The Pan-American League of Associations of Rheumatology (PANLAR) Congress is the most important gathering of Pan-American Rheumatology, and this year marks the Congress’s 20th year, being held in Buenos Aires Argentina in April 2018. This gathering is very special for several reasons. PANLAR will return to Argentina after 21 years since the last Congress was held in this region at a very special moment for PANLAR, which is celebrating its 75th anniversary.
This supplement includes all the abstracts that were selected for presentation. This year the selection process was very difficult, as there were a record number of abstract submissions (more than 500 abstracts) from all around the world. The supplement includes all scientific investigation abstracts, but does not include case reports. Case reports are an important part of the Congress, and will be presented at the meeting, but have not been included in this supplement. The abstracts have been organized by the type of presentation and topic.
The PANLAR Congress organizers thank all the authors for their hard work, and for choosing to submit their abstracts to present their investigation at the 2018 PANLAR meeting. We believe that the PANLAR Congress encourages rheumatologists and allied health professionals to continue their rheumatologic research. Through scientific investigation, rheumatology care in the Americas continues to improve.We especially thank Dr. Graciela S. Alarcón and her team for their incredible work in the editing of all the abstracts.
ANTIPHOSPHOLIPID SYNDROME IN PEDIATRICS: MORBIDITY BEYOND THROMBOSIS, MULTICENTER IBERO-AMERICAN STUDY
C. Vargas-Rincon1,5, C. Malagon2,5, J. Anton3, C. Mosquera2,5, M.P. Gomez4,5, and R. Yepez4,5. 1Universidad del Valle, Cali, Colombia; 2Universidad El Bosque, Bogotá, Colombia; 3Sant Joan de Déu Hospital, Barcelona, Spain; 4Universidad Libre, Cali, Colombia; 5Pediatric Rheumatology and Immunology Group, Colombia.
Objectives: To describe the clinical and paraclinical characteristics of a group of pediatric patients with positive antiphospholipid antibodies.
Methods: Descriptive multi-center study of case series. Review of medical records with data collection format in Bogotá, Cali and Barcelona. Data analysis with SPSS 20.
Results: N = 117. Average age of diagnosis 12.5 years. 82% women with a F: M ratio for the general group of 4.7: 1 and with thrombosis 2: 1. 58% were associated with SLE, 41% were primary and one case with SS. 42% had at least one thrombotic event, 53% venous, 40% arterial and 14% cerebrovascular disease. 2.5% developed CAPS and 10% presented recurrence of thrombosis mainly in the lower limbs and CNS. Male sex was a factor associated with risk of thrombosis (p = 0.001). 70% presented non-thrombotic manifestations and were more frequent in patients <10 years. Hematological compromise was dominated by thrombocytopenia in 44%, hemolytic anemia 25% and Evans syndrome 11%. Neurological manifestations: migraine 16%, seizures 6.8% and chorea 6%. 18% had ANA titers ≥1,280 and 70% had at least one aCL or positive LA. The presence of aCL-IgM antibodies was associated with non-thrombotic manifestations. There were no significant differences in the recurrence of thrombosis between primary APS or associated with another autoimmune disease, nor association with positivity of autoantibodies.
Conclusions: APS generates an important morbidity in pediatrics and should be considered as a cause of thrombosis in children, even in the absence of other autoimmune diseases. The criteria for diagnosis of APS were developed for adults and may fail to recognize a group of patients with non-thrombotic manifestations, present in 70% of our cases, especially when the compromise is hematological or neurological isolated. Therefore, validated criteria for pediatric patients that consider APS not necessarily as a thrombotic disease should be developed.
MECHANIMS INVOLVED IN THE INDUCTION OF IL-6 IN FIBROBLAST-LIKE SYNOVIOCYTES BY STIMULATION WITH SPONDYLOARTHRITIS SYNOVIAL FLUID
M.S. Di Genaro1,2, E. Callegari3, R. Blas4, A. Munarriz5, R. Pardo-Hidalgo6, and H. Tamashiro7. 1Instituto Multidisciplinario de Investigaciones Biológicas-San Luis (IMIBIO-SL), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis, Argentina; 2Universidad Nacional de San Luis, San Luis, Argentina; 3SD Biochemical Research Infrastructure Network (SD BRIN), Vermillion, USA; 4Centro Médico MEDICI, San Luis, Argentina; 5Centro Médico CENYR, San Luis, Argentina; 6Centro de Rehabilitación Médica CER, San Juan, Argentina; 7Clínica Bolívar, San Luis, Argentina.
