Ljudmila Stojanovich

Objectives: To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD). Methods: AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ≤ 5 participants. Articles in English and regarding patients ≥ 16 years of age, were eligible. Results: Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive. Conclusion: Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright The etiology of autoimmune disease is multifactorial, including genetic, environmental, hormonal, and immunological factors. Nevertheless, the onset of autoimmune disorders remains enigmatic. Physical and psychological stresses have been suggested in the development of autoimmune disease, since numerous animal and human studies demonstrated the effect of stressors on immune function. Moreover, many retrospective studies had found that a high proportion (up to 80%) of patients reported uncommon emotional stress before disease onset. This, however, is not surprising as the disease itself causes significant stress in the patient. Recent reviews discuss the possible role of psychological stress, and of the major stress-related hormones, in the pathogenesis of autoimmune disease and presume that the stress-triggered neuroendocrine hormones lead to immune dysregulation, which ultimately results in autoimmune disease by altering or amplifying cytokine production. However, there is no evidence based research to support this concept. Nonetheless, stress reactions should be discussed with autoimmune patients. Applied implications are discussed, concentrating on the need for multidisciplinary care interventions that target patients' disease symptoms and help them cope with their illness.

To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD).AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ≤ 5 participants. Articles in English and regarding patients ≥ 16 years of age, were eligible.Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive.Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.

The aim of this study was to evaluate the role of antiphospholipid antibodies (APA) in human reproduction. The investigation included 150 patients with systemic lupus erythematosus (SLE), and a group of 931 women, with the history of recurrent spontaneously miscarried pregnancies of unknown origin, even after a detailed examination in obstetric-gynecological institution. APA were investigated by means of tests to lupus anticoagulant (LA), applying a set of coagulation tests, including two tests with viper's poison, and cardiolipin antibodies (ACL) were determined by a standard immunoenzyme method, where a cardiolipin (Sigma, USA) was used as an antigen. The analysis of obstetric history in women with SLE has shown a considerable increase in frequency of obstetric complications in APA-positive group of patients (p < 0.001). Screening-examination to APA, proved its presence in 254 of the total of 931 women (27%), and a complete evaluation of the positive group enabled the estab...

Autoantibodies to complement factor H (FH) are associated with atypical hemolytic uremic syndrome, but can also be detected in patients with rheumatoid arthritis and in patients positive for lupus anticoagulants and thus potentially antiphospholipid syndrome (APS). To our knowledge, no data are available on the association between the presence of FH autoantibodies in APS and clinical manifestations. We determined FH autoantibody levels using ELISA in 2 cohorts of patients with primary (PAPS) and secondary APS (SAPS) from Serbia and Italy, and an additional cohort including patients with venous thromboembolism (VTE) from Sweden. FH autoantibodies were detected in 13.7% of patients (n = 73) with PAPS and 30.3% of patients (n = 33) with SAPS in the Serbian cohort. FH autoantibody frequency in the Italian cohort was 33.3% (n = 15) and 36% (n = 25) in PAPS and SAPS, respectively. Both FH autoantibody levels and frequencies observed in both APS cohorts were significantly higher than in ma...

The aim of the study was to investigate serum concentrations of interleukin (IL)-17 and IL-17-inducing cytokines IL-23 and transforming growth factor (TGF)-β, as well as IL-17 single nucleotide polymorphism (SNP) rs2275913 in patients with primary antiphospholipid syndrome (PAPS). We studied fifty patients with PAPS and fifty age- and sex-matched healthy controls. The cytokine levels were measured by ELISA, while the rs2275913 SNP located in promoter region of IL-17 gene was genotyped using real-time PCR. The significantly higher levels of IL-17 (p=0.002), IL-23 (p<0.001) and TGF-β (p=0.042) were found in PAPS patients (median 13.1, 9.4, and 125.6 pg/ml, respectively) compared to the control group (6.8, 4.9 and 44.4 pg/ml). There was a significant positive correlation between concentrations of IL-17 and IL-23 (r=0.540, p<0.001), but not between those of IL-17 and TGF-β. No statistically significant differences were observed in the distribution of genotypes and alleles of the IL-17 rs2275913 variants in patients with PAPS compared to healthy subjects. The blood concentrations of IL-17 did not differ in subjects with different rs2275913 genotypes or patients with or without antiphospholipid antibodies. Finally, a trend toward higher IL-17 levels (p=0.063) and the significantly higher IL-17 concentrations (p=0.012) were observed in PAPS patients with deep vein thrombosis and thrombocytopenia, respectively. These data demonstrate that IL-23/IL-17 axis, stimulated independently of TGF-β increase IL-17A gene polymorphism and antiphospholipid antibody production, might contribute to vascular manifestations of PAPS.

