E Grau Garcia

Instituto de Investigación Sanitaria La Fe

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I. Chalmeta Verdejo

Instituto de Investigación Sanitaria La Fe

C. Alcañiz Escandell

Instituto de Investigación Sanitaria La Fe

I. Cánovas Olmos

Hospital Vilardebó

E. Vicens Bernabéu

Instituto de Investigación Sanitaria La Fe

I. Martínez Cordellat

Instituto de Investigación Sanitaria La Fe

R. Negueroles Albuixech

Instituto de Investigación Sanitaria La Fe

CM Feced Olmos

Instituto de Investigación Sanitaria La Fe

F. Ortíz-Sanjuán

Hospital Universitari i Politècnic La Fe

L. González Puig

Instituto de Investigación Sanitaria La Fe

Rachel Gonzalez

Caribou Biosciences (United States)

Cooperative Institutions

Instituto de Investigación Sanitaria La Fe

Center for Rheumatology

Hospital Universitari i Politècnic La Fe

Inserm

Leitat Technological Center

Hôpital Edouard Herriot

Centre Léon Bérard

Centre National de la Recherche Scientifique

Hospital Universitario Doctor Peset

Université Claude Bernard Lyon 1

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THU0229 Dna hypomethylation and decreased hydroxymethylation is associated with decreased antioxidant response in systemic lupus erythematous patients

Annals of the Rheumatic Diseases (2017)

E Grau Garcia CM Feced Olmos M Fernandez Matilla E Sánchez Labrador F. Ortíz-Sanjuán

Background

Systemic lupus erythematous (SLE) shows increased DNA demethylation. An intermediate step to DNA demethylation is the DNA hydroxymethylation, where 5-mC is oxidized into 5-hmC. Hydroxymethylation is not completely understood and it may be related to oxidative stress in SLE patient.

Objectives

To analyze the association between the hydroxymethylation and demethylation, with the antioxidant response and SLE pathophysiology.

Methods

We analyzed in 142 SLE patients and 34 healthy controls the serum concentration of glutathione (GSH) and glutathione disulphide (GSSG) by UPLC-MS/MS, superoxide dismutase (SOD) and total antioxidant capacity (TAC) by colorimetric methods. 5-mC and 5-hmC levels were measured by colorimetric methods. Complete blood-test was made and clinical data by personal interview was collected. Biostatistical analysis with R (3.3.2.) was performed.

Results

There is a correlation between the methylation and hydroxymethylation rate (P<0.001), and both were lower in patients than in controls (P=0.024; P<0.001). GSH and GSSG values were lower in patients (P=0.033 y P=0.003), but GSH/GSSG ratio was not statistically different in both groups. SOD levels were higher in patients (P=0.001), but TAC did not show significant differences. Higher demethylation is associated to lower TAC values in patients and healthy controls (P=0.005; P=0.01). In patients, decreased SOD values are associated with higher demethylation and lower hydroxymethylation rates (P<0.001; P=0.007). SOD and TAC levels are increased in SLE patients with higher demethylation and lower hydroxymethylation (P=0.001; P<0.001). We did not observe any association between 5-mC or 5-hmC levels and GSH, GSSG or GSH/GSSG ratio. Higher demethylation is associated to vascular symptoms (defined by RELESSER study) and lupus anticoagulant (AL) positivity (P=0.041; P=0.015), and lower hydroxymethylation to mucocutaneous damage (defined by RELESSER study) and AL positivity (P=0.015; P=0.009). Lower levels of GSH and GSSG were associated to increased accumulated damage assessed by SLICC (P=0.01; P=0.005), and lower SOD values with longer disease duration (P=0.001).

Conclusions

We observed higher demethylation and lower hydroxymethylation in SLE patients than in controls, related to increased SOD activity. Moreover higher demethylation leads to lower TAC levels. These epigenetic disorders are related to antioxidant response disruptions in SLE patients, probably because of the chronic inflammatory condition. Our results suggest that epigenetic processes are involved in SLE physiopathology.

Acknowledgements

Financial support by GVA (GV15/83) is acknowledged.