Objectives: In previous studies we have reported that synovial fluid (SF) of spondyloarthritis (SpA) patients induces interleukin (IL)-6 production in fibroblast-like synoviocytes (FLS), and this cytokine modulates metalloproteinase-9 activity of these cells. However, the molecules of the SpA synovial microenvironment that trigger this pro-inflammatory circuit are unknown. The purpose of the present work was to examine the candidate endogenous molecules of SpA SF, and the mechanisms involved in the induction of IL-6 in FLS.
Methods: The SF of SpA patients were pooled (n=9). Human synovial fibroblasts of the SW982 cell line were stimulated with SpA SF pool at dilution 1:10 in DMEM culture medium in absence or presence of anti-tumor necrosis factor (TNF) (Infliximab, 200 g/ml), TNF inhibitor (Etanercept, 100 g/ml), anti-IL-17 (Sekukinumab, 100 g/ml), anti-IL-6 receptor (IL-6R) (Tocilizumab, 200 g/ml), Toll-like receptor 4 (TLR4) activation inhibitor (Polymyxin B, 50 g/ml), ERK, JNK or p38 mitogen-activated protein kinase (MAPK) inhibitor (10 M), or Janus kinase (JAK) 1/3 inhibitor (Tofacitinib, 1000nM). SF treated with Hyaluronidase (50 g/ml) (H-SF) or Proteinase K (500 g/ml) (P-SF) was also used for stimulation of FLS. The IL-6 levels in the supernatants were measured by a commercial enzyme-linked immunosorbent assay (ELISA) kit. In addition, IL-6-inducter alarmins in SpA SF were identified by a Gel-free and Gel-LC botton-up mass spectrometry-based proteomics through the 2D-nano-liquid chromatography-tandem mass spectrometry (2D-nano-LC-MS/MS) analysis. The data were analyzed by one-way analysis of variance (ANOVA) followed by Tukey multiple comparison test. A p value ≤ 0.05 was considered statistically significant.
Results: We found that anti-TNF, anti-IL-17 and anti-IL-6R significantly reduced IL-6 secretion by FLS (p<0.05, p<0.01 and p<0.01, respectively). No difference in IL-6 induction was detected when H-SF was used for stimulation, or when JNK or JAK1/3 was inhibited. In contrast, P-SF stimulation (p<0.001), and TLR4, ERK or p38 inhibition significantly affected IL-6 production by FLS (p<0.01). The proteomic analysis showed that the most abundant proteins of the SpA SF come from extracellular location and cytoplasm. The IL-6-inducter alarmin S1008A8 (calcium binding protein A8) was detected in position 116 in the rank of the most abundant proteins of SpA SF.
Conclusions: The results indicate that TNF, IL-17 and IL-6 themselves enhance SpA SF- induced IL-6 production by FLS, supporting a fine-tuning cytokine in the inflammation process in the synovial microenvironment. In addition, S1008A8, as an endogenous molecule released to the extracellular synovial milieu, may be involved in IL-6 induction in FLS by SpA SF. TLR4 pathway, and ERK and p38 MAPKs participate in the IL-6 production by FLS. Understanding the pathogenic mechanisms associated with the synovial microenvironment may contribute to suggest new therapeutic approaches for SpA.
ARTHRITIS: PRIMARY RESULTS THROUGH 52 WEEKS FROM A PHASE-3 RANDOMIZED PLACEBO-CONTROLLED STUDY (FUTURE 4)
A. Kivitz1, P. Nash2, H. Tahir3, A. Everding4, P. Pellet5, A. Widmer5, L. Pricop6, K. Abrams6, and on behalf of the FUTURE 4 Study Group. 1Altoona Centre for Clinical Research, Duncansville, PA, United States; 2University of Queensland, Brisbane, Australia; 3Barts Health NHS Trust, London, United Kingdom; 4Hamburger Rheuma Forschungszentrum II, Mönckebergstraße, Hamburg, Germany; 5Novartis Pharma AG, Basel, Switzerland; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States.
