition to infection, trauma, and other common triggers.

Seferović PM, Ristić AD, Maksimović R, Simeunović DS, Ristić GG, Radovanović G, Seferović D, Maisch B, Matucci-Cerinic M. · Department of Cardiology, Institute for Cardiovascular Diseases of the Clinical Center of Serbia, Koste Todorovica 8, 11000 Belgrade, Serbia. · Rheumatology (Oxford). · Pubmed #16980722 links to  free full text

Abstract: Rhythm and conduction disturbances and sudden cardiac death (SCD) are important manifestations of cardiac involvement in autoimmune rheumatic diseases (ARDs). In patients with rheumatoid arthritis (RA), a major cause of SCD is atherosclerotic coronary artery disease, leading to acute coronary syndrome and ventricular arrhythmias. In systemic lupus erythematosus (SLE), sinus tachycardia, atrial fibrillation and atrial ectopic beats are the major cardiac arrhythmias. In some cases, sinus tachycardia may be the only manifestation of cardiac involvement. The most frequent cardiac rhythm disturbances in systemic sclerosis (SSc) are premature ventricular contractions (PVCs), often appearing as monomorphic, single PVCs, or rarely as bigeminy, trigeminy or pairs. Transient atrial fibrillation, flutter or paroxysmal supraventricular tachycardia are also described in 20-30% of SSc patients. Non-sustained ventricular tachycardia was described in 7-13%, while SCD is reported in 5-21% of unselected patients with SSc. The conduction disorders are more frequent in ARD than the cardiac arrhythmias. In RA, infiltration of the atrioventricular (AV) node can cause right bundle branch block in 35% of patients. AV block is rare in RA, and is usually complete. In SLE small vessel vasculitis, the infiltration of the sinus or AV nodes, or active myocarditis can lead to first-degree AV block in 34-70% of patients. In contrast to RA, conduction abnormalities may regress when the underlying disease is controlled. In neonatal lupus, 3% of infants whose mothers are antibody positive develop complete heart block. Conduction disturbances in SSc are due to fibrosis of sinoatrial node, presenting as abnormal ECG, bundle and fascicular blocks and occur in 25-75% of patients.

Lapcević M. · Health Centre, Vozdovac, Belgrade. · Srp Arh Celok Lek. · Pubmed #16405263 No free full text.

Abstract: Autoimmune thyroid disease (ATD) is a multifactorial, genetic disease. It is the sequelae of the impaired immunoregulation, tolerance and poor recognition of one's own proteins, oligopolysaccharides and polypeptides, due to development of somatic lymphocyte mutations. It is manifested by different clinical and morphological entities, inter-related by etiopathogenetic association, i.e., all of them are caused by disorder of immune system regulation. Chronic autoimmune thyroidism (Thyreoiditis lymphocytaria Hashimoto, HT), as well as immunogenic hyperthyroidism (Morbus Graves Basedow, MGB) are frequently associated with autoimmune diseases of other organs, such as: chronic insufficiency of salivary glands (Sy Sjögren), autoimmune hemolytic anemia, megalocytic pernicious anemia, thrombocytopenia, Rheumatoid arthritis, Diabetes mellitus (more often type 2, but also type 1), Morbus Addison, Coeliakia, and other autoimmune diseases such as systemic diseases of connecting tissue (Lupus erythematosus-SLE, Sclerodermia, Vasculitis superficialis). The incidence of autoimmune diseases has been at increase in all age groups of our population. The prevalence of organ-specific and organ-nonspecific antibodies increases with the age. Antigenicity of thyroid epithelial cell may be triggered by different chemical and biological agents (repeated viral infections), repeated stress, and in individuals with genetic propensity. Unrecognized ATD progressively leads to hypothyroidism with hyperlipidemia, blood vessel changes, osteoporosis, deformities, invalidity which substantially reduces the quality of life of patient and requires medical attention and expensive treatment on what account it is medically and socio-economically significant. Multiple diagnostic procedures contribute to faster recognition of this condition. The goal of the primary health care physician (given that preclinical phase of ATD and other associated diseases have different duration) and other specialists is to recognize ATD and, by early diagnosis and multidisciplinary treatment, to take secondary preventive measures of manifestation of above-mentioned associated autoimmune diseases, and in that way, to avoid the development of comorbidity and complications. It is particularly supported by medical doctrine based on evidence of application of corticosteroids, cytostatics, thyro-suppressive and substitution therapy, antilipemics, bisphosphonates and other drugs, significant for autoimmune diseases.

Trbojević B, Djurica S. · Institute of Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Serbia, Belgrade. · Srp Arh Celok Lek. · Pubmed #16405253 No free full text.

