Artur Pahor

Antiphospholipid antibodies and atherosclerosis: Insights from Rheumatoid arthritis – A five-year follow-up study

OBJECTIVES Life expectancy in rheumatoid arthritis (RA) patients is reduced by 3-10 years, probably due to cerebrovascular and cardiovascular diseases associated with atherosclerosis. In the present study, we wanted to verify if previously reported IgA anti-beta 2-glycoprotein I (2GPI) antibodies possibly represented an independent risk factor for atherosclerosis in RA patients during a longer period of follow up. METHODS The follow-up study (after 5.5 years) comprised all initially included patients and controls (premenopausal women, non-diabetic, normotensive at the start of the study), except for two RA patients (one died and one not available). The same clinical, laboratory and ultrasound assessments were performed. RESULTS Patients and controls were divided into three categories: Intima-media thickness (IMT) progressors, plaque progressors, IMT and plaque progressors. In controls, 55% represented IMT progressors and 5% IMT and plaque progressors. No statistically significant differences were detected comparing the progressors with delta (Δ=difference between follow-up and baseline study for each group in a time span of 5.5 years) LDL cholesterol, homocysteine and IgA anti-β2GPI. In patients, there were 48.5% IMT progressors, 5.8% plaque progressors and 19.1% IMT and plaque progressors. The progression was statistically significant associated with the levels of Δ homocysteine and Δ apolipoprotein B but not with LDL cholesterol and IgA anti-β2GPI. CONCLUSIONS The follow-up study showed advanced atherosclerosis in RA patients compared to sex and age matched controls. However, we were not able to confirm our initial impression that IgA anti-β2GPI might represent an independent risk factor for atherosclerosis.

Augensymptome als Initialzeichen von Wegener-Granulomatose

OBJECTIVE Wegeners granulomatosis (WG) is a systemic, necrotising, granulomatous vasculitis of unknown aetiology. Ocular involvement is present in up to 60 %. The aim of our study was firstly to evaluate the presence of ophthalmic manifestations as the first sign of WG in patients without obvious systemic manifestations of WG, and secondly to evaluate the clinical manifestation of ocular symptoms as the initial signs of WG. METHODS The medical records of all patients with a diagnosis of WG examined at the Department of Rheumatology and Immunology during the 5-year period from January 2003 to January 2008 were reviewed. Initial manifestation of WG, initial ocular presentation, biopsy results, laboratory testing results, treatment and the final outcome were determined. Only patients in whom WG was not diagnosed at the time of the ocular symptoms were included in the study. RESULTS Fifteen patients diagnosed with WG were identified. Six patients (40 %) developed no ocular symptoms before and after WG was diagnosed. Two patients (13.3 %) had a systemic disease first and subsequently developed ocular symptoms. Seven patients (46.7 %) had ocular symptoms as the first signs of WG (necrotising sclerokeratitis in two patients, peripheral ulcerative keratitis in two patients, non-granulomatous uveitis in one patient, anterior necrotising sclerokeratitis and nodular posterior scleritis with serous retinal detachment in one patient, severe retinal and chorioidal vascular occlusions with ischaemic optic disc neuropathy and complete visual loss in one patient). CONCLUSIONS In nearly 50 % of patients with WG, ocular symptoms were observed as the initial signs before WG was diagnosed. The initial symptoms may be obscure and may vary from one patient to another. Knowledge of the ocular initial symptoms of WG is very important and can contribute to a better prognosis and prevention of visual loss.

Postoperative inflammation after cataract surgery in patients with rheumatoid arthritis.

The purpose of the present study was to assess the influence of preoperative activity of rheumatoid arthritis (RA) on early postoperative anterior chamber inflammation after phacoemulsification and intraocular lens implantation. Twenty-three eyes in 18 patients were included in our study. On the first postoperative day, anterior chamber inflammation was observed in 11 eyes (47.8%). Five days after surgery, we found postoperative inflammation only in 1 eye (4.3%). Keratic precipitates were observed in 1 eye (4.3%) on the second postoperative day. We found no correlation between the extent of anterior chamber inflammation and the preoperative activity of RA. Postoperative anterior chamber inflammation was also not associated with the medical management of RA.

STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity

Activation of the STAT5 signaling pathway up‐regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (Tcons). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RA−FOXP3hi activated regulatory T cells (aTregs) were described. We assessed Tcon/Treg subsets and phosphorylation of STAT5 (pSTAT5) in blood T cells from patients with SLE by using conventional and imaging flow cytometry. Forty‐one patients with SLE, 33 healthy controls, and 29 patients with rheumatoid arthritis were included. Long‐term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL‐7–dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low‐expressing CD4+ T cell subsets but not in the aTreg subset, which was significantly decreased in patients with SLE. In contrast to aTreg, SLE Tcon displayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of Tcon‐expressing proliferation marker Ki‐67 was significantly increased in patients with SLE and was positively correlated with CD4 T cell pSTAT5 levels. Finally, a subgroup of patients characterized by an increased Tcon–pSTAT5/aTreg–pSTAT5 ratio experienced a more aggressive‐relapsing disease course and displayed higher time‐adjusted cumulative CD4 T cell pSTAT5 levels during follow‐up, which were positively correlated with time‐adjusted cumulative disease activity. Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki‐67 expression, may confer survival and proliferative advantage to Tcon over aTreg and could represent a possible marker of SLE disease severity.

Gesichtsfelddefekte bei der Erstuntersuchung von Patienten mit nichtarteriitischer anterioren ischämischen Optikusneuropathie

Das Ziel dieser Studie war es, Gesichtsfelddefekte bei der Erstuntersuchung von Patienten mit nichtarteriitischer anterioren ischämischen Optikusneuropathie (NA-AION) mittels automatischer statischen Perimetrie zu analysieren. Retrospektiv wurden medizinische Befunde aller Patienten mit der ersten akuten NA-AION, die zwischen 2004 und 2014 in unsere Abteilung aufgenommen wurden, überprüft. Von 140 NA-AION-Patienten entsprachen 85 Patienten unseren Ein- und Ausschlusskriterien für die Studie. Bei allen Patienten wurde eine automatische statische Perimetrie durchgeführt. Gesichtsfelddefekte wurden erst in zwölf Kategorien und später in fünf Kategorien eingeteilt. Das Durchschnittsalter unserer Patienten war 64,8 Jahre, in einer Bandbreite von 36 bis 94 Jahre. Der Großteil der Patienten waren Männer: 49 von 85 (57,6 %). Bis auf das Krankheitsbild mit AION waren andere ophthalmologische Befunde normal. Ein typischer altitudinaler inferiorer Defekt mit einem scharfen Rand entlang des horizontalen Meridians wurde bei 30 von 85 Patienten bemerkt (35,3 %). Ungeachtet des Umfanges des Gesichtsfelddefektes wurde die inferiore bei 54 von 85 Patienten (63,5 %) und die superiore Zone bei 20 von 85 Patienten (23,5 %) beeinträchtigt. Konzentrische Verengung des Gesichtsfelddefektes kam bei 14 von 85 Patienten (16,5 %) vor. Bei drei Patienten (3,5 %) wurde ein parazentrales Skotom und bei zwei Patienten (2,4 %) wurden temporale Defekte entdeckt. Unsere Studie bestätigte, dass der relative Defekt in der Zone altitudinal inferior in Kombination mit dem absoluten Defekt in der Zone inferior nasal die häufigste Form des Gesichtsfelddefektes bei der mit einer automatischen statischen Perimetrie durchgeführten Erstuntersuchung von NA-AION-Patienten darstellt. The aim of our study was to analyze visual field defects in patients with non-arteritic anterior ischemic optic neuropathy (NA-AION) at initial examination using automated static perimetry. Medical records of all patients with first attack of acute NA-AION who were admitted to our department during the period of 11 years (2004–2014) were retrospectively reviewed. At the end, from 140 NA-AION patients, 85 patients who fulfilled our inclusion and exclusion criteria remained in the study. In all patients automated static perimetry was performed. Visual field defects were classified into 12 categories and condensed into 5 categories. The average age of our patients was 64.8 years, ranging from 36 to 94. The majority were men, 49 of 85 (57.6 %). Except for clinical picture of AION other ophthalmological findings were normal. Typical inferior altitudinal defect with sharp border along the horizontal meridian was observed in 30 of 85 patients (35.3 %). Regardless the extent of the visual field defects, inferior part was affected in 54 of 85 patients (63.5 %) and superior in 20 of 85 (23.5 %). Concentric narrowing of the visual field occurred in 14 of 85 patients (16.5 %). In three patients (3.5 %) paracentral scotoma and in two patients (2.4 %) temporal defects were observed. Our study confirmed that a combination of relative inferior altitudinal defect with absolute inferior nasal defect is the most common pattern of visual field defects at initial examination in NA-AION patients also using automated static perimetry.