Objectives: To assess efficacy and safety of secukinumab (SEC) 150mg sc administered with or without loading dose (LD) in patients (pts) with active psoriatic arthritis (PsA) in the FUTURE 4 study (NCT02294227).
Methods: Patients aged ≥18 years with active PsA were randomized 1:1:1 to receive SEC 150mg sc with LD, SEC 150mg sc with no LD and placebo (PBO). All received SEC or PBO at Weeks (Wks) 0, 1, 2, 3, 4 and every 4 Wks thereafter. PBO pts were switched to SEC 150mg sc at Wk 16 (non-responders) or at Wk 24 (responders). Pts were stratified for randomization by prior anti-TNF therapy (anti–TNF-naïve and intolerant/inadequate response [IR]). The primary endpoint was ACR20 response at Wk 16. ACR20 was analyzed by logistic regression with treatment and TNF-α status as a factor, and weight as a covariate. Missing values were imputed as non-responders. Secondary endpoints included DAS28-CRP, PASI 75 response, SF-36 PCS, and ACR50 at Wk 16.
Results: Of 341 randomized pts, 326 (95.6%) completed 16 wks and 288 (84.5%) completed 52 wks of treatment. Primary endpoint was met; ACR20 response rate was significantly greater at Wk 16 in the SEC 150mg sc LD (41.2%; P<0.001) and 150mg sc no LD (39.8%; P<0.001) groups vs. PBO (18.4%). Significant improvements in the secondary endpoints were also observed at Wk 16 for SEC vs. PBO. Clinical responses observed at Wk 16 were sustained or continued to improve up to Wk 52 in both SEC groups (Table). Improvements across the endpoints were also observed in both anti–TNF-naïve and -IR pts, with better responses in anti-TNF-naïve pts (Table, ACR20). SEC LD provided earlier and better responses than the no LD regimen from Wk 4 onwards across most endpoints; this trend was most pronounced for higher hurdle endpoints and in the TNF-IR group. The most common AEs up to Wk 16 were nasopharyngitis (11.4% and 9.7% vs. 13.2%) and upper respiratory tract infections (6.1% and 6.2% vs. 5.3%) for LD, no LD vs. PBO, respectively. Exposure adjusted incidence rates through 52 Wks for SEC for AEs of interest were: Crohn’s disease (0.4), malignancies (1.1) and major adverse cardiac events (0.4). No deaths were reported.
Conclusions: SEC 150mg administered with and without LD demonstrated significant and sustained improvements in the signs and symptoms of PsA. Numerically greater and earlier responses were observed with LD mainly in the TNF-IR pts and the higher hurdle endpoints. The safety profile was similar with and without LD, and consistent with previous reports.
CONCURRENT ORAL SESSIONS
EDUCATIONAL NEEDS OF LATIN-AMERICAN LUPUS PATIENTS: INSIGHTS FROM AN ONGOING FACEBOOK PROGRAM
Y. Fuentes-Silva1,2, C. Acosta2, C. Elera-Fitzcarrald3, S. Ibañez4, E. García-Carrión5, C. Reátegui-Sokolova3, B. Pons-Estel6, and C. Drenkard7. 1Universidad de Oriente, Ciudad Bolívar, Bolívar, Venezuela; 2Complejo Hospitalario Universitario Ruiz y Páez, Ciudad Bolívar, Bolívar, Venezuela; 3Hospital Guillermo Almenara Irigoyen, Lima, Perú; 4Sanatorio Güemes, Buenos Aires, Argentina; 5Hospital Dr. Raúl Leoni, Ciudad Guayana, Bolívar, Venezuela; 6Centro Regional de Enfermedades Autoinmunes y Reumatología (CREAR), Sanatorio Parque, Rosario, Santa Fe, Argentina; 7Emory School of Medicine, Atlanta, GA, USA.
Objectives: Education is critical to support effective management in people with lupus. We described the educational needs of Latin-American patients with lupus and explored associations with sociodemographic characteristics.