Abstract: Autoimmune thyroid disease (AITD) is the most common organ specific autoimmune disorder usually resulting in dysfunction (hyperfunction, hypofunction or both) of the thyroid gland. The syndromes comprising autoimmune thyroid disease are many intimately related illnesses: Graves' disease with goitre, hyperthyroidism and, in many patients, associated ophthalmopathy, Hashimoto's thyroiditis with goitre and euthyroidism or hypothyroidism but also thyroid dysfunction occurring independently of pregnancy and in 5-6% of postpartum women and thyroiditides induced by different drugs and other environmental influences. The immunological mechanisms involved in these diseases are closely related, while the phenotypes probably differ because of the specific type of immunological response that occurs. The syndromes are connected together by their similar thyroid pathology, similar immune mechanisms, co-occurrence in family groups, and transition from one clinical picture to another within the same individual over time. In some patients, other organ specific and nonorgan specific autoimmune syndromes are associated with autoimmune thyroid disease, including pernicious anemia, vitiligo, myasthenia gravis, primary adrenal autoimmune disease, celiac disease, rheumatoid arthritis or lupus. Thyroid peroxydase, TPO, the primary enzyme involved in thyroid hormonogenesis, was initially identified in 1959 as the 'thyroid microsomal antigenn. It is uncertain whether TPO autoantibodies or TPO-specific T cells are the primary cause of thyroid inflammation, which can lead, in some individuals, to thyroid failure and hypothyroidism. TPOAbs are the hallmark of AITB and are present in almost all patients with Hashimoto's thyroiditis, in two-thirds of patients with postpartum thyroiditis and also in 75% of patients with Graves' hyperthyroidism. The antibodies are mainly produced by lymphocytic infiltrate in the thyroid gland and only to a small extent by regional lymph nodes or the bone marrow. Unlike antibodies against thyroglobulin (Tg), TPO antibodies are capable of inducing antibody-dependent cell-mediated cytotoxicity. Antibodies to TSH-R mimic the function of TSH, and cause disease by binding to the TSH-R and stimulating (or inhibiting) thyroid cells. The TSHR, a member of the G protein-coupled receptor family with seven membrane-spanning segments. Patients with autoimmune thyroid disease may have both stimulating and blocking antibodies in their sera, the clinical picture being the result of the relative potency of each species; blocking antibodies seem more common in Graves' patients with ophthalmopathy compared to those without this complication. The major T cell epitopes are heterogeneous and T cell reactivity against certain TSH-R epitopes has been present in high proportion in normal subjects. More diversified response to TSH-R, with heterogeneity of epitope recognition by TSAb, is predictive of likely remission after antithyroid drug treatment for Graves' disease.

Miljkovic D, Trajkovic V. · Institute for Biological Research, Belgrade, Serbia and Montenegro. · Cytokine Growth Factor Rev. · Pubmed #14746811 No free full text.

Abstract: Interleukin-17 (IL-17) is a proinflammatory T cell cytokine presumably involved in physiological responses to infection, but also in immunopathology of autoimmune disorders such as rheumatoid arthritis. The proinflammatory action of IL-17 depends considerably on its ability to trigger the expression of inducible nitric oxide (NO) synthase (iNOS), an enzyme responsible for the generation of cytotoxic and immunoregulatory free radical NO. Here we discuss the role of IL-17 in the cytokine network controlling iNOS expression, and analyze signaling pathways employed by IL-17 for the initiation of iNOS gene transcription. We also propose biological consequences of IL-17-mediated NO release that could be relevant for the mechanisms or therapy of autoimmune and inflammatory disorders.

Draca S. · Clinic Dr M. Zotović, Sokobanjska 13, 11 000 Belgrade, Yugoslavia. · Autoimmunity. · Pubmed #12515284 No free full text.

Abstract: Pregnancy and parturition are the physiological conditions that affect the course and severity of numerous autoimmune diseases. If genotype might be primarily considered as a determinant of whether or not autoimmunity develops, clinical heterogeneity of the disease might arise from the interaction of the genotype and the environment. Numerous external factors with extremely important immunoregulatory properties, including hormones, affect an in vivo open complex immune system. The further investigation of the role of neuroendocrine-immunological network, including a pregnancy-associated immunomodulation, as much as the role of "causative" or "trigger" agents, may allow the rational basis of new alternative treatment of numerous autoimmune diseases.

Milic DJ, Zivic SS, Bogdanovic DC, Karanovic ND, Golubovic ZV. · Clinic for Vascular Surgery, Clinical Center Nis, Nis, Republic of Serbia. · J Vasc Surg. · Pubmed #19233601 No free full text.

