Gabriella Szűcs

Association of systemic and thyroid autoimmune diseases.

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

Plasma homocysteine levels, the prevalence of methylenetetrahydrofolate reductase gene C677T polymorphism and macrovascular disorders in systemic sclerosis: risk factors for accelerated macrovascular damage?

The purpose of this study was to investigate plasma homocysteine (Hcy) levels in patients with systemic sclerosis (SSc) and to study the association between plasma Hcy, C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), and the clinical manifestations in SSc. Associations of Hcy level, C677T MTHFR polymorphism, and macrovascular diseases were investigated in 152 patients with SSc and 58 controls. No significant differences in Hcy levels and MTHFR genotypes were found in SSc patients compared to controls or in SSc patients with limited cutaneous compared to diffuse disease. Significantly higher Hcy concentration was observed in patients with macroangiopathy/thromboembolic events compared to patients without such clinical manifestations (p < 0.05). There was significant correlation between age and macrovascular disorders, between Hcy level and the disease duration (r = 0.164; p < 0.05). Seventy-one percent of patients with macrovascular disorders had MTHFR polymorphism. In addition, 45% of patients with hyperhomocysteinemia had pulmonary hypertension. The presence of MTHFR C677T mutation influences the incidence of macrovascular abnormalities in SSc patients. Elevated Hcy levels may be associated with disease duration and the evolution of macrovascular disorders and pulmonary hypertension in SSc.

A4.3 Effects of anti-TNF therapy on markers of bone homeostasis in rheumatoid arthritis and ankylosing spondylitis

Background and objectives Uncoupling of bone resorption and formation has been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Generalised bone loss and erosions are characteristic for RA, while in AS, bone formation overrides resorption. The RANKL/OPG and the Wnt/DKK-1/sclerostin systems have been implicated in disturben bone homeostasis in arthritides. Anti-TNF biologics may beneficially influence erosions and bone loss in RA, however, they have little effect on bone formation in AS. In the present study, we assessed the effects of 1-year anti-TNF treatment on various bone biomarkers. Patients and methods Altogether 43 arthritis patients including 30 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 13 AS patients treated with ETN were included in a 12-month follow-up study. Disease activity (DAS28 or BASDAI), CRP, IgM rheumatoid factor, anti-CCP, calcium (Ca), phosphate (P), osteocalcin (OC), P1NP, CTX, BNP, sclerostin (SOST), DKK-1, soluble RANKL (sRANKL), cathepsin K (cathK) and vitamin D3 (vitD) levels were assessed at baseline, as well as 6 and 12 months after treatment initiation. Results Anti-TNF treatment was highly effective in both diseases, as the mean DAS28 decreased from 6.32 to 3.16 (p = 0.02) in RA, mean BASDAI decreased from 5.87 to 1.84 (p < 0.001) in AS. In RA, anti-TNF treatment significantly decreased DKK-1 (60.5 ± 28.9 pM and 54.7 ± 20.8 pM, p = 0.036) and CathK (28.7 ± 6.2 pm and 26.8 ± 4.0 pm, p = 0.014) but increased SOST (107.0 ± 47.5 pM and 131.2 ± 85.2 pM, p = 0.04) levels from baseline to 12 months, respectively. In RA, ETN and CZP treatment also increased OPG/sRANKL ratio after 6 months (51.9) vs. baseline (43.9) (p = 0.01). In AS, ETN therapy significantly increased the bone formation marker P1NP (49.4 ± 19.0 pM and 56.9 ± 28.7 pM, p = 0.03) and SOST (70.6 ± 29.0 pM and 82.4 ± 48.3 pM, p = 0.022) levels from baseline to 12 months, respectively. ETN therapy also increased OPG/sRANKL ratio after 6 months (44.5) and 12 months (46.9) compared to baseline (34.5) in AS (p < 0.01). Both baseline and 12-month SOST levels were significantly lower in AS compared to RA (p < 0.001). When RA and AS data were pooled, TNF inhibition resulted in significantly decreased DKK-1 (p = 0.035) and cathK (p = 0.008) but increased P1NP (p = 0.04) and SOST (p = 0.04) after 12 months. In this study, biologics did not affect Ca, P, OC, CTX, BNP, vitD levels. Conclusions In a mixed cohort of RA and AS patients, anti-TNF therapy resulted in a restoration of bone homeostasis by decreasing DKK-1 and CathK, increasing P1NP, SOST and OPG/sRANKL ratio. Lower SOST levels in AS compared to RA, as well as the induction of bone formation over resorption may account for the inefficacy of TNF inhibitors on syndesmophyte formation in AS.