Methods: We conducted a 6-month survey to evaluate Let’s Talk about Lupus (Hablemos de Lupus), a Facebook (FB) program in Spanish that aims at educating the Latin-American population living with lupus. Since May 2017, FB/Hablemos de Lupus delivers information about lupus and self-management through animated videos (AV) and live videochats (LVC) with providers. Using open-ended questions, we asked users to propose topics for AV and LVC, and overall suggestions (OS). Using 38 predefined topics, we codified up to five needs (N1 to N5) per responder, which were classified in eight themes within three domains: lupus knowledge, self-management/quality of life, and lupus awareness/healthcare resources. We used Chi-square test to examine associations between needs and sociodemographic characteristics.
Results: Within 20 days of its initial posting, 936 followers responded the survey, and 806 (86%) of them reported to have lupus (mean age 37 ± 11 years, 97% females, 48% ≤ 5 years since diagnosis). Most respondents were from North America (32%), followed by the South Cone (31%), Bolivarian Region (24%) and Central American/Caribbean (10%). While 51% of the sample achieved a university degree, only 36% reported working fulltime. There were 579, 582, and 187 respondents that proposed at least one topic for AV, LVC, and OS, respectively. Table 1 shows the frequency of N1 to N5. There were not significant associations between educational needs and sociodemographic factors (age, gender, region, education, occupation, disease duration).
Conclusions: There is consistency in the educational needs of Latin-American lupus patients across regions and sociodemographic groups suggesting that there is a substantial gap in the education of this population. The role of social media-based education on patients’ empowerment and behavioral change warrants further assessment.
RADIOGRAPHIC KNEE OSTEOARTHRITIS IN PATIENTS COMPLAINING OF KNEE PAIN: ULTRASOUND FEATURES
I.J. Gandino, M. Brom, S. Ruta, M. Scolnik, J. Zacariaz, J. Marin, J. Rosa, R. Garcia-Monaco, and E.R. Soriano. Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
Objectives: To date, the diagnosis of knee osteoarthritis (OA) is based on clinical examination and radiological features. Our objective was to evaluate the diagnostic test properties of ultrasound (US) for the detection of radiographic knee OA.
Exclusion criteria were: Younger than 18 years of age, history of knee surgery or trauma, severe knee deformities and a corticosteroid injection within the preceding 2 months. US examinations were performed by an experienced rheumatologist, blinded to clinical and radiological data, using a MyLab 70 machine (Esaote) provided with a multi-frequency linear transducer (4–13 MHz). Standardized scanning method was adopted in order to evaluate the following US abnormal findings: osteophytes (protrusions at the joint margin seen in two planes and visualized as either proximal or distal to the joint) and degenerative femoral hyaline cartilage involvement (presence of at least two of the following: loss of sharpness of the cartilage margins, loss of homogeneity of the cartilage layer and cartilage thinning focal or extend to the entire cartilaginous layer)
Weight-bearing anteroposterior (AP) and lateral knee radiographs were read by an experienced rheumatologist, blinded to the clinical and US data, who determine the presence or absence of radiological degenerative changes and classified the severity of knee OA using Kellgren-Lawrence (KL) grading scale.
Results: 281 patients (mean age 64 ± 17 years, 173 (61,6%) female) were included for a total of 322 knees evaluated (41 patients complained of bilateral knee pain). Both the presence of osteophytes and/or femoral hyaline cartilage involvement detected by US were more frequent in those knees with radiographic changes indicative of OA regardless of its severity according with the KL grading scale (Table 1).
Table 2 shows the diagnostic test properties of the US abnormal findings for the detection of knee OA using radiological data as reference method.
Conclusions: US demonstrate an excellent sensitivity with an adequate specificity for the detection of radiographic knee OA. US femoral hyaline cartilage involvement and/or US osteophytes showed the best sensitivity while isolated US osteophytes showed the best specificity. US could be used in patients with knee pain when OA is suspected.
EFFICACY AND SAFETY OF CONTINUING VERSUS WITHDRAWING ADALIMUMAB IN MAINTAINING REMISSION IN PATIENTS WITH NON-RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS
R. Landewé1, J. Sieper2, P. Mease3, R.D. Inman4, X. Wang5, M. Li5, A. L. Pangan5, and J. K. Anderson4. 1University of Amsterdam, Amsterdam, Netherlands; 2Charité Universitätsmedizin Berlin, Berlin, Germany; 3Swedish Medical Center and University of Washington, Seattle, WA, USA; 4University of Toronto, Toronto, Canada; 5AbbVie, North Chicago, IL, United States.