Disclosure of Interest

None declared

Demethylation

DNA demethylation

10.1136/annrheumdis-2017-eular.2905

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SAT0279 ANTI-RO52 KDA and ANTI-RO60 KDA analysis in systemic lupus erythematous patients to detect ANTI-RO false-negatives

Annals of the Rheumatic Diseases (2017)

E Grau Garcia I. Chalmeta Verdejo E Sánchez Labrador M Fernandez Matilla F. Ortíz-Sanjuán

Background

Systemic lupus erythematous (SLE) is an autoimmune disease characterized by immune system disruption with autoantibodies production. One of the upregulated autoantibodies is the specific to the Ro antigen, a ribonucleoprotein associated to a small RNA, constituted by the 52KDa and 60 KDa polypeptides, whose epitopes are mainly conformational. The routine detection method for anti-Ro is an enzyme immunoassay, however, is possible to obtain false-negatives for anti-Ro and this could be avoided by analyzing both subunits separately.

Objectives

To identify false-negatives for anti-Ro by analyzing both 52KDa and 60 KDa subunits separately, as well as to characterize if there are clinical or molecular differences in this subgroup of patients compared to anti-Ro negative cases.

Methods

A cross-sectional, observational study of patients diagnosed of SLE according to SLICC 2012 criteria was performed. In these patients a complete blood-test was made, and clinical data by personal interview was collected. INF1A, Anti-Ro, anti-Ro52KDa and anti-Ro60KDa levels where measured by colorimetric methods. Biostatistical analysis was performed with R 3.3.2.

Results

We selected 69 SLE patients with negative results for anti-Ro (2.34±4.17 U/mL) out of 142 total SLE patients. A total of 51 patients were negative for both anti-Ro subunits and 18 cases presented positive results (up to 20 pg/mL) for at least one of them. The subgroup of patients that exhibit simultaneously high levels of anti-Ro52KDa and anti-Ro60KDa have higher clinical activity compared to negative anti-Ro cases (75% of active patients against 41.2% in anti-Ro negative patients). However, no differences in the accumulated damage evaluated by SLICC score between negative anti-Ro cases and patients with at least one positive subunit were observed. We analyze serum levels of INF1A cytokine in the four groups of patients, and anti-Ro and subunits negative cases showed significant lower INF1A levels than the other patients (8.26±14.87 pg/mL and 26.62±40.71 pg/mL respectively; P=0.04). In addition, patients with high levels of anti-Ro52KDa subunit are those with the highest INF1A levels (anti-Ro 52+/anti-Ro60- 23.5±47.6pg/mL of INF1A; anti-Ro 52+/anti-Ro60+ 36.4±37.9pg/mL of INF1A).

Conclusions

In our anti-Ro seronegative patients, a 26% of false-negative cases were detected. These cases with high levels of almost one anti-Ro subunit showed significantly higher levels of INF1A in contrast to negative cases, supporting the fact that they are indeed a different group from the negative cases. Moreover, the high INF1A levels could be the reason of the observed differences in the clinical activity measured by SLEDAI score in both groups.

Disclosure of Interest

None declared

10.1136/annrheumdis-2017-eular.5758

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FRI0275 Systemic lupus erythematosus patients with positives autoantibodies with remission or low activity exhibit both lower interferon alpha and interleukin-10 levels

Annals of the Rheumatic Diseases (2017)

E Grau Garcia F. Ortíz-Sanjuán M Fernandez Matilla CM Feced Olmos E Sánchez Labrador

Background

Systemic lupus erythematous (SLE) is an autoimmune disease characterized by immune system disruption, including T and B cell activation and upregulation of autoantibody and immunocomplexes production that could damage different organs. Sometimes, patients with positives autoantibodies and serological manifestations show low disease activity or clinical remission. There is not enough information about persistent positive autoantibodies in absence of clinical activity neither the role of proinflamatory cytokines in this context.

Objectives

To assess the clinical and molecular differences in SLE patients with positives autoantibodies and with low clinical activity or in clinical remission compared to the group with clinical activity.

Methods

A cross-sectional, observational study of patients diagnosed of SLE according to SLICC 2012 criteria was performed. In these patients a complete blood-test was made, and clinical data by personal interview was collected. We analyzed the serum concentration of IL10, BLyS and INF1A by colorimetric methods. Biostatistical analysis was performed with R 3.3.2.

