Showing papers by "Matija Tomšič published in 2015"

Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group

Abstract: OBJECTIVES To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. METHODS Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. RESULTS 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs -7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs -7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. CONCLUSIONS The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc.

Validation of EULAR primary Sjogren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)

Abstract: Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjogren's syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjogren's Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r= 0.59; ESSRPI with PGA: r= 0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

On the crossroads of current polyelectrolyte theory and counterion-specific effects

Abstract: Aqueous solutions of polyelectrolytes are studied here by means of neutron scattering, with emphasis on backbone hydrophobicity and counter ion specific effects. Ionene polyelectrolytes with varying chain charge density and different counter ions are considered. Their neutron scattering data feature a number of aspects and trends that clearly deviate from the predictions of the existing theory. Ionenes challenge the current hydrophilic–hydrophobic classification of water-soluble polyelectrolytes. The hydrophobic character of their hydrocarbon backbone emerges only for very low chain charge densities (at 15% of charged monomers), which is significantly lower than for other polyelectrolytes with a more complex structure. Universality in the counter ion specific effect seen in ionene solutions with Br− or F− counterions is established. The polyelectrolyte peak in the scattering spectra of Br-ionenes disappears beyond a specific charge concentration, which is identical across all ionene chain charge densities. In addition, scattering spectra of Br-ionenes and F-ionenes feature contrasting temperature trends, which are accentuated with decreasing chain charge density. Our interpretation of the F–Br effect, based on the different hydration properties of the counter ions, is supported by additional NMR measurements on ionenes with mixed counter ion clouds. Overall, the study of ionene polyelectrolytes points clearly to the need for combining the scaling concepts with those of ion specificity, to obtain a theoretical framework encompassing the wealth of phenomena occurring in polyelectrolyte solutions.

Evaluating SAXS Results on Aqueous Solutions of Various Bacterial Levan utilizing the String-of-Beads Model

Abstract: Polysaccharide levan is a homopolymer of fructose and is an important component of plants, yeast, fungi and some bacterial biofilms. In this paper we report on the structural properties of aqueous solutions of bacterial levan utilizing small-angle X-ray scattering and light microscopy. In addition to commercially available levan isolated from Zymomonas mobilis and Erwinia herbicola , we also studied levan isolated and purified from the biofilm of Bacillus subtilis . The results of small-angle X-ray scattering data were analyzed by the string-of-beads model that revealed qualitative differences in the structure of levan molecules. Levan can be represented as a semi-flexible chain that interacts intra- and inter-molecularly and therefore forms various suprastructures on larger size scales. Increasing the concentration of levan makes the levan structure more compact, which was observed on the nano as well as on the micro scale. The structures with most homogeneously distributed polymer local density were found in B. subtilis levan solutions.

Testing Classical Approach to Polymer Solutions on SAXS Data of λ-Carrageenan, κ-Carrageenan and Methylcellulose Systems

Abstract: In this paper we present the performance of the classical approach to polymer solutions in evaluation and interpretation of the experimental SAXS data obtained for aqueous solutions of two gelling polysaccharides κ-carrageenan and methylcellulose and a non-gelling polysaccharide λ-carrageenan. In a systematic structural SAXS study of various types of polymer solutions we pointed out and discussed the issues encountered and connected to the fact that the studied gels are obviously not "homogeneous gels" in terms of the structural details that the SAXS technique can resolve and the issues connected to the limited experimental resolution of the SAXS technique for such systems. In parallel the necessary modifications of the classical approach equations for the evaluation of the SAXS data are discussed. Furthermore, the detailed structural results of the studied aqueous polymeric systems in liquid state, during the onset of the gelation, and even in the gel state are presented.