Abstract: BACKGROUND: Compression therapy is the most widely used treatment for venous leg ulcers and it was used in different forms for more than 400 years. Published healing rates of venous ulcers obtained with compression therapy vary widely from 40-95%. According to numerous studies, it has been suggested that the application of external pressure to the calf muscle raises the interstitial pressure resulting in improved venous return and reduction in the venous hypertension. Several risk factors have been identified to be correlated with the failure of venous leg ulcers to heal with compression therapy (longer ulcer duration; large surface area; fibrinous deposition present on >50% of the wound surface and an Ankle Brachial Pressure Index (ABPI) of <0.85. METHODS: An open prospective single-center study was performed in order to determine possible risk factors associated with the failure of venous ulcers to heal when treated with multi-layer high compression bandaging system for 52 weeks. In the study, 189 patients (101 women, 88 men; mean age 61 years) with venous leg ulcers (ulcer surface >5 cm(2); duration >3 months) were included. The study excluded patients with arterial disease (ABPI <0.8), heart insufficiency with ejection fraction (EF) <35, pregnancy, cancer disease, rheumatoid arthritis, and diabetes. Based on clinical opinion and available literature, the following were considered as potential risk factors: sex, age, ulceration surface, time since ulcer onset, previous operations, history of deep vein thrombosis, body mass index (BMI), reduction in calf circumference >3 cm during the first 50 days of treatment, walking distance during the day <200 meters, calf:ankle circumference ratio <1.3, fixed ankle joint, history of surgical wound debridement, >50% of wound covered with fibrin, depth of the wound >2 cm. RESULTS: Within 52 weeks of limb-compression therapy, 24 (12.7%) venous ulcers had failed to heal. A small ulceration surface (<20 cm(2)), the duration of the venous ulcer <12 months, a decrease in calf circumference of more than 3 cm, and emergence of new skin islets on >10% of wound surface during the first 50 days of treatment were favorable prognostic factors for ulcer healing. A large BMI (>33 kg/m(2)), short walking distance during the day (<200 m), a history of wound debridement, and ulcers with deepest presentation (>2 cm) were indicators of slow healing. Calf:ankle circumference ratio <1.3, fixed ankle joint, and reduced ankle range of motion were the only independent parameters associated with non-healing (P < .001). CONCLUSION: The results obtained in this study suggest that non-healing venous ulcers are related to the impairment of the calf muscle pump.

Andjelkovic Z, Vojinovic J, Pejnovic N, Popovic M, Dujic A, Mitrovic D, Pavlica L, Stefanovic D. · Department of Rheumatology, Military Medical Academy, Belgrade, Yugoslavia. · Clin Exp Rheumatol. · Pubmed #10464556 No free full text.

Abstract: OBJECTIVE: Vitamin D analogues such as 1 alpha (OH) D3 (alphacalcidiol) have a possible physiological paracrine effect on cell proliferation and differentiation. Experimentally established possibilities to prevent autoimmune diseases suggest that alphacalcidiol may have therapeutic value as an immunomodulatory agent in patients with rheumatoid arthritis. METHODS: We organized a 3-month open-label trial on 19 patients being treated with standard DMARD therapy for acute RA. They were divided into 2 subgroups, those with highly active RA and those with moderately active RA. Their regular drug regimen was maintained during the trial and oral alphacalcidiol 2 micrograms/day was added. Therapy results were evaluated by ESR, CRP, morning stiffness, the Richie index, and the Lee index. Immunomodulatory effects were investigated by measuring lymphocyte proliferation and apoptosis both in the patients and in vitro in 10 nM alphacalcidiol-supplemented culture medium. RESULTS: After 3 months, high dose oral alphacalcidiol therapy showed a positive effect on disease activity in 89% of the patients (45% or 9 pts. with complete remission and 44% or 8 pts. with a satisfactory effect). Only two patients (11%) showed no improvement, but no new symptoms occurred. No side effects were observed. CONCLUSION: These results suggest that alphacalcidiol is a powerful immunomodulatory agent with fairly low hypercalcemic activity. Clinical improvement was strongly correlated with the immunomodulating potential of this agent. We noticed dual effects on lymphocyte proliferation and apoptosis according to the prior cell activation state. Alphacalcidiol could therefore possibly be used as an adjunct therapy with DMARDs in patients with rheumatoid arthritis.

Dimitrijević I. · Institute of Psychiatry, Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia. · Psychiatr Danub. · Pubmed #19556955 No free full text.

Abstract: Animal-assisted therapy is a familiar method of treatment in the rehabilitation of many illnesses and conditions, but is still not applied sufficiently in our milieu. This paper gives an overview of the available literature and some of the research which demonstrates that the interaction between the patient, animal and therapist provides a context which improves communication, elevates self-confidence, reduces the symptoms of diseases, and improves the quality of life. The dog, cat, horse, birds and toy animals are most often used in therapy. Short-term contacts with animals are used, as well as long term keeping of animals, which are looked after by patients following a particular methodology. The therapy is used in the treatment of psychiatric patients afflicted with depression, schizophrenia, phobias and addiction problems. Loneliness is easier to endure in the company of animals. It is also applied in cardiovascular diseases, dementia, Alzheimer's disease, child cerebral paralysis, rheumatoid arthritis, AIDS, and other diseases. Research shows a more rapid reduction of symptoms of many diseases when animals are included in the therapeutic process.