D-vitamin-anyagcsere és osteoporosis szisztémás sclerosisban

In the past few years more and more data have become available on the important role of vitamin D in immunological processes and inflammation. The role of vitamin D deficiency in the pathogenesis as well as in disease progression of different autoimmune and inflammatory conditions is suspected. Vitamin D deficiency is prevalent in several autoimmune diseases, including systemic sclerosis. Hypovitaminosis has been found to be associated with low bone mineral density and higher prevalence of osteoporosis in this group of patients. Determinants of low bone density in SSc are poorly understood. Studies have shown the importance of both traditional osteoporotic as well as disease-specific factors (extent of skin involvement, presence of internal organ manifestation, malabsorption, systemic sclerosis subtype, serological profile, medication) in the development of low bone mineral density. The relationship between low bone density in systemic sclerosis patients and the above mentioned risk factors may be more complex and the real role of each factor is unclear. Yet very few studies reported clinically relevant low bone mass outcomes such as fracture risk assessment and fracture associated mortality in scleroderma. This review aims to synthesize data about the essential role of vitamin D in immune homeostasis as well as the prevalence of hypovitaminosis, low bone density, changes in bone turnover markers and presence of osteoporosis in scleroderma patients. Orv Hetil. 2017; 158(32): 1252-1258.In the past few years more and more data have become available on the important role of vitamin D in immunological processes and inflammation. The role of vitamin D deficiency in the pathogenesis as well as in disease progression of different autoimmune and inflammatory conditions is suspected. Vitamin D deficiency is prevalent in several autoimmune diseases, including systemic sclerosis. Hypovitaminosis has been found to be associated with low bone mineral density and higher prevalence of osteoporosis in this group of patients. Determinants of low bone density in SSc are poorly understood. Studies have shown the importance of both traditional osteoporotic as well as disease-specific factors (extent of skin involvement, presence of internal organ manifestation, malabsorption, systemic sclerosis subtype, serological profile, medication) in the development of low bone mineral density. The relationship between low bone density in systemic sclerosis patients and the above mentioned risk factors may be more complex and the real role of each factor is unclear. Yet very few studies reported clinically relevant low bone mass outcomes such as fracture risk assessment and fracture associated mortality in scleroderma. This review aims to synthesize data about the essential role of vitamin D in immune homeostasis as well as the prevalence of hypovitaminosis, low bone density, changes in bone turnover markers and presence of osteoporosis in scleroderma patients. Orv Hetil. 2017; 158(32): 1252-1258.

A6.12 Effects of anti-tnf therapy on markers of angiogenesis and vascular pathology in arthritis: a comparative approach

Background and objectives Accelerated atherosclerosis, increased cardiovascular (CV) morbidity and mortality, as well as the perpetuation of angiogenesis and abundant production of angiogenic factors have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Biologics may influence both vascular function and angiogenesis. However, the effects of targeted therapies on vascular function and angiogenesis have been poorly studied in a comparative manner. Therefore, vascular function, markers of atherosclerosis and angiogenesis, as well as the effects of anti-TNF therapy on these biomarkers were assessed in the very same arthritis patient cohort. Patients and methods Altogether 31 arthritis patients including 18 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 13 AS patients treated with ETN were included in a 12-month follow-up study. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), a marker of endothelial dysfunction; common carotid intima-media thickness (ccIMT), a marker of atherosclerosis and pulse-wave velocity (PWV), an arterial stiffness parameter in all patients. Furthermore, circulating markers of angiogenesis including vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), angiopoetin 1 and 2(Ang1, Ang2) and thrombospondin 1 (TSP-1) were assessed in the sera by ELISA. DAS28, BASDAI and CRP, markers of disease activity, were also determined. All assessments were performed at baseline, as well as 6 and 12 months after treatment initiation. Results Anti-TNF treatment was highly effective in both diseases, as the mean DAS28 decreased from 5.00 to 2.97 (p < 0.001) in RA, mean BASDAI decreased from 5.99 to 1.82 (p < 0.001) in AS and CRP decreased from 13.8 to 3.9 mg/l (p = 0.021) in RA+AS over a 12-month period. Anti-TNF treatment resulted in significant improvement in FMD (from 7.15% to 9.11%; p = 0.009) and a tendency of improvement in PWV (from 7.57 to 6.82 m/sec; p = 0.190). Among markers of angiogenesis, mean VEGF (from 268.3 to 222.6 pg/ml; p = 0.006) and PDGF-BB (from 8187 to 6020 pg/ml; p = 0.012) levels significantly decreased after 12 months of therapy. Moreover, PDGF levels after 12 months, as well as Ang2 levels at all time points correlated with disease duration (p < 0.05) and Ang1, Ang2 and TSP1 levels all correlated with CRP at baseline (p < 0.05). When markers of vascular function and angiogenesis were compared, baseline PDGF levels correlated with baseline ccIMT (p < 0.05). Conclusions In a mixed cohort of RA and AS patients, anti-TNF therapy improved endothelial function and decreased the circulating levels of some angiogenic markers. Both impaired vascular function and the perpetuation of angiogenesis may be due to active systemic inflammation associated with these arthritides.