Laboratory Methodology Important in the Diagnosis and Prognosis of Antiphospholipid Syndrome

Abstract: Antiphospholipid syndrome (APS) is an autoimmune disease, characterized by thrombosis and pregnancy complications with persistently elevated levels of antiphospholipid antibodies (aPL). Recently, a unique mathematical calculation has been presented to assess the risk of thrombosis in patients with APS called antiphos‐ pholipid score or global antiphospholipid syndrome score (GAPSS). This new approach in the diagnosis of APS leads to the assessment of the risk of thrombosis considering the results of different aPL (lupus anticoagulants (LA), anticardiolipin antibodies (aCL), antibodies against β2GPI (anti-β2GPI), and phosphatidylserinedependent antiprothrombin antibodies (aPS/PT) (isotypes IgG and IgM). This chapter provides an overview of the algorithm strategy for APS diagnosis with the aims of characterizing in detail the laboratory methodology of criteria aPL (LA, aCL, and antiβ2GPI) and noncriteria aPL, such as IgA aCL and IgA anti-β2GPI, anti-domain I β2GPI, and antiprothrombin antibodies. In order to improve APS diagnosis, several new approaches in aPL detection have recently been suggested, such as multiline immunodot assay, detection of aPL by flow cytometry using beads with particular surface properties, and the newly developed automated BioPlex system technology for parallel detection of aCL and anti-β2GPI antibodies of IgG, IgA, and IgM isotypes. A completely different and promising approach in future research lies in the potential of microRNAs as biomarkers for risk of thrombosis and/or obstetric complication.

FRI0169 Smoking and Response to Rituximab in Anti-CCP Positive and Negative Rheumatoid Arthritis – Results from an International European Collaboration

Abstract: Background Smoking is a negative predictor of response to antirheumatic therapy. Objectives To assess whether smoking influence the response to rituximab (RTX) in Rheumatoid Arthritis (RA). Methods Pooled data from the Collaborating European Registries for RTX in RA (CERERRA) were used. Patients who received at least 1 cycle with RTX were included. Smoking status was defined as smokers (current smokers) and non-smokers (never and ex-smokers). Analysis of co-variance (ANCOVA) was performed with DeltaDAS28 at 6 months as the dependent variable and smoking status as well as other baseline variables (age, sex, disease duration, number of prior biologic DMARDs) as covariates. Separate analyses were made for anti-CCP positive and negative patients. Results A total of 2274 patients were included - 1815 (80%) non-smokers and 459 (20%) smokers. 81% were female and 80% (out of 1199 patients with available anti-CCP) were anti-CCP positive. Smokers had shorter disease duration than non-smokers (median (IQR) 8 (4-13) years vs. 10 (5-16), p Smokers had less improvement in disease activity than non-smokers at 6 months (mean ± SD DeltaDAS28 -1.5±1.7 vs. -1.8±1.7, respectively, p=0.04). However, the difference was no longer significant after adjustment for baseline differences (p=0.40). When the analysis was stratified by anti-CCP status, smoking did not influence the response to therapy in the anti-CCP negative subset (p=0.39) but there was a trend in the anti-CCP positive subset (p=0.06, figure 1). For the anti-CCP negative patients, 67% of non-smokers and 69% of smokers achieved EULAR response (p=0.6), while in the anti-CCP positive the respective response rates were 76% among non-smokers and 70% among smokers (p=0.09). Conclusions Smoking was negatively associated with the response to rituximab therapy in RA patients who were anti-CCP positive. References Khan A. et al. Smoking, rheumatoid factor status and responses to rituximab. Ann Rheum Dis 2012;71:1587-1588 doi:10.1136/annrheumdis-2012-201758 Saevarsdottir S. et al. Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedis Reumatology register cohorts. Arthritis Rheum 2011;63:26–36. Chatzidionysiou K. et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed. Pooled data from 10 European registries. Ann Rheum Dis 2011;70:1575–80. Disclosure of Interest K. Chatzidionysiou: None declared, E. Lie: None declared, E. Nasonov: None declared, G. Lukina: None declared, M. Hetland: None declared, E. Hauge: None declared, K. Pavelka Consultant for: MSD, AbbVie, Pfizer, Roche, BMS, C. Gabay Grant/research support from: Roche, Merck, Abbvie, Consultant for: Roche, Abbvie, Pfizer, BMS, Sanofi-Aventis, Merck, AB2 Bio, D. Nordstrom Consultant for: AbbVie, BMS, MSD, Pfizer, Roche, UCB, H. Canhao: None declared, M. Tomsic: None declared, P. van Riel: None declared, J. Gomez-Reino: None declared, I. Ancuta: None declared, T. Kvien: None declared, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, S. Saevarsdottir: None declared

Comment on: High-risk pregnancy and the rheumatologist.