Damjanov N, Kauffman RS, Spencer-Green GT. · Belgrade University School of Medicine, Belgrade, Serbia. · Arthritis Rheum. · Pubmed #19404957 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and safety of VX-702, a p38 MAPK inhibitor, in patients with active, moderate-to-severe rheumatoid arthritis (RA). METHODS: Two 12-week, double-blind, placebo-controlled studies of VX-702 were conducted in patients with active, moderate-to-severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX-702. In Study 304, 117 patients received placebo, daily VX-702, or twice weekly VX-702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments. RESULTS: The numerically superior ACR20 response rates among patients receiving VX-702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX-702, 5 mg of VX-702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX-702 daily plus MTX, 10 mg VX-702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C-reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX-702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX-702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%). CONCLUSION: The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.

Obradović-Tomasević B, Vujasinović-Stupar N, Tomasević R. · Internisticka klinika, Klinicko-bolnicki centar Zemun, Zemun. · Med Pregl. · Pubmed #19368280 No free full text.

Abstract: INTRODUCTION: In the last three decades numerous epidemiologic studies have shown the correlation between risk factors and cardiovascular diseases. Clinical research has proven that rheumatoid arthritis patients (RA) have higher prevalence of classical risk factors in relation to general population, and over the last few years there has been an emphasis on some new risk factors which can contribute to cardiovascular diseases (CVD). MATERIAL AND METHODS: This study examined risk factor values for CVD in 88 patients with RA treated at Rheumatology Department, Clinical Hospital Centre, Zemun. All patients have been thoroughly examined (clinical findings, laboratory and echocardiographic examination). Apart from classical factors, "new" risk factors have been examined in all patients: C-reactive proteine (CRP), high-sensitive C-reactive proteine (hs-CRP) and homocystein. RESULTS: It has been determined that RA patients have more frequent higher new risk factors in comparison to classical ones. 84.1% of patients had higher CRP values, 97.1% had hsCRP and 39.5% had homocystein. The mean CRP values, especially hsCRP have been higher in patients with positive rheumatoid factor finding. DISCUSSION: Rheumatoid arthritis patients may have worse "background atherosclerosis" than even subjects matched for classical cardiovascular risk factors. Continuous exposure to high grade systemic inflammation may be linked to accelerated atherosclerosis. CONCLUSIONS: Timely identification of patients with risk factors, particularly with new risk factors, enables adequate approach in prevention of and treatment for CVD in rheumatoid arthritis patients.

Adzić TN, Stojsić JM, Radosavljević-Asić GD, Bouros D. · Institute for Lung diseases and Tuberculosis, Clinical Centre of Serbia, Belgrade, Serbia. · Eur J Intern Med. · Pubmed #19046717 No free full text.

This publication has no abstract.

Janic D, Loncarevic S, Krstovski N, Dokmanovic L, Lazic J, Rodic P. · University Children's Hospital, Belgrade, Serbia. · Pediatr Hematol Oncol. · Pubmed #18728977 No free full text.

Abstract: The diagnosis of juvenile idiopathic arthritis (JIA) is an exclusion one due to heterogeneous clinical presentation and lack of specific laboratory tests. The authors investigated bone marrow of 25 untreated children with JIA at the onset of the disease. Bone marrow smears were evaluated for cell populations as well as myelodysplastic features and compared to two control groups. The characteristic of bone marrow in JIA was myeloid hyperplasia and elevated plasmocyte count. There was no difference between JIA patients and control groups in terms of myelodysplastic features. These findings can be helpful in explaining hematological alterations in JIA.

Dugonjić S, Ajdinović B, Stefanović D, Jauković L. · Vojnomedicinska akademija, Institut za nuklearnu medicinu, Beograd, Srbija. · Vojnosanit Pregl. · Pubmed #18368937 No free full text.

Abstract: BACKGROUND/AIM: Beside many actual groups of classification criteria, uniform classification criteria for Sjögren's syndrome (SS) are still missing. The ophtalmic component of SS is well defined. Criteria for classifying its oral component remain controversial. The fifth item of the European Union and the United States of America (EU-US) revised diagnostic classification criteria in 2002, is an objective evidence of xerostomia, diagnosed by one of the tests: unstimulated whole sialometry (UWS), parotid sialography, and dynamic salivary gland scintigraphy (DSGS). The aim of this study was to evaluate senstitivity, specificity, positive and negative predictive value and accuracy of DSGS with ascorbic acid stimulation in detecting xerostomia in SS patients and to compare DSGS findings with UWS values. METHODS: Tests DSGS and UWS were done in 20 patients with SS and in 10 of the control subjects. The findings of DSGS were graded from 1 to 4 scintigraphie (SCT) grade 1--normal finding; SCT grade 2--moderate function damage; SCT grade 3--serious function damage, SCT grade 4--very serious function damage. UWS measured 1.5 hour after the breakfast lasted 15 minutes. UWS bellow 2.5 ml/15min min. considered pathological. RESULTS: All SS patients had pathological SCT findings. Comparing SCT grade between the patients and the control group, high statistical significance was found (p < 0.001). The estimated sensitivity of DSGS was 100%, specificity 80%, positive predictive value 91%, negative predictive value 100% and accuracy 93%. The calculated sensitivity of UWS was 75%. Salivary function damage detected by scintigraphy was in positive correlation with UWS findings. CONCLUSION: DSGS is a diagnostic test with high sensitivity, specificity, accuracy and positive and negative predictive values in detecting salivary function damage in SS patients. DSGS and UWS are very sensitive diagnostic tests for objective evidence of xerostomia, and have to be ones of the earliest investigations which shoud be performed in subjects suspected of SS. Test DSGS is more sensitive, and seems to better reflect symptoms of dry mouth than UWS.