Results

We selected 130 SLE patients with serological manifestations (defined by RELESSER study) out of 142 SLE patients. 91 cases showed low activity or remission (SLEDAI<6) and 39 presented moderate or high activity (SLEDAI>6). SLE patients with positives autoantibodies without clinical activity showed significantly lower anti-dsDNA levels (P=0.006), lower complement consumption (P=0.003) and lower accumulated damage evaluated by SLICC score (P=0.041). No differences on time of evolution in both groups were observed. In addition, SLE patients with positives autoantibodies without clinical activity exhibit significantly lower levels of IL10 (P<0.001) and INF1A (P=0.019). No differences on BLyS levels in both groups were observed. Finally, SLE patients with positives autoantibodies with clinical activity present more mucocutaneous lesions (P=0.014), musculoskeletal manifestations (P=0.004), neuropsychiatric manifestations (P=0.002), renal manifestations (P<0.001) and lymphopenia (P=0.008) than patients with positives autoantibodies and without clinical activity.

Conclusions

In our series of SLE patients with both serological manifestations and low clinical activity have lower levels of IL10 and INF1A, compared to patients with high clinical activity. This result would suggest that differences in the cytokine levels are not related to autoantibodies presence but there are other mechanisms involved in cytokine production that would also be involved in maintenance of clinical remission.

Disclosure of Interest

None declared

10.1136/annrheumdis-2017-eular.5766

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AB1080 Results in the follow-up of the nursing consultation for the monitoring of rheumatologic patients treated with intravenous therapies

Annals of the Rheumatic Diseases (2017)

C. Nájera Herranz I. Cánovas Olmos J. Ivorra Cortés E Grau Garcia C. Alcañiz Escandell

Background

In the management of rheumatologic patients treated with intravenous therapies, its regular monitoring is recommended in order to ensure its safety. The Nursing Consultation for monitoring rheumatologic patients treated with Intravenous Therapies (NCIT) represents a major support to patient caring for it provides patient monitoring before treatment administration and prior to rheumatologist consultation.

Objectives

To analyze number and types of incidents detected in the NCIT.

Methods

A cross-sectional longitudinal, observational study of data from patients followed-up in the NCIT (which was initiated in 2012) was performed. We have collected data of gender, diagnosis, drug administered, incidents detected previously to the drug administration, and if the incident was detected by telephone (one day before drug administration) or by personal interview. Biostatistical analysis with R (3.3.2.) was performed.

Results

We analyzed 7809 drug infusions corresponding to 545 patients (73% women). 48.25% of patients were diagnosed with osteoporosis (OP), 30.1% rheumatoid arthritis (RA), 5.7% ankylosing spondylitis (AS), 4.2% systemic lupus erythematous (SLE), 2.9% psoriatic arthritis (PsoA) and 8.3% had other diagnosis. The intravenous therapies were antiosteoporotic drug (7.8%) and biological and immunosuppressive treatment, being the most common drugs tocilizumab (38.89%), infliximab (31.9%) and abatacept (18.05%). In the 7809 treatment infusions, 477 incidents (4.1%) were registered, 33 of them related to the antiosteoporotic therapies and the other 444 incidents (93%) occurred in the biological therapies. The 63.7% of the incidents were detected by telephone one day before drug infusion. Statistical analysis showed that SLE patients exhibit higher tendency to incidents (4.8% of incidents in the 392 treatments for SLE patients; P=0.026) than other autoimmune diseases. On the other hand, RA and AS patients have incidents detected mainly by telephone ((P=0.047 y P=0.029 respectively). We also observed a high number of incidents in the intravenous administration of TCZ (P=0.009).

Conclusions

The NCIT has performed the follow-up of more than 5oo patients with only 6% of incidents, contributing to an improvement in the patients9 health and in its caring. Moreover, the fact of identifying the incidents helps to reduce the number of personal consultations, avoids drug preparation in those cases where this infusion is suspended, and in summary it improves management of hospital resources.