A6.15 Genetic signatures may be associated with vascular pathology in rheumatoid arthritis

Background and objectives Accelerated atherosclerosis, increased cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA). In single SNP studies, CD40, HLADRB1, MTHFR, SMAD3 and possibly other alleles have been associated with cardiovascular disease (CVD) or vascular pathophysiology in RA. Endothelial dysfunction, carotid atherosclerosis and arterial stiffness that may predict the development of CVD are assessed by bracial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV), respectively. In this study, we wished to determine expression profiles of multiple genes that may differentiate between physiological and pathological vascular function in RA. Patients and methods Altogether 16 RA patients were recruited. FMD, ccIMT and PWV were assessed in all patients using standard B-mode ultrasound techniques. FMD < 6%, ccIMT > 0.6mm and PWV > 9 m/sec were considered abnormal. Peripheral blood mononuclear cell samples were obtained and used in microarray. The signature of those genes were determined by principal component analysis (PCA) and hierarchic clustering (GeneSpring software), which significantly differentiated patient subsets with normal vs. abnormal FMD, ccIMT and PWV. Results Among RA patients, 11 had low (impaired) and 5 had normal FMD, 11 had high (increased) and 5 had normal ccIMT and 9 had high (increased) and 7 had normal PWV. Altogether 20 genes differentiated patients with low vs. normal FMD. Altogether 33 genes separated high vs. normal PWV. Finally, 240 genes differentiated increased vs. normal ccIMT. Conclusions Using microarray, genetic signatures may differentiate RA patients with and without vascular pathology.

AB0082 Effects of Anti-Tnf Therapy on Circulating Oxldl-Beta2Gpi Complex Levels in Arthritis

Background and objectives Accelerated atherosclerosis, increased cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Oxidised LDL (oxLDL) and beta 2 glycoprotein I (beta2gpI) antigens have been implicated in atherosclerosis, as well as antiphospholipid syndrome. High circulating oxLDL/beta2gpI levels may reflect vascular damage in acute coronary, syndrome, SLE, and other autoimmune diseases. However, the role of these complexes in RA and AS has not yet been evaluated in relation to therapy. Therefore, circulating complex levels, as well as the effects of anti-TNF therapy on these complexes were assessed in RA and AS patients. Complex levels were also correlated with various autoimmune-innflammatory and metabolic markers. Patients and methods Altogether 43 arthritis patients including 30 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 13 AS patients treated with ETN were included in a 12-month follow-up study. Circulating oxLDL/beta2gpI complexes were assessed by an AtherOx® ELISA system (Corgenix). In addition, disease activity (DAS28 or BASDAI), CRP, IgM rheumatoid factor, anti-CCP, and lipid levels (total cholesterol, TC; LDL-C, HDL-C and triglyceride) were also assessed. Assessments were performed at baseline, as well as 6 and 12 months after treatment initiation. Results Anti-TNF treatment was highly effective in both diseases, as the mean DAS28 decreased from 6.32 to 3.16 (p = 0.02) in RA, mean BASDAI decreased from 5.87 to 1.84 (p < 0.001) in AS. In RA, AS and the mixed arthritis population (n = 43) baseline oxLDL/beta2gpI levels were 0.235 ± 0.1, 0.245 ± 0.1 and 0.238 ± 0.1, respectively. There were no significant differences between RA and AS patients. In RA, ETN/CZP treatment resulted in non-significant decreases in complex levels after 6 months (0.214 ± 0.1) and 12 months (0.206 ± 0.1). In AS, oxLDL/beta2gpI complex levels did not change after 6 months of ETN therapy, but significantly decreased after one year (0.195 ± 0.1; p = 0.01). In the RA+AS population, anti-TNF treatment significantly decreased oxLDL/beta2gpI levelés after 12 months (0.203 ± 0.1, p = 0.02). In addition, baseline oxLDL/beta2gpI complex levels positively correlated with TC (RA: r = 0.563, p = 0.002; AS: r = 0.542, p = 0.049; RA+AS: r = 0.532, p < 0.001), and LDL-C (RA: r = 0.630, p < 0.001; AS: r = 0.756, p = 0.004; RA+AS: r = 0.648, p < 0.001) in both diseases. Circulating oxLDL/beta2gpI levels did not correlate with DAS28, BASDAI or CRP. Conclusions In a mixed cohort of RA and AS patients, anti-TNF therapy suppressed the circulating levels of oxLDL/beta2gpI complexes, markers of atherosclerosis and vascular disease in SLE or APS. Moreover, oxLDL/beta2gpI levels correlated with TC and LDL-C in arthritides. oxLDL/beta2gpI complexes do not seem to be markers of disease activity in RA or AS.