Adzić TN, Pesut DP, Nagorni-Obradović LM, Stojsić JM, Vasiljević MD, Bouros D. · Institute of Lung diseases and Tuberculosis, Clinical Centre of Serbia, Belgrade, Serbia. · Respir Med. · Pubmed #18178071 No free full text.

Abstract: BACKGROUND: Connective tissue diseases (CTD) might be associated with various malignancies, and one of the most frequent is lung cancer (LC). Despite our understanding of pathogenesis, this association remains still unclear. The aim of the present study is to describe the clinical characteristics of patients with CTD who developed LC. METHODS: Of 375 successive patients with CTD followed up to University Hospital between 1995 and 2004, 24 patients were diagnosed with LC: 11 (46%) had systemic sclerosis (SSc), 6 (25%) rheumatoid arthritis (RA), 6 (25%) systemic lupus erythematosus (SLE), and 1 (4%) dermatomyositis. We analyzed LC stage, radiological presentation, histological type, patients' smoking status, method of diagnosis, treatment applied, and disease outcome. RESULTS: Average duration of CTD was 13.95 (range 0-30) years. Non-small cell lung cancer (NSCLC) was significantly more frequent than small-cell lung cancer (SCLC). Among patients with NSCLC, 21 patients (85%) presented with stage III or IV. With regard to treatment, 13% patients underwent surgery, 25% chemotherapy, 4% patients combined chemo- and radiotherapy and 58% patients had only supportive therapy. The median survival was 5 months (range 1-96 months). CONCLUSION: The majority of CTD patients who developed LC were diagnosed at advanced stage and had poor survival. Efforts for early detection of LC in CTD patients' group are warranted.

Stojanovich L, Milovanovich B, de Luka SR, Popovich-Kuzmanovich D, Bisenich V, Djukanovich B, Randjelovich T, Krotin M. · Bezhanijska Kosa University Medical Center, Belgrade, Serbia. · Lupus. · Pubmed #17432103 No free full text.

Abstract: Neurological manifestations are known to occur in patients with autoimmune diseases, often subclinically, but autonomic nervous system (ANS) involvement has rarely been studied, and studies have shown conflicting results. We performed cardiovascular ANS assessment in 125 patients with autoimmune diseases in this case-control study, including 54 patients with systemic lupus erythematosus (SLE), 39 with rheumatoid arthritis (RA), 20 with primary Sjbgren syndrome (pSS), eight patients with polymyalgia rheumatica (PR), four patients with scleroderma (Ssc) and 35 healthy control subjects. The control group was formed to approximately match the mean age of SLE, RA and pSS patients; controls did not differ significantly by gender from the autoimmune pations. All patients with were in stable condition. Autonomic nervous system dysfunction was diagnosed by applying cardiovascular reflex tests according to Ewing, and was considered to exist if at least two tests were positive. Vagal dysfunction was established by applying three tests: Valsalva manoeuvre, deep breathing test, and heart rate response to standing. Sympathetic dysfunction was examined by applying two tests: blood pressure response to standing and handgrip test. In all cardiovascular reflex tests, frequencies of abnormal results were significantly higher among the patients than among the controls (P < 0.05). The difference between the autoimmune patients and the controls was particularly significant in sympathetic and parasympathetic tests, with P < 0.0001. No correlation was found between disease duration, clinical manifestations, cardiovascular risk factors and diseases activity on the one hand, and ANS dysfunction on the other hand. Cardiovascular autonomic dysfunction was revealed in the majority of autoimmune patients.

Zlatković-Svenda MI, Stojanović RM, Milenković MP, Vlajinac HD, Le Bihan E, Guillemin F. · Clinical Rheumatology, Institute of Rheumatology, Belgrade, Serbia. · Clin Exp Rheumatol. · Pubmed #17417994 No free full text.