Klinische Befunde bei Patienten mit nicht arteriitischer anteriorer ischämischer Optikusneuropathie (NAION) unter 50 Jahren

BACKGROUND The aim of our study was to determine the prevalence of NA-AION patients younger than 50 years among all our NA-AION patients and to compare clinical findings between young and elderly NA-AION patients. METHODS This was a retrospective review of complete ophthalmic examinations, including fluorescein angiography and visual field testing, performed on all patients with the first attack of acute NA-AION admitted to our department during the period of ten years (2004 to 2013). Of 120 NA-AION patients, 10 (8.3 %) were under 50 years of age. RESULTS The majority of these were men: 8 of 10 (80 %). The average best corrected visual acuity on admission was 0.34 (fingers counted up to 1.0) and on discharge 0.53 (fingers counted up to 1.0). Of 10 eyes, 6 were emmetropic and 4 hyperopic, from + 0.50 D to + 2.0 D. Aside from the clinical picture of AION, other ophthalmological findings were normal. In fluorescein angiography, typical changes for ischaemic optic neuropathy were observed in all patients. In a majority of patients, an inferior altitudinal visual field defect was found. As regards systemic risk factors, hyperlipidaemia was observed in 7, arterial hypertension in 3, diabetes mellitus without diabetic retinopathy in 3, and ischaemic heart disease in 1 of 10 patients. One patient was treated for rheumatoid arthritis without signs of vasculitis. In 3 patients, more than one systemic risk factor was observed. Two of our patients had no systemic risk factors except moderate hyperopia. Bilateral manifestation was observed only in one patient 8 months after the first attack. None of the patients experienced recurrent attacks. CONCLUSION The prevalence of younger patients in our study was lower than in previous studies. The reason could be the better medical prevention in our region. Our study confirmed that even in young NA-AION patients, moderate hyperopia could be a predisposing factor. Our study did not confirm the differences between young and elderly NA-AION patients as observed in previous studies. During a period of 10 years, we did not observe recurrences, high risk of other eye involvement or severe vision loss in our young patients compared to the elderly.

Opportunities and challenges in rheumatology research in Central Europe

The Central European Congress of Rheumatology (CECR) has been organized by seven Central European countries: Austria, Croatia, Czech Republic, Hungary, Poland, Slovakia, and Slovenia. These countries have lots of similarities, but also differences, with respect to rheumatology research. In this paper, based on questionnaires, we wish to demonstrate achievements and difficulties in rheumatology research performed in our region.