Objectives: It is not known whether TNF blockers can be stopped in non-radiographic (nr-axSpA) patients who are in remission. ABILITY-3 (NCT01808118), reported here, assessed if ADA can be discontinued or should be continued in nr-axSpA pts in sustained remission after a 28-wk open-label period.
Methods: ABILITY-3 enrolled adult pts diagnosed with nr-axSpA, fulfilling ASAS criteria but NOT modified New York criteria who had objective evidence of active MRI inflammation in the SI joints or spine or elevated high-sensitivity CRP at screening, active disease at baseline (ASDAS ≥2.1, BASDAI ≥4, total back pain ≥4), and inadequate response to ≥2 NSAIDs. Pts who achieved ASDAS inactive disease (ASDAS <1.3) with open-label ADA 40 mg every other wk at wk 16, 20, 24, and 28 were randomized to 40-wk, double-blind PBO (withdrawal) or ADA (continuation) in period 2. The primary efficacy endpoint was the proportion of patients who did not experience a flare (ASDAS ≥2.1 at 2 consecutive study visits) during period 2. Secondary endpoints were also assessed up to wk 68 (nonresponder imputation).
Results: Of 673 enrolled pts, 305 (45%) were randomized to double-blind treatment. A significantly greater proportion of patients treated with ADA vs. PBO had no flares (70% vs. 47%; P < 0.001) at wk 68; the relative risk of flare with treatment withdrawal was 1.77. Time to flare analysis showed significantly lower risk of flare for ADA vs. PBO. At wk 68, significantly greater proportions of ADA vs. PBO patients achieved secondary endpoints, except for HAQ-S (Table). Among pts who received ADA at any time, 77% reported adverse events (AEs) and 4% reported a serious AE; nasopharyngitis (17%), upper respiratory tract infection (12%), worsening of axSpA (9%), headache (8%), and diarrhea (6%) were the most common. During period 2, incidence of AEs was similar for ADA and PBO (65% vs. 69%), incidence of serious AEs was higher for PBO vs. ADA (7% vs. 1%), and the most common AEs in both the ADA and PBO groups were nasopharyngitis (16% vs. 13%), upper respiratory tract infection (13% vs. 8%), and worsening of axSpA (6% vs. 14%; none serious).
Conclusion: In pts with nr-axSpA who achieved sustained remission with ADA, continued therapy was associated with significantly more patients maintaining remission and lower disease activity than treatment withdrawal. These results support the continuation of ADA therapy after achievement of sustained remission. Safety findings were consistent with the established safety profile of ADA.
ULTRASOUND DEFINITIONS AND SCORES FOR PEDIATRIC ENTHESIS
J. Roth1, L. Barzola2, L. Campos3, C. Hernandez4, D. Petry5, L. Ventura4, and T. Cazenave6. 1Childrens Hospital of Eastern Ontario and University of Ottawa, Ontario, Canada; 2Reumatologia, Hospital de Niños Ricardo Gutierrez, Buenos Aires, Argentina; 3Pediatric Rheumatology Unit, Instituto da Criança - Hospital das Clínicas, University of São Paulo Medical School, Sao Paulo, Brazil; 4Laboratorio de ultrasonido músculo esquelético y articular. Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, México City, México; 5Department of Pediatrics and Division of Rheumatology, Department of Medicine, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil; 6Instituto de Rehabilitacion Psicofisica, Buenos Aires, Argentina.
Background and Aims: Musculoskeletal ultrasound (MSUS) is increasingly being utilized in children but validation has been limited to synovitis so far. The enthesis is an equally important structure and pediatric specific definitions as well as reliable scoring systems are needed given the unique pediatric anatomy. The aim of this study was to develop and assess reliability of B-Mode and Doppler definitions and scoring systems for the pediatric enthesis.