ABSTRACT Objectives Antiphospholipid syndrome (APS) patients suffer from various clinical manifestations with the presence of antiphospholipid antibodies (aPL). APS may manifest itself as a primary disease (PAPS) or as a secondary disease (SAPS), most commonly in the context of Systemic Lupus Erythemathosus (SLE) Methods We analyzed 488 patients: 346 PAPS (70.9%) (77.7% female and 22.3% male) average age 44.1±13.0 years and 142 patients with secondary APS (SLE) patients (29.1%) (90.8% female and 9.2% male) average age 47.2±14.8 years. aPL analysis included analysis of aCL (IgG/IgM), β2GPI (IgG/IgM) and LA. aPL analysis included analysis of aCL (IgG/IgM), β2GPI (IgG/IgM) and LA. In all patients data considering cardiac, vascular, pulmonary, neurological, skin and hematological disorders were collected. Results There was 30.8% aCL-IgG, 49.7% aCL-IgM, 31.4% β2GPI IgG, 40.4% β2GPI IgM and 54.0% LA positive PAPS patients. Among SAPS patients 57.9% were aCL-IgG, 61.4% aCL-IgM, 40.7% β2GPI IgG, 45.0% β2GPI IgM and 51.1% LA positive. We observed 56.3% with neurological, 23.0% patients with skin, 27.3% with cardiac, 20.8% with hematological and 15.2% with pulmonary disorders. 54.3% of patients had peripheral vascular thrombosis (arterial, venous or both) in PAPS and 70.4% SAPS patients with skin, 77.3% with neurological, 40.8% with cardiac, 64.8% with hematological and 12.0% with pulmonary disorders. 57.9% of SAPS patients had peripheral vascular thrombosis. Between SAPS and PAPS patients we observed highly statisticaly significant difference considering neurological (p=0.0001), cardiac (p=0.002), skin (p=0.0001) and hematological manifestations (p=0.0001) in favour of patients with SAPS. Conclusions Patients with SAPS suffer more often from various clinical features comparing to patients PAPS. Additional autoimmune burden in those patients presented through aPL presence besides actual autoimmune disease pannel, could be an explanation. References Acknowledgements This work was supported by research grant number 175041 for 2011-2014, issued by the Ministry of Science of the Republic of Serbia. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2428

ABSTRACT Background Patients with antiphospholipid syndrome (APS) have an increased risk of atherosclerosis. Objectives The aim of our study was to determine whether there are subclinical arterial changes in APS patients, and what is the best diagnostic choice for their establishment. Methods In this study we analyzed 50 patients with primary antiphospholipid syndrome (PAPS) and 50 patients with Systemic Lupus Erythematosus and APS (SAPS). The results were compared to 30 controls. The groups were comparable with respect to age, gender, and traditional risk factors except for the lipid status, since controls had significantly higher levels of cholesterol and triglycerides. Study was conducted on 64-multi-sliced computed tomography (64-MSCT) and only the new changes that have not been verified until this exam were taken into analysis. Results There was significantly higher incidence of overall arterial changes in PAPS and SAPS patients, as compared to healthy controls. We detected a total of 70 arterials stenosis in PAPS patients, and 79 arterial stenosis in SAPS patients, compared to 43 in the control group (χ2=16.95, p <0,001, χ2=30.14, p <0,001, respectively). There were 20 newly discovered visceral blood vessel lesions in the patients with APS and 5 lesions in the control group. There was significantly higher incidence of overall visceral arterial changes comparing to controls since in PAPS patients the sum of 10 and in SAPS the sum of 5 arterials stenosis compared to 5 in control group was detected (p< 0.001). Significant changes in PAPS and SAPS patients comparing to controls were detected on celiac artery (10pts vs.3pts vs. 3pts; p< 0.05), superior mesenteric artery (6pts vs. 2pts. vs. 0pts; p< 0.05) and right renal artery (4pts vs. 0 pts. vs. 2pts; p< 0.05). Conclusions APS patients suffer from accelerated atherosclerosis, and the 64-MSCT angiography is the method of choice in monitoring disease progression, because it is a safe, has the lowest degree of error, and provides an overview of the arteries that are otherwise difficult to access. This enables timely treatment of these patients with drugs or interventional radiology procedures References References Acknowledgements We thank all patients who participated in this study and our colleagues from many clinics in Serbia. This work was supported by research grant number 175041 for 2011 - 2014, issued by the Ministry of Science of the Republic of Serbia. Disclosure of Interest None Declared