Abstract: OBJECTIVE: To adapt and validate a telephone questionnaire for case detection of rheumatoid arthritis (RA) and spondyloarthropathies (SpA) in the Serbian population. METHODS: A questionnaire, developed by the French Society of Rheumatology and successfully tested in France, was adapted to the Serbian language using a cross-cultural adaptation process. It was validated in 150 patients: 50 with RA, 50 with SpA and 50 with degenerative rheumatic disorders. They were recruited from Institute of Rheumatology in Belgrade, hospital registry, years 2001 and 2002. The questionnaire validity was assessed in reference to clinical diagnosis and ACR 1987 and ESSG 1991 classification criteria. A logistic regression model was used for RA-control and SpA-control comparison to identify the set of items that best discriminates these groups. RESULTS: Cross-cultural adaptation of the Questionnaire was successfully achieved, verifying its equivalence with the original (semantic, idiomatic, experiential, conceptual). According to the logistic regression, two items selected for RA provided 92.1% agreement when using either clinical diagnosis or ACR classification criteria as a standard. SpA-control comparison included five items providing 96.8% agreement with clinical diagnosis and four items providing 94.1% agreement with ESSG criteria. Results of the present study are similar to those found in the French study. CONCLUSION: Validation results of the telephone questionnaire, translated and adapted to the Serbian language, confirm that it can be used as a detection tool for RA and SpA cases in the population of Serbia, whose diagnoses would have to be further confirmed.

Miletić T, Kovacević-Jovanović V, Vujić V, Stanojević S, Mitić K, Lazarević-Macanović M, Dimitrijević M. · Immunology Research Center Branislav Janković, Institute of Immunology and Virology Torlak, Vojvode Stepe 458, 11121 Belgrade, Serbia. · Immunobiology. · Pubmed #17336830 No free full text.

Abstract: There is extensive evidence for the critical role of reactive oxygen species (ROS) and nitric oxide (NO) produced by phagocytes in development of inflammatory processes and pathogenesis of numerous diseases, including rheumatoid arthritis (RA). Apart from their function as mediators of inflammation and tissue damage, recent research supports their role as signaling and regulatory molecules. In the present study we have investigated the production of ROS and NO over the course of adjuvant arthritis (AA) and oil-induced arthritis (OIA), by resident peritoneal macrophages of two rat strains: Dark Agouti (DA), susceptible, and Albino Oxford (AO), resistant to induction of AA and OIA. We have compared levels of ROS and NO produced by susceptible vs. resistant rat strain, and investigated their relevancy for arthritis development and severity. In addition, we have stimulated macrophages in vitro with Mycobacterium bovis BCG, and two heat shock proteins (HSP): endogenous HSP47 and mycobacterial HSP71 (mHSP71). Our results suggest a possible contribution of increased ROS production to arthritis resistance of AO rats. The ROS production in AO rats is potentiated by endogenous HSP47, but not with mycobacterial cell and mHSP71, suggesting HSP47 participates in AA control. We have found no fundamental relationship between the magnitude of NO production and AA and OIA susceptibility and severity, suggesting that NO has no effector role in AA and OIA. Our results advocate a regulatory type action of NO molecule might be more significant in arthritis development.

Stojanovich L. · Bezhanijska Kosa University Medical Center, Belgrade University, Serbia. · Clin Dev Immunol. · Pubmed #17162380 links to  free full text

Abstract: The role of influenza vaccination in patients suffering from autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), has long been a subject of discussion. The risk of exacerbation of the main disease following vaccination is of particular concern, and needs to be carefully evaluated against the risk of disease flares as a result of infections. Our study included 69 SLE patients and 54 RA patients, all in stable condition. We split the groups into two subgroups each: patients in SLE1 (23 patients) and RA1 (23 patients) received the flu vaccine ("Vaxigrip", Aventis Pasteur) in November 2003. Patients in SLE2 (46 patients) and RA2 (31 patients) were not vaccinated. Throughout the following year, we studied parameters of disease activity and the occurrence of viral respiratory and bacterial infections in our patients. The vaccine was well tolerated in all cases. Vaccinated patients had significantly fewer occurrences of infections. Every viral and bacterial infection resulted in the worsening of the main disease. We believe that influenza vaccine is indicated for SLE and RA patients in stable condition. However, this decision must be made on a patient-by-patient basis. We plan to continue our study with the goal of formulating a better protocol for the clinical practice.

Miletić T, Kovacević-Jovanović V, Stanojević S, Vujić V, Kosec D, Mitić K, Dimitrijević M. · Immunology Research Center Branislav Janković, Institute of Immunology and Virology, Torlak, Belgrade, Serbia. · Scand J Immunol. · Pubmed #17083618 No free full text.