Methods: As part of the PANLAR ultrasound group, seven rheumatologists developed B-Mode and Doppler definitions for the assessment of lower extremity entheses in children. This was done through a comprehensive literature review followed by a practical exercise and consensus process. Similarly, a Doppler scoring system was developed through both literature review and consensus process and subsequently validated by a practical exercise. A total of six children (3 healthy, 3 enthesitis related juvenile arthritis) were scanned during this exercise by six rheumatologists each and all images were analyzed by all participants. B-Mode assessments included thickness, hypoechogenicity, erosions, enthesophytes and bony irregularities and increased blood flow was assessed with Power Doppler. The following entheses were assessed: Quadriceps tendon into the patella, proximal and distal patella tendon and Achilles tendon. Agreement with the definitions was determined using definition as 4 or 5. Presence of structural changes on B-Mode were scored dichotomously as present and absent and agreement between raters on the Doppler scores was determined using two-way single score intraclass correlation coefficients (ICC).
Results: An overall definition for findings of the healthy and pathologic enthesis on B-mode, separate definitions for hypoechogenicity and thickening and a definition for Doppler findings reached 89 % agreement among the participants. Agreement on the presence and absence of structural changes was 92 % but the presence of structural changes was overall low. ICC for all Doppler images was 0.78 (CI 0.70-0.85) but Doppler signals were present in both healthy children and children with enthesitis related arthritis and even among the children with enthesitis related arthritis in entheses without B-mode changes as well as those with abnormal B-mode findings.
Conclusion: B-Mode and Doppler definitions for the healthy and pathologic entheses in children as well as a Doppler Scoring system were developed and validated through a consensus process. The presence of structural changes was overall low and Doppler signals may be present in a relatively large proportion of healthy entheses as well. Future studies will address criteria to differentiate findings suggestive of pathology from physiologic findings.
PATTERNS OF CHANGE OF A SECOND BIOLOGICAL DMARD IN A COHORT OF RHEUMATOID ARTHRITIS PATIENTS
R. Rolón Campuzano1, AL Coronel Ale1, O.L. Cerda1, F. Dal Pra1, E.E. Schneeberger1, M.A. Correa1, M.G. Rosemffet1, E. Buschiazzo2, R. García Salinas3, S.B. Papasidero4, B.I. Barrios4, Ficco H. Maldonado5, and G. Citera1. 1Instituto de Rehabilitación Psicofísica, Buenos Aires, Argentina; 2Hospital Señor del Milagro, Salta, Argentina; 3Hospital Italiano La Plata, Buenos Aires, Argentina; 4Hospital General de Agudos “Dr E Tornú”, Buenos Aires, Argentina; 5Hospital San Antonio de Padua, Río Cuarto, Córdoba, Argentina.
Objectives: To evaluate the survival of the second biological disease modifying anti-rheumatic drug (bDMARD), the causes of its discontinuation and the time that had elapsed between the discontinuation of the first bDMARD and the beginning of the second one.
Methods: Patients ≥ 18 years of age who met ACR/EULAR 2010 criteria for RA and who had started their second bDMARD between 01/2006 and 12/2017 were included. Socio-demographic variables (age, sex, employment status, marital status, health coverage, education, number of cohabitants), and clinical variables (comorbidities, smoking status, date of symptoms onset, the time elapsed between the interruption of the first bDMARD and the beginning of the second bDMARD and the response to this second bDMARD) were obtained. Statistical analysis: Chi2 test, Student’s t test and ANOVA. Cumulative survival was evaluated using Kaplan Meier curves and log rank test for comparisons.
Results: 347 patients were included, with a median age of 57.8 years (IQR: 48–65), 89.6% were women, 96.5% were RF positive and 60.8% were anti-CCP antibodies positive. 70.6% had health coverage, 16,3% were smokers and 51.2% had some comorbidities. 187 (53.9%) patients discontinued the 1st b-DMARD of which 96 (27.6%) started a 2nd bDMARD (Abatacept, 41,2% Etanercept 25%, Adalimumab 16.7%, Tocilizumab 14.6%, Certolizumab 6.3% and Rituximab 1%). The time between the 1st and the 2nd bDMARD was 9.5 months (SD 17.8). Thirty-eight patients (41.3%) discontinued the 2nd bDMARD, being the causes of discontinuation: lack of efficacy 35.9%, inability to get the compound 30.8% and adverse events (AE) 20.5%. The median survival time of the 2nd bDMARD was 11 months (95% CI: 4–17.9), with no significant difference between the different drugs. In almost 90% of patients who had received an anti-TNF agent as 1st bDMARD, the cause of its discontinuation was inability to get the compound; a TNF inhibitor was started a again. On the other hand, we opted for a change in the compound’s mechanism of action for those patients who discontinued a bDMARD due to AE (69.2%) or lack of efficacy (77.7%). There was no difference in the survival of the 2nd bDMARD with respect to its use as monotherapy or combined with c-DMARD. In those patients, in whom the cause of discontinuation of the 1st bDMARD was AE, the survival of the second bDMARD was significantly lower (3.6 months) compared to those who stopped the 1st bDMARD due to lack of efficacy (21.5 months) or inability to get the compound (20.5 months), Log Rank: p = 0.03.