Disclosure of Interest

None declared

Abatacept

Tocilizumab

10.1136/annrheumdis-2017-eular.5702

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AB0494 Increased levels of interferon alpha and interleukin-10 as clinical activity biomarkers in systemic lupus erythematous patients

Annals of the Rheumatic Diseases (2017)

E Grau Garcia M Fernandez Matilla CM Feced Olmos E Sánchez Labrador F. Ortíz-Sanjuán

Background

Systemic lupus erythematous (SLE) is an autoimmune disease characterized by immune system disruption, including deregulation of cytokine production. Interferon alpha (INF1A) is considered a key molecule in SLE etiopathogenesis, being responsible of the differentiation of dendritic cells from monocytes, and indirectly of interleukin 10 (IL10) upregulation. The B lymphocyte stimulating factor (BLyS) is involved in autoantibodies production and clinical activity, and is regulated by other cytokines as IL10 and INF1A.

Objectives

To analyze the association among INF1A, IL10 and BLyS levels and clinical activity in SLE.

Methods

A cross-sectional, observational study of 142 patients diagnosed of SLE according to SLICC 2012 criteria and 34 healthy controls was performed. A complete blood-test was made, and clinical data by personal interview was collected. We analyzed serum concentration of IL10, BLyS and INF1A by colorimetric methods. Patients were dichotomized as high and low levels for each cytokine based on the cytokine level above 2 SD of the mean in healthy controls. Biostatistical analysis with R (3.3.2.) was performed.

Results

In our SLE patients we observed higher values of IL10, BLyS and INF1A than controls (P<0.001, P=0.005 and P=0.043 respectively), showing an average values in patients of 13.39±27.73 pg/mL INF1A, 9.99±15.84 pg/mL IL10 and 1811.31±1757.81 pg/mL BLyS. The mean clinical activity measured by SLEDAI was 5.91±5.06. Statistical analysis indicate that INF1A levels are correlated to IL10 levels (P=0.001) and BLyS levels (P=0,034). Due to this finding, we categorized SLE patients by low or high level of the three cytokines: 44 INF1A(-)IL10(-)BLyS(-); 61 INF1A(+)IL10(-)BLyS(-); 5 INF1A(+)IL10(-)BLyS(+); 18 INF1A(+)IL10(+)BLyS(-) and 14 INF1A(+)IL10(+)BLyS(+). There is a high association of increased IL10-INF1A levels and the increased of clinical activity by SLEDAI score (P<0.001), and to a lesser extent with increased IL10-INF1A-BLyS levels. Patients with high IL10-INF1A and IL10-INF1A-BLyS showed a significant rise in C3-C4 consumption (P<0.001 and P=0.001 respectively) and high anti-dsDNA (P=0.001 and P=0.002 respectively). Patients with increased INF1A-BLyS exhibited high anti-dsDNA (P=0.004) and ENA positivity (P<0.001). In addition, patients with increased levels of IL10-INF1A-BLyS showed ANAs (P<0.001) and antiphospholipid autoantibody positivity (P=0.004).

Conclusions

The 69% of our SLE patients displayed almost one cytokine increased, being the INF1A the cytokine that mainly is increased. However, increased IL10 levels, irrespective of whether there is also increased levels of BLyS and/or INF1A, is the cytokine which best fits to clinical activity in SLE.

Disclosure of Interest

None declared

10.1136/annrheumdis-2017-eular.4180

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Interleukin (IL)-10 and IL-6 are produced in vivo by non-Hodgkin's lymphoma cells and act as cooperative growth factors.

PubMed (1996)

N. Voorzanger Robert Touitou E Grau Garcia Henri‐Jacques Delecluse F Rousset

The in vivo production of interleukin (IL)-10, IL-6, IL-2, and tumor necrosis factor (TNF)-alpha in tumor samples was investigated by immunohistochemistry in 54 non-Hodgkin's lymphomas (NHLs). Respectively, 55, 89, 23, and 29% of tumor samples were found positive for IL-10, IL-6, IL-2, and TNF-alpha expression by immunohistochemistry. Using reverse transcription-PCR, the mRNA of IL-10 and IL-6 were detectable in all samples tested and in 90 and 34% of the samples for TNF-alpha and IL-2, respectively. In 13 patients, fresh tumor tissue was available for B NHL cell purification with Dynabeads. IL-10, IL-6, IL-2, and TNF-alpha were detectable in the supernatant of 38, 100, 0, and 23% of purified tumor cell preparations (PTCPs), respectively. All patients with detectable IL-10 in culture had increased serum IL-10. IL-6 production by tumor cells and serum IL-6 levels were also found to be highly correlated (P < 0.0001). This suggests that tumor cells are a major source of serum IL-1O and IL-6 in these patients. Exogenous IL-10, IL-6, IL-2, and TNF-alpha significantly enhanced the [3H]thymidine uptake in 13 of 13 (100%), 5 of 13 (38%), 9 of 13 (69%), and 2 of 10 (20%) PTCPs costimulated with anti-CD40, respectively. IL-2, IL-6, and TNF-alpha synergized with IL-10 in 54, 23, and 30% of PTCPs. The combination of IL-10, IL-2, and IL-6 induced the maximal level of proliferation in 12 (92%) of 13 PTCPs. CD40 ligand mRNA expression was also detectable in vivo using reverse transcription-PCR in 28 of the 29 (97%) tumor samples tested, including 11 of those tested for [3H]thymidine incorporation. These results show that IL-1O, IL-6, IL-2, and TNF-alpha are produced in NHL tumors and may cooperate in vivo to increase NHL cell proliferation.