Abstract: SIR, We thank Sonja Praprotnik for her interest in our paper and due diligence in reading the original publication [1, 2]. She raises a valid point that would benefit from further discussion [3]. In the article by Daniel et al. [2], there was no increased risk of fetal malformations in 119 women exposed to selective cyclooxygenase 2 (COX-2) inhibitors in the first trimester. While there were additional data on concomitant drugs prescribed in the first trimester, these data were not included in the multivariate logistic regression because the authors deemed that there was no increased risk. Similarly, these data were excluded from sensitivity analysis, in which individual classifications of malformations were further explored. In the category of musculoskeletal malformations, the absolute numbers affected were small (n = 5 in COX-2 selective inhibitor use) and confidence intervals very wide. A similar trend towards increased risk of musculoskeletal malformations was observed for indomethacin, for which again the absolute numbers were small (n = 4). These results should be interpreted with caution. Additionally, there was significantly more maternal inflammatory disease in the COX-2 selective inhibitor group (2.6% vs 0.1% in the non-exposed group, P< 0.001); it is possible that they may have been prescribed concomitant drugs to manage their inflammatory disease, and it is probable that these drugs (e.g. MTX) could be contributing to the overall risk of musculoskeletal malformations seen in this group. MTX traditionally causes limb skeletal abnormalities (partial or absent ossification of bones, shortened limbs, syndactyly, absent digits and multiple cranial ossification abnormalities); hence, it is within the realms of possibility that these are in keeping with the musculoskeletal abnormalities described in the sensitivity analysis [4]. COX is responsible for the production of prostaglandins—COX-1 and COX-2. NSAIDs interrupt the conversion of COX to prostaglandins, and thereby non-selectively inhibiting both COX-1 and COX-2 production. COX-2 inhibitors discussed in our paper have a more streamlined effect on both maternal and fetal tissues. So, one could hypothesize that the dual blockade of COX-1 and COX-2 by NSAIDs would have a greater effect on the developing fetal organs than seen in COX-2 inhibition alone. This is very much evident in the use of COX-2 inhibitors for the treatment of preterm labour when oligohydramnios is less profound and preterm closure of the ductus arteriosus is delayed when compared with NSAID use [5, 6]. There is now good evidence for lack of teratogenicity with NSAIDs; this is despite early reports to the contrary and possible association with a variety of anomalies [7]. Drugs often require decades of use before they are accepted as safe in pregnancy, simply because pregnant women are excluded from most drug trials. We believe the data for the safety of COX-2 selective inhibitor use in pregnancy will be even slower to emerge, because many clinicians will be more inclined to swap pregnant women on COX-2 selective inhibitors to a NSAID with a more established safety profile. However, the strengths of COX-2 selective inhibitors may lie in their use beyond 32 weeks’ gestation for women who require intermittent NSAID use in pregnancy for the management of inflammatory pain. Nevertheless, we agree with Dr Praprotnik that until further evidence is available, we should exercise caution in the use of COX-2 inhibitors in early pregnancy, hence our sentence “data for the safety of COX-2 inhibitors is emerging . . .”. In retrospect, the disclaimer was somewhat ambiguous, and we hope this reply better quantifies the risk of COX-2 selective inhibitor use in pregnancy.

Guidelines for prevention and management of gastrointestinal adverse effects in patients receiving non-steroidal anti-inflammatory and antiaggregant therapy