Abstract: Because of high sequence homology between microbial and endogenous heat shock proteins (HSP), immunological cross-reactivity to microbial HSP has been suggested as a possible cause of the development of autoimmune diseases, such as rheumatoid arthritis. The present study aimed to determine a potential role of HSP47, a molecular chaperone involved in the synthesis and assembly of collagen molecules, and microbial HSP71 (mHSP71) in adjuvant arthritis (AA) in two rat strains: Dark Agouti (DA), susceptible to AA induction and Albino Oxford (AO), which is resistant to AA induction. Immunization with complete Freund's adjuvant (CFA) induced an increased expression of HSP47 in joints of DA rats, which exhibited severe clinical signs of AA at the time of disease peak, while this protein was not detectable in joints of AO rats. In contrast, no strain differences in HSP72 (rat analogue of mHSP71) expressions in joints were observed. The increased levels of anti-HSP47 antibodies were detected in sera of DA rats during the AA peak, while the immunization with CFA increased levels of anti-mHSP71 antibodies in sera of AO rats. HSP47 and mHSP71 reduced proliferation of draining inguinal lymph node cells (LNC) in resistant AO rat strain, leading to a hypothesis that both HSP participated in AA control. Finally, mHSP71 potentiated the apoptotic response of LNC in susceptible DA rat strain. In conclusion, our findings indicate involvement of HSP47 in the development of AA in the rat, and point out to the regulatory role for both HSP47 and mHSP71.

Pavlov-Dolijanović S, Damjanov N, Ostojić P, Susić G, Stojanović R, Gacić D, Grdinić A. · Institute of Rheumatology-Belgrade, Resavska, Belgrade, Serbia and Montenegro. · Pediatr Dermatol. · Pubmed #17014637 No free full text.

Abstract: To assess the prognostic value of capillaroscopy findings for the development of connective tissue disease in children and adolescents with Raynaud phenomenon, we followed up a group of 250 (mean age 15 years) for 1 to 6 years after the first capillaroscopy was performed. Every 6 months they were screened for signs and symptoms of connective tissue disease. Analysis was performed on capillary changes registered 6 months before the development of connective tissue disease. Capillary changes were classified into three types: normal, nonspecific, and sclerodermatous. At the end of the follow-up period, 191 (76%) subjects had primary Raynaud phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a specific connective tissue disease. Systemic lupus erythematosus was found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of them with juvenile onset rheumatoid arthritis), and scleroderma spectrum disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%), juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and systemic lupus erythematosus (6/9, 67%) had normal capillary findings. Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27 (15%) with undifferentiated connective tissue disease, and 18 of 191 (9%) with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed sclerodermatous disease type capillary changes 6 months before the expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus, and one had undifferentiated connective tissue disease. We concluded that there were no specific capillary changes predictive for future development of systemic lupus erythematosus, juvenile onset rheumatoid arthritis/rheumatoid arthritis, and undifferentiated connective tissue disease in children and adolescents with Raynaud phenomenon. Most of our study subjects with Raynaud phenomenon who developed these diseases had normal capillary findings or nonspecific changes. Children and adolescents who developed scleroderma spectrum disorders showed a sclerodermatous type of capillary changes 6 months before the expression of the disease, indicating that this type of capillary changes in children and adolescents with Raynaud phenomenon highly correlated with further development of scleroderma spectrum disorders.

Markovic M, Stuhlmeier KM. · Institute of Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia. · J Mol Med. · Pubmed #16955275 No free full text.

Abstract: Fibroblast-like synoviocytes (FLS) play a key role in the genesis of rheumatoid arthritis (RA). FLS are among the most versatile cells with the potential to activate an array of genes that are able to initiate and propagate inflammation in RA-affected joints. Controlling activation of FLS might hold the key to restraining inflammation in RA-affected joints. In this study, we investigate the effect and mechanisms of short-term hyperthermia on a series of proinflammatory genes in FLS. In vitro experiments demonstrate that exposure of FLS to elevated temperatures for the duration of 30 min prevents activation of a series of genes with proinflammatory properties. Exposure to hyperthermia reduces IL-1beta-induced prostaglandin E2 release, suppresses activation of the adhesion molecules VCAM-1, ICAM-1, the cytokines TNFalpha, IL-1alpha, IL-1beta, IL-8 as well as COX-2 protein synthesis. Real time reverse transcriptase-polymerase chain reaction showed that hyperthermia altered gene expression at the transcriptional level. The amount and the duration of inhibition is gene-specific and lasts for up to 25 h. As to the mechanism of inhibition, electrophoretic mobility shift assay experiments demonstrated that exposure of FLS to hyperthermia prevents IL-1beta-induced NF-kappaB translocation and subsequent DNA binding. Many mechanisms have been shown to be involved in hyperthermia-mediated effects on NF-kappaB-DNA interactions. We demonstrate by Western blot experiments that in FLS, hyperthermia prevents the phosphorylation and subsequent degradation of IkappaBalpha, therefore retaining the NF-kappaB complex in the cytoplasm. Carefully controlled in vivo tests are certainly needed before one can take full advantage of those phenomena; however, the ease by which the temperature in joints can be modulated might offer an opportunity for manipulating inflammatory processes in joints by simple balneological means.

Petrović-Rackov L. · Vojnomedicinska akademija Klinika za reumatologiju i klinicku imunologiju. · Med Pregl. · Pubmed #16526229 No free full text.