The clinical manifestations of Sneddon's syndrome (cerebrovascular disorder, livedo reticularis, peripheral venous thrombosis++, cardiac pathology, obstetric pathology--fetal loss and intrauterine fetal death) are characteristic of the antiphospholipid syndrome. A lupus anticoagulant (LA), one of the types of antiphospholipid antibodies, was detected in the blood plasma of 18 out of 30 patients with Sneddon's syndrome. The negative results of LA-examination in 12 patients don't exclude the presence of other antiphospholipid antibodies. So 16 of 30 patients had anticardiolipin antibodies, among them being 6 LA-negative patients. The authors discuss the significance of antiphospholipid antibodies in the genesis of vascular abnormalities in patients with Sneddon's syndrome.

The pathogenicity of antibodies against β2-glycoprotein I (anti-β2GPI) depends on multiple factors such as subclass type, epitope binding and avidity. Due to their large heterogeneity, their impact on antiphospholipid syndrome (APS) onset is still not fully clarified. We studied the binding characteristics of IgG anti-β2GPI with known avidity from sera of 201 autoimmune patients (87 with APS, 67 with APS associated with systemic lupus erythematosus (SLE), 47 with only SLE) to six β2GPI peptides corresponding to amino acid clusters on domains I-II, II, III and III-IV by indirect ELISA and evaluated their association with clinical features of APS. Peptides A (LKTPRV; domain I-II), B (KDKATF; domain IV) and C (TLRVYK; domain III) were derived from a hexapeptide phage display library previously shown to react with pathogenic monoclonal anti-β2GPI. Peptides D (NGPANSK; domain III), E (YNPLWFV; domain II) and F (KMDGNHP; domain III-IV) represent surface amino acid clusters on β2GPI. The p...

Production of the antiphospholipid antibodies is usually associated with the development of antiphospholipid syndrome. The caracter of this syndrome is: venous and arterial thromboses, pregnancy loss, thrombocytopenia and some damages of blood-vessels. We have studies 150 pts with Systemic Lupus Erythematosis, 100 women with unknown for pregnancy loss and 36 pts with Sneddons Sy. Antikardiolipin antibodies were determined by the standard ELISA method, Lupus Anticoagulant by 4 phospholipid-depent coagulation test using the snake poison. The significant correlation (p<0,110) was found between antiphospholipid antibodies and development of antiphospholipid syndrome by the pts with autoimmune patology.

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 dysfuncti...

The authors present some literature and their own data on the antiphospholipid syndrome (venous and arterial thromboses; obstetric pathology: spontaneous abortions and intrauterine death of a fetus; CNS involvement: from headaches and disorientation to psychic disorders and cerebral infarctions; thrombocytopenia, early aseptic osteonecrosis and pulmonary hypertension). Altogether 58 patients with lupus erythematosus and 20 patients with a complicated obstetric history were examined. Lupoid anticoagulant and antibodies to cardiolipin were revealed in 27 patients. The determination of antiphospholipid antibodies was shown to be of practical value from the view-point of the knowledge of humoral immunity disorders in systemic lupus erythematosus, more detailed clinico-laboratory characterization of patients, the diagnosis and prediction of disorders of the blood coagulation system, and the development of obstetric pathology.