THU0178 Comprehensive Disease Control with Golimumab in Patients with Rheumatoid Arthritis

Background Comprehensive management of rheumatoid arthritis (RA) involves clinical goals such as remission and low disease activity (LDA) and outcomes important to patients such as daily functioning and minimization of pain. Objectives To evaluate comprehensive disease control with 6 months of add-on golimumab (GLM) treatment in a broad sample of patients with active RA despite disease-modifying antirheumatic drugs (DMARDs). Methods GO-MORE was an open-label, multinational, prospective study in biologic-naïve patients with active RA (DAS28-ESR ≥3.2) despite DMARD treatment. Patients received 50-mg SC GLM once monthly for 6 months. Patients completed the Health Assessment Questionnaire Disability Index (HAQ-DI) and patient acceptable symptom state (PASS). PASS was assessed with one yes/no question as to whether the patient would be satisfied to stay in their current disease state. Effects of baseline disease activity on DAS28-CRP, remission, and LDA (based on DAS28-ESR and simplified disease activity index [SDAI]) were evaluated with chi-square tests. Results Among 3280 efficacy-evaluable patients, the baseline mean age was 52.3 (SD=12.8) years, and mean disease duration was 7.63 (SD=7.903) years. The baseline mean DAS28-ESR, DAS28-CRP, and HAQ-DI values were 5.97 (SD=1.10), 5.41 (SD=1.00), and 1.44 (SD=0.67), respectively. At baseline, 21.3% of patients had moderate disease activity (DAS28-ESR EULAR 3.2 to 5.1), and 78.7% had high disease activity (DAS28-ESR EULAR >5.1). At month 6, remission based on DAS28-ESR and SDAI was attained by 23.9% and 14.2% of patients, respectively. LDA based on DAS28-ESR and SDAI was reached by 37.4% and 48.3% of patients, respectively, at month 6. Month 6 DAS28-CRP levels of <2.6 or 2.6 to <3.2 occurred in 32.5% and 49.5% of patients, respectively. Patients with moderate baseline disease activity were more likely to reach remission or low disease activity state than those with high baseline disease activity (Table). At month 6, PASS and minimal or no functional impairment (HAQ-DI ≤0.5) were achieved by 66.0% and 37.4% of patients, respectively. Conclusions In patients who had inadequate control of RA with a variety of nonbiologic DMARDs, 6 months of add-on treatment with once-monthly GLM resulted in good comprehensive disease control as measured by composite indices of clinical activity and patient-reported outcomes. Disclosure of Interest B. Combe Grant/research support from: Pfizer, Roche-Chugai, Consultant for: Merck, Pfizer, Roche-Chugai, and UCB, D. Veale Grant/research support from: Abbott, MSD, Pfizer and Roche, Consultant for: MSD, Pfizer, Roche and UCB, Speakers bureau: MSD, Pfizer, Roche and UCB, R. Burgos-Vargas: None Declared, G. Szűcs: None Declared, M. Leirisalo-Repo Consultant for: MSD, R. Yao Employee of: Merck, M. Govoni Employee of: Merck, N. Vastesaeger Employee of: Merck, H. Weng Employee of: Merck