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T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.

The Journal of Experimental Medicine (1996)

François Fossiez Odile Djossou Pascale Chomarat Leopoldo Flores‐Romo Smina Aït‐Yahia

Analysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame of Herpesvirus saimiri. Here we report on the cloning of human IL-17 (hIL-17), the human counterpart of murine IL-17. hIL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4+ T cells. Although devoid of direct effects on cells of hematopoietic origin, hIL-17 and the product of its viral counterpart, ORF13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte-colony-stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hIL-17, fibroblasts could sustain the proliferation of CD34+ hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hIL-17 may constitute (a) an early initiator of the T cell-dependent inflammmatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis.

Interleukin 15

Proinflammatory cytokine

Interleukin 3

10.1084/jem.183.6.2593

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IL-10, IL-2, IL-6 are produced in vivo by non hodgkin's lymphoma cells and act as cooperative growth factors

N. Voorzanger R. Touitou E Grau Garcia Henri‐Jacques Delecluse F Rousset

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SAT0388 Analysis of the musculoskeletal manifestations in inflammatory bowel disease patients and its relationship with biological treatment

Annals of the Rheumatic Diseases (2017)

S Mainero Mendoza CM Feced Olmos L. González Puig J. Ivorra Cortés I. Martínez Cordellat

Background

Crohn9s disease (CD) and ulcerative colitis (UC) are the main entities of inflammatory bowel disease (IBD). Both present extraintestinal manifestations that do not always depend on the IBD activity. The most common manifestations involve the musculoskeletal system and they are included in the seronegative spondiloarthritis group. If there is active or known IBD, treatment of this is priority because it usually improves joint disease. However, joint disease can also have an independent course of the intestinal manifestations as in patients with IBD and ankylosing spondylitis (AS).

Objectives

To analyze the prevalence of extraintestinal manifestations in IBD patients and treatment provided.

Methods

Retrospective observational analysis of IBD patients that have been remitted to the rheumatology department of HUP La Fe with musculoskeletal manifestations. Demographic, clinical and treatment data of patient were collected. Biostatistical analysis with R (3.3.2.) was performed.

Results

We recruited 183 patients diagnosed with IBD (57.4% women), 117 with CD and 66 with UC, with a mean age at diagnosis of 37.03±14.02 years old. 29 of them have axial affection and 51 peripheral affection, and simultaneously in 22 cases. We observed no statistical differences in axial or peripheral affection according to the IBD diagnosis. 79 cases were on biological therapy, and these treatments were conducted by Rheumatology in the 44% of cases and by Digestive Department in the 66% of cases. We observed that patients with axial affection present higher probability that the treatment has been conducted by Rheumatology (P=0.007), and broken down axial affections AS diagnosis had the most probability to be conducted by Rheumatology (n=36 P=0.0102). Related to peripheral manifestations, uveitis diagnosis had the most probability to be conducted by Rheumatology (n=14 P=0.0337).

Conclusions

In our patient series with IBD and musculoskeletal manifestations, the most common were peripheral affection. Among patients with IBD and axial and/or peripheral manifestation, 44% were conducted by Rheumatology, and are cases with axial predominance, where IBD treatment does not improve musculoskeletal disease and a primary spondyloarthritis treatment is needed.

Disclosure of Interest

None declared

10.1136/annrheumdis-2017-eular.5687

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