HPLC–MS/MS method optimisation for matrix metalloproteinase 3 and matrix metalloproteinase 9 determination in human blood serum using target analysis

A quantitative analysis of zinc endopeptidases matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 3 (MMP3) from human blood serum are presented. Both matrix metalloproteinases (MMP) are present in human blood serum and can be used as biomarkers for different diseases. The analysis was performed using LC-MS/MS with a triple quadrupole mass spectrometer, based on two specific peptides of each MMP in comparison with an enzyme-linked immunosorbent assay (ELISA). While the conditions for the LC-MS/MS analysis of MMP9 peptides were previously reported for bronchoalveolar lavage fluid, the analysis of MMP3 peptides was newly quantified for human blood serum herein for the first time. For MMP3, the linear behaviour was determined in the concentration range from 1.0-200.0ng/mL (R2=0.997) with an LLOD of 0.5ng/mL. For MMP9, linearity was determined in the concentration range from 6.5-65.0ng/mL (R2=0.995) with an LLOD of 2.0ng/mL.

PRECLUDE® Pericardial Membrane für die Behandlung von perforiertem Hornhautulkus bei Patienten mit systemischen autoimmunentzündlichen Erkrankungen

ZusammenfassungZielsetzungDie Verwendung von PRECLUDE® Pericardial Membrane, die aus expandiertem Polytetrafluorethylen (e-PTFE, sonst bekannt als Gore-Tex®) besteht, als eine Alternativtherapie für die Behandlung eines perforierten Hornhautulkus bei Patienten mit systemischen autoimmunentzündlichen Erkrankungen wurde evaluiert.MethodenEs wurden Krankenberichte von allen Patienten retrospektiv überprüft, die auf unserer Abteilung zwischen Dezember 2009 und Dezember 2013 hospitalisiert wurden und einer chirurgischen Reparatur mit PRECLUDE® Pericardial Membrane wegen eines perforierten Hornhautulkus unterzogen wurden. Bei drei Patienten mit systemischen autoimmunentzündlichen Erkrankungen wurde eine nicht absorbierbare, mikroporöse, wasserdichte 0,1 mm dicke e-PTFE-Membrane zur Schließung des Hornhautulkus benutzt. Ein passender Membranteil wurde zurechtgeschnitten, um den Defekt entsprechend zu überdecken und die erwünschte Gewebeanhaftung zu erzielen. Die Membran wurde mit zahlreichen nicht-resorbierbaren Fäden befestigt.ErgebnisseHornhautperforation wurde mit der e-PTFEMembrane erfolgreich abgedeckt. Keiner der Patienten hatte Schmerzen oder andere Beschwerden. Bei der Verlaufskontrolle wurden keine Anzeichen für Infektionen oder Entzündungen beobachtet. Bei einem Patienten mit Granulomatose mit Polyangiitis und bei einem Patienten mit systemischer Vaskulitis wurde die e-PTFE-Membrane drei Monate nach dem chirurgischen Eingriff entfernt, bei einem Patienten mit Sjögren-Syndrom acht Monate nach dem Eingriff. Die darunter liegende Hornhaut war in allen Fällen dünn, fest, stabil und vollständig vaskularisiert.SchlussfolgerungenPRECLUDE® Pericardial Membrane stellte sich als eine sichere und wirksame Alternativmethode für die chirurgische Behandlung eines perforierten Hornhautulkus bei Patienten mit systemischen autoimmunentzündlichen Erkrankungen dar. Bei Risikopatienten, bei denen die Gefahr einer Transplantatabstoßung besteht, könnte dieses Verfahren die Methode der Wahl zum Augenerhalt und zu einer aufgeschobenen Hornhauttransplantation sein. Weitere Studien sind erforderlich, um unsere Ergebnisse zu bestätigen.SummaryPurposeTo evaluate the use of PRECLUDE® Pericardial Membrane composed of expanded polytetrafluoroethylene (e-PTFE, widely known as Gore-Tex®) as an alternative surgical procedure for the management of perforated corneal ulcer closure in patients with systemic autoimmune inflammation.MethodsMedical records of all patients who were admitted to our department and underwent surgical repair of perforated corneal ulcer with PRECLUDE® pericardial membrane between December 2009 and December 2013 were retrospectively reviewed. In 3 patients with systemic autoimmune inflammation non-absorbable, microporous, watertight 0.1 mm thick e-PTFE membrane was used for corneal ulcer closure. Proper size of membrane was cut to overlap the defect adequately and to achieve a desired tissue attachment. Membrane was fixated with several non-absorbable sutures.ResultsCorneal perforation was successfully covered with e-PTFE membrane. None of the patients had pain or discomfort. No signs of infections or inflammations were detected on follow-up examinations. Three months after surgical treatment the e-PTPE membrane was removed in patient with granulomatosis with polyangiitis and in patient with systemic vasculitis and eight months after surgery in patient with Sjögren syndrome. Underlying cornea was thin, firm, stable and completely vascularised.ConclusionPRECLUDE® Pericardial Membrane was found to be a safe and effective as an alternative surgical procedure for perforating corneal ulcer closure in patients with systemic autoimmune inflammation. In these high risk patients for graft rejections this procedure could be the method of choice for eye preservation and for delayed corneal transplantation. Further studies are necessary to confirm our results.