Abstract: Adverse effects of nonsteroidal antiinflammatory drugs and antiaggregants on gastrointestinal tract can be prevented or reduced by rational prescribing, use of proton pump inhibitors and Helicobacter pylori eradication. Nonsteroidal antiinflammatory drugs should not be used to treat patients with high risk for serious adverse effects on either upper gastrointestinal or cardiovascular system. Proton pump inhibitors in standard oral dosages are used for treatment of dyspepsia or gastric and duodenal erosions and ulcers, caused by nonsteroidal antiinflammatory drug or antiaggregant use. Peptic ulcer hemorrhage is treated with endoscopic hemostasis and proton pump inhibitors (72-hour continuous infusion followed by 4 – 8 week standard dose oral treatment). Patients can be stratified into three groups based on risk for upper gastrointestinal system adverse effects associated with nonsteroidal antiinflammatory drugs or antiaggregants use. Absence of risk factors denotes low-risk patient population, one or two risk factors are associated with medium risk; high-risk patients harbor either three or more risk factors or history of complicated peptic ulcer disease. Helicobacter pylori should be eradicated (if present) in all medium and high-risk patients prior to introduction of nonsteroidal antiinflammatory drugs or antiaggregants and proton pump inhibitors in standard daily dose should be prescribed for the duration of the treatment. Risk of gastrointestinal hemorrhage should be considered when planning invasive cardiovascular procedures or introduction of antiaggregant or anticoagulant treatment. In the context of acute gastrointestinal hemorrhage, antiaggregants should not be discontinued for longer than 7 days and oral anticoagulant therapy should be stopped and converted to low-molecular-weight heparin after complete hemostasis.

SAT0414 Antiphospholipid Antibodies in Patients with Cerebrovascular Events

Abstract: Background Determining the cause of a cerebrovascular event (CVE) can greatly influence further management of the patient. Testing for hypercoagulable states is an important part in etiologic evaluation, which comprises also testing for antiphospholipid antibodies (aPL). Objectives The primary aim was to determine the frequency of patients experiencing CVE and fulfilling the criteria for antiphospholipid syndrome (APS) [1] or non-criteria APS (when persistently positive for non-criteria aPL against anti-cardiolipin (aCL) IgA, anti-β 2 glycoprotein I (anti-β 2 GPI) IgA, anti-phosphatidylserine/prothrombin (aPS/PT) and/or anti-annexinV (aANXV) - all isotypes). The second aim was to determine whether persistence of aPL-positivity is a risk factor for experiencing an episode of CVE. Methods Eighty-nine consecutive patients (mean age 48 years, range 18-67) with acute CVE (transitory ischemic attack, ischemic cerebrovascular insult or venous sinus thrombosis) were prospectively followed for one year after the index event. In the comparative group, there were 25 patients with migraine (mean age 40 years, range 18-58) and 20 patients with Huntington9s disease (mean age 53 years, range 32-67 years). Demographic data on smoking, hypertension, hyperlipidemia, diabetes and the use of oral contraceptives were obtained by an interview and examinations. For all patients at least two sera taken 3 months apart were tested for lupus anticoagulants, aCL, anti-β 2 GPI, aPS/PT and aANXV of IgG, IgM and IgA isotypes [2-5]. Data were analysed with multiple logistic regression model. Results We found that 20/89 (22%) CVE patients were persistently positive (at least twice, with the first testing not earlier than 3 months after CVE) for one or more isotypes of tested aPL, 17/20 had criteria aPL and 3/20 non-criteria aPL; comparing to 3/45 (7%) positive in comparative group. Using TOAST CVE classification [6] with aPL, the cause of CVE could be consecutively explained in 16% of the patients with formerly unexplained CVE (Figure 1). We found significant association between persistently present aPL (of any class or isotype) and CVE (cumulative OR 4.62; 95% CI 1.09 to 19.66). Among other risk factors, only hypertension and hyperlipidemia showed a significant association with CVE (OR 4.31; 95% CI 1.33 to 13.92 for hypertension and OR 15.23; 95% CI 4.13 to 56.15 for hyperlipidemia). Conclusions aPL are one of the possible etiologic factors for CVE. In our group of patients 16% of formerly unexplained CVE could be explained with the persistent presence of aPL (as required to fulfill the APS criteria). Furthermore, aPL are not only a diagnostic parameter, but they themselves represent an independent risk factor for thrombosis. They should be tested, especially in cases without other recognized common etiologic factors for CVE. References Miyakis S, et al. J Thromb Haemost 2006; 4: 295-306. Brandt JT, et al. Thromb Haemost 1995; 74: 1185-90. Cucnik S, et al. Clin Chem Lab Med 2000; 38: 777-783. Avcin T, et al. Rheumatology 2001; 40: 565-573. Zigon P, et al. Clin Chem Lab Med 2011; 49: 1011-1018. Adams HP Jr, et al. Stroke 1993; 24; 24: 35-41. Disclosure of Interest None declared