Conclusions: The survival of the 2nd bDMARD was 11 months; no difference between the different bDMARDs was observed. The most frequent cause of treatment discontinuation was lack of efficacy. For most patients who failed an anti-TNF or presented an AE to it, a change in the compound’s mechanism of action was preferred. The only variable associated with a decreased survival of the 2nd bDMARD was the discontinuation of the 1st one due to an AE.
CORTICAL AND TRABECULAR BONE RESPONSES IN THE PROXIMAL FEMUR OF WOMEN WITH OSTEOPOROSIS TREATED WITH DENOSUMAB OR ZOLENDRONIC ACID USING 3D MODELLING TECHNIQUES OBTAINED FROM DXA
F. Cons-Molina*1, M. Feuchter1, L. Bejarano1, D. Wiluzanski2, C. Altieri2, E. Romero2, J.L. Mansur3, Y. Martelli4, and L. Humbert4. 1Centro de Investigación en Artritis y Osteoporosis, Mexicali, México; 2CENTROSEO, Montevideo, Uruguay; 3Centro de Endocrinología y Osteoporosis, La Plata, Argentina; 4Galgo Medical, Barcelona, Spain.
Objectives: The purpose of this study was to assess the changes that occur after 2 years of treatment with Denosumab(DMAb) or Zolendronic acid (ZOL) in the areal bone mineral density (aBMD) obtained by DXA and in volumetric BMD (vBMD) evaluating 3 bone compartments (trabecular, cortical and integral). All of them were assessed with 3D modelling techniques from a standard proximal femur DXA (hip-DXA).
Methods: We examined the data from 260 patients with postmenopausal osteoporosis. The cohort was stratified by treatments for comparison purposes: DMAb naïve n=50; DMAb Pretreated n=50; Naïve treatment n=30, Zolendronic Acid (ZOL) n=30. Patients came from 3 osteoporosis care centers in Mexico, Uruguay and Argentina. From a hip-DXA acquisition in addition to aBMD, volumetric trabecular total (vBMDTrab), cortical surface density(CSD) and volumetric BMD Integral (vBMDInt) were assessed using a 3D-Shaper software (Galgo Medical, Spain). The changes observed at 2 years were evaluated in terms of percent change in vBMD. Paired Students’ t tests were used to compare parameters from baseline. All hip-DXA were acquired using GE-Prodigy devices.
Results: After 2 years, in the naïve treatment group, a significant decrease was observed in all 3D parameters when compared to baseline, additionally a decrease in aDMO was also observed. In the ZOL group only a significant increase was observed in CSD (2.3%) and in vBMDInt (2.4%). A greater trabecular response was observed in DMAb naïve group vBMDTrab (6.9%) compared to DMAb Pretreated (2.4%). The cortical response(CSD) was higher in both DMAb groups compared to ZOL (2.6%, 2.8% vs.2.3%) whereas trabecular response (vBMDTrab) was only superior in DMAb naïve (6.9% vs.2.8%). Changes in aBMD were greater in both DMAb groups (2.5%, 2.0% vs.1.3%) in ZOL group. The response was analyzed in both DMAb groups divided in tertiles vBMD at baseline (low, medium, high) for all 3D parameters showing only in DMAb naïve group a greater response in those from THE lowest tertile vs. the medium and high (vBMDTrab 13.3%, 4.0%, 0.2%), CSD 6.2%, 2.2%,1.3%), vBMDInt (5.7%, 2.5%, 0.1%). On the other hand, DMAb Pretreated group showed no differences between tertiles in response to treatment (vBMDTrab (2.8%, 1.4%, 2.5%), CSD (4.0%, 3.3%, 3.2%), vBMDInt (3.8%, 2.6%, 2.3%).