AB0327 Progression of Atherosclerosis in Premenopausal Rheumatoid Arthritis Patients Treated with Methotrexate – A Five Year Follow up Study

Background Life expectancy in rheumatoid arthritis (RA) patients is reduced by 3-10 years mainly due to cardiovascular diseases. In the core study, we found that selected normotensive, non-diabetic, premenopausal RA patients had increased intima media thickness and more plaques, and thereby accelerated atherosclerosis, comparing to controls. In present follow up study we studied the impact of treatment with methotrexate and disease activity on progression of atherosclerosis in the same RA patients in a time span of 5.5 years. Methods The study group comprised of 22 female RA patients who were treated with methotrexate. RA was diagnosed according to the 1987 revised criteria of the American College of Rheumatology. 46 RA patients not treated with methotrexate were selected as a control group. Ultrasound examination of carotid arteries was performed. Results of intima media thickness (IMT) and plaques were statistically studied and correlated with classical and non-classical risk factors for atherosclerosis as well with cytokines, adhesion molecules, CRP and disease activity score-28 (DAS-28). Results The IMT in patients treated with methotrexate was 0.63±0,08 mm and 0.64±0,11mm in those untreated (p>0.05). We also calculated the difference in plaque number in patients who were treated with methotrexate and those who were not. We found plaques in 6 patients treated with methotrexate and in 11 untreated patients (p>0.05).We compared DAS-28 in patients who were treated with methotrexate and those who were not. The DAS-28 in patients treated with methotrexate was 4.19±1.71, and the DAS-28 in patients who did not receive methotrexate was 3,84±1.34 (p>0.05). Conclusions The IMT in study RA patients with severe disease treated with methotrexate had lower values of IMT and fewer atherosclerotic plaques in comparison to RA patients who did not receive methotrexate. However they did not reach a statistically significant difference. The patient number is small and the time span is also relatively short. More patients and a longer treatment time are required for definitive results. It should also be noted that patients with a severe disease are expected to have increased IMT in comparison to those with a less severe disease. Patients with more severe disease in our study group received methotrexate, which obviously delayed IMT progression. References Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002 Apr 6;359(9313):1173-7. Wallberg-Jonsson S, Öhman M-L, Rantapää-Dahlquist S. Which factors are related to the presence of atherosclerosis in rheumatoid arthritis. Scand J Rheumatol. 2004; 33:373-9. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009 Jul;68(7):1100-4. Turiel M, Tomasoni L, Sitia S, Cicala S, Gianturco L, Ricci C, Atzeni F, De Gennaro Colonna V, Longhi M, Sarzi-Puttini P. Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis. Cardiovasc Ther. 2010 Oct;28(5):e53-64. doi: 10.1111/j.1755-5922.2009.00119.x. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3316