Abstract: The aim of this research was to determine the clinical significance of tumor necrosis factor-alpha (TNF-alpha), IL-12, IL-15 and IL-18 in evaluation of the activity of rheumatoid arthritis. Cytokine concentrations in serum samples and synovial fluid were measured by immunoenzymatic methods using kits for human interleukins and the Disease Activity Score 28 in 64 patients with active disease. The control group consisted of 25 subjects with arthritis of the knee and osteoarthrosis. Patients with rheumatoid arthritis have significantly high (p < 0.01) concentrations of examined cytokines in relation to patients with osteoarthritis. By comparing concentrations in 30 patients with high, 14 patients with moderate and 20 patients with mild activity of rheumatoid arthritis, it was established that patients with high degree of disease activity have significantly high (p<0.01; p<0.05) concentrations of examined cytokines in the blood and synovial fluid in relation to patients with moderate and mild disease. We have concluded that cytokine concentrations are good indicators of the degree of rheumatoid arthritis activity. This research is a contribution to understanding the insufficiently known pathogenetic mechanisms of cytokines, especially IL-18, in active disease.

Petrović-Rackov L. · Vojnomedicinska akademija, Klinika za reumatologiju i klinicku imunologiju, Beograd. · Vojnosanit Pregl. · Pubmed #16471244 No free full text.

Abstract: BACKGROUND/AIM: Experimental in vitro and in vivo investigations in a mouse model have proved that TNF-alpha, IL12, IL-15 and IL18 participate in the pathogenesis of erosive inflammatory arthritis. The aim of this research was to determine the clinical significance of cytokines in the evaluation of the activity of rheumatoid arthritis (RA). METHODS: Inside a 4-year period we followed-up 64 patients with RA as newly ocurred or in the phase of worsening. We observed the clinical manifestation of the disease upon which we divided the patients in to 3 groups: the patients with low active RA, patients with moderate active RA, and the patients with wild active RA. The control group (n=25 patients) included the patients with osteoarthrosis (OA), and arthritis of the knee. In the samples of serum of all of the patients the concentratin of cytokines TNF-alpha, IL-12, IL-15, and IL-18 were determined using the immunoenzymatic methods in mice for human interleukines. By comparing the concentrations in 30 patients with the high, 14 patiens with moderate, and 20 patiens with the mild activity of RA it was determined that the patients with the high degree of the disease activity, had significantly high (p < 0.01; p < 0.05) concentrations of the examined cytokines in blood and synovial fluid as compared to the patients with the moderate and mild active disease. There was a relationship (p < 0.01) between the concentrations of cytokines in blood and synovial fluid with the quantity of the Disease Activity Score in 28 joints. CONCLUSIONS: Cytokines concentrations could be good indicators of the degree of the general activity of RA. This research could contribute to the interpretation of insufficiently well known views of the pathogenesis role and significance of citokines in an active disease.

Petrovic-Rackov L, Pejnovic N. · Clinic of Rheumatology and Clinical Immunology, Military Medical Academy, Belgrade, Serbia and Montenegro. · Clin Rheumatol. · Pubmed #16362448 No free full text.

Abstract: The aim of the study was to evaluate the clinical significance of serum (S) and synovial fluid (SF) interleukin (IL)-18, IL-15, IL-12 and the tumor necrosis factor alpha (TNF-alpha) measurements in relation to laboratory and clinical measures of disease activity of patients with active rheumatoid arthritis (RA). Sixty-four patients with RA and 25 patients with osteoarthritis (OA) were included in this study. RA activity was determined using the Disease Activity Score (DAS) 28 index. Concentrations of IL-18, IL-15, IL-12 and TNF-alpha were measured by ELISA. Serum C-reactive protein (CRP) levels were also determined. Cross-sectional correlations between S and SF levels of cytokines and values of DAS 28 index were calculated. The results have shown that IL-18, IL-15, IL-12 and TNF-alpha levels in S and SF of patients with RA were significantly higher than the levels obtain from patients with OA (p<0.01). Significantly higher levels of IL-18, IL-15 and TNF-alpha were found in the SF compared to the S of patients with RA (p<0.01). Significantly higher S and SF levels of all four cytokines and serum CRP values were found in RA patients with high disease activity (DAS 28>5.1) compared to those with mild (DAS 28>3.2) and low disease activity (DAS 28>2.6) (p<0.01). Serum and SF concentrations of all four cytokines positively correlated with DAS 28 index values, i.e., disease activity. A poor correlation was found for S and SF IL-12 whereas the highest coefficient of correlation was found for SF IL-18 (r=0.879, p<0.01), and SF TNF-alpha (r=0.827, p<0.01) and disease activity in this study. Strong correlation was found between SF TNF-alpha and SF IL-18 levels (r=0.732, p<0.01). In conclusion, SF IL-18 and TNF-alpha levels in RA patients are good indicators of disease activity. The results obtained support the use of the DAS in clinical practice as a reliable method in assessing disease activity in RA patients.