Examination of 115 women for detection of phospholipid antibodies (PLA), lupus anticoagulant and cardiolipin antibodies has demonstrated that in the absence of PLA all pregnancies terminated in the birth of full-term healthy children, while in their presence there were repeated abortions and (or) intrauterine death of a fetus. Obstetrical pathology in women in the presence of PLA was attended by venous and arterial thrombosis, thrombocytopenia, cerebral vasculitis and vascular affections, which is typical of the picture of the antiphospholipid syndrome. A new approach has been suggested to the treatment of such patients with reduction of the activity of lupus anticoagulant and cardiolipin antibodies owing to which pregnancy can be terminated in the birth of viable children.

Forty-one patients (31 women, 10 men) aged 15-56 (mean age, 38) with Sneddon's syndrome characterised by cerebrovascular disease and widespread livedo reticularis in the absence of typical lupus features were studied. 16 patients (39%) had clinical and/or electrocardiographic signs of ischemic heart disease, with 2 of them having survived myocardial infarction. Cardiac murmurs (usually mitral systolic) were heard in 15 patients (37%). Echocardiography revealed mitral valve thickening in 13 of 32 tested patients (41%). Anticardiolipin antibodies were found in 22 patients (54%) and lupus anticoagulant in 25 of 38 tested patients (66%). In 6 patients (15%) neither anticardiolipin antibodies nor lupus anticoagulant were observed. Anticardiolipin antibodies were more often present in patients with ischemic heart disease (12 of 16), than in those without (10 of 25) (p less than 0.05). Mitral valve thickening was revealed more often in patients with antiphospholipid antibodies (12 of 2...

Gastrointestinal (GI)-related autoantibodies (Abs) are rarely evaluated in autoimmune diseases (AID) other than inflammatory bowel disease, autoimmune hepatitis and celiac disease. Our aim was to determine the prevalence of these antibodies in a wide spectrum of AID. We examined 923 serum samples representing 18 AID and compared them with 338 samples from healthy subjects. We used the BioPlex 2200-immunoassay (Bio-Rad, USA) to test samples for the presence of IgA and IgG directed at gliadin (AGA), tissue-transglutaminase (tTG), and Saccharomyces cerevisiae (ASCA). Prevalence of IgA AGA was significantly higher in antiphospholipid syndrome (APS) (7.1 %, P=0.012) and in pemphigus vulgaris (25%, P =0.008) patients, as compared with healthy controls. Presence of IgG-AGA was more common among Crohn's disease (20.5%, P = 0.023) and rheumatoid arthritis (6.5%, P=0.027) patients. IgG anti tTG were frequently observed in APS (6.1%, P=0.012), in giant cell arteritis (11.5%, P=0.013) and i...

The antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity in the presence of antiphospholipid autoantibodies (aPL). aPL are a heterogeneous family of autoantibodies with diverse cross-reactivities whose origin and role have not been fully elucidated. Many of the autoantibodies associated with APS are directed against phospholipid-binding plasma proteins, such as beta2-GPI and prothrombin, or phospholipid-protein complexes. The mechanisms by which aPL cause thrombosis are not completely understood. There is no unique mechanism able to explain all symptoms associated with the presence of aPL. Different theories have been proposed, including the effect of aPL on endothelial cells, monocytes, and platelets. aPL are able to recognize, injure, or activate cultured vascular endothelial cells. Cultured endothelial cells incubated with aPL express increased levels of cell adhesion molecules and tissue factor (TF), an effect mediated by beta2-GPI, and may promote inflammation and thrombosis. Overexpression of TF has been also shown in monocytes in vitro and ex vivo. TF is the major initiator of coagulation in vivo; thus, its dysregulation may be one of the most important contributors to thrombosis. Effects of aPL upon platelets are not completely elucidated. aPL bind anionic phospholipid but they are normally in the inner side of cell membranes. When platelets are activated by different agonists, anionic phospholipids are exposed. There is some evidence showing that activated platelets are present in aPL-positive patients. Increased levels of beta-thrombomodulin, and microvesicle formation seem to support this hypothesis. Activated platelets may contribute to thrombosis by persistent exposure of a procoagulant surface.

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. Eve...