Conclusions: As expected, treatment naïve group after 2 years showed a significant loss in aBMD & vBMD; aBMD response after 2 years of ZOL (1.3%) and DMAb (2.5%) was lower than expected. Significant vBMD increases were observed in cortical & trabecular compartments in the ZOL group and the DMAb groups. Applying 3D modelling techniques, may allow us to obtain better results using DMAb in the subgroup of patients at high risk of fractures. 3D modelling techniques are a promising new technology for identification/monitoring of vBMD changes in patients with osteoporosis. More studies are required to confirm these results.
EPIDEMIOLOGY AND MANAGEMENT PRACTICES IN CHILDHOOD-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS: A LATIN AMERICA SURVEY
J. C. Ferreira1, V. C. Trindade1, G. Espada2, Z. Morel3, E. Bonfá4, C. S. Magalhães5, and C. A. Silva1. 1Children’s Institute, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil; 2Hospital de Niños Dr Ricardo Gutierrez, Buenos Aires, Argentina; 3Pediatric Service, Hospital de Clinicas, Universidad Nacional De Asuncion, Paraguay; 4Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil; 5São Paulo State University (UNESP) – Faculdade de Medicina de Botucatu.
Objectives: The objective of the present cross-sectional survey study was to assess childhood-onset systemic lupus erythematosus (cSLE) patients’ reports regarding the epidemiology, classification criteria, disease activity and other instruments used in clinical practice, laboratory and other exams availability, general supportive care, drugs availability, infections, non-live vaccines use, issues observed in adolescents, reproductive health issues and transition-focused program to adult care among Latin America Pediatric Rheumatologist (LAPR).
Methods: A cross-sectional study consisting of a web-base survey about cSLE practices was carried out among 288 LAPR from 21 countries. All physicians are members of the Pan-American League of Association for Rheumatology (PANLAR).
Results: The response rate of web-based survey by LAPR was 170/288(59%); the majority of the responders worked at University Hospitals (63%). The ACR and/or SLICC classification criteria (99%) and disease activity tools (97%) were almost universally used by LAPR, whereas the damage index (70%) and CHAQ (58%) instruments were less frequently used. Laboratory exams, diagnostic imaging and biopsies were generally available (>75%); however, there was low availability for densitometry (66%). Drug access was excellent for the most common prescribed medications (>75%), except for belimumab (11%). Endemic illnesses were reported by LAPR in at least one cSLE patient during the previous year: tuberculosis (16%) and Hansen’s disease (2%). Emerging mosquito-borne diseases were also reported: Dengue (20%), Chikungunya (11%) and Zika (8%). Groups were further divided in two, according to the number of cSLE patients followed by LAPR in the last year: group A (≥25 patients) and group B (<25 patients). Frequencies of condom use in combination with other contraceptive methods were significantly higher in group A than B (69% vs. 48%, p = 0.01). The frequencies of reported pregnancies (50% vs. 16%, p < 0.001) and non-adherence to therapy were significantly higher in group A (100% vs. 93%, p = 0.023). Alcohol intake (42% vs. 21%, p = 0.004) and illicit drug use (19% vs. 5%, p = 0.007) were also reported more frequently reported by group A in at least one cSLE patient.
Conclusion: This first large web-based survey demonstrated an overall excellent access for diagnosis and therapy of cSLE by LAPR, probably related to their high rate of practicing at tertiary care places (University Hospitals). Adherence to therapy, pregnancy and substance abuse were identified as major challenges in this population, particularly in larger centers.
IS THERE ACHILLES TENDON DAMAGE IN RHEUMATOID ARTHRITIS PATIENTS?
M. Fornaro1, T. Cazenave1, M.C. Orozco1, M.V. Martire1, E. Reyes1, H. Schmulevich1, G. Citera1, and M.G. Rosemffet1. 1Instituto de Rehabilitación Psicofísica, CABA, Buenos Aires. Argentina.
Background: Ankle involvement is common in Rheumatoid Arthritis (RA). It has been reported that more than 90 % of patients develop ankle symptoms over the course of the disease. In spite of this, it remains a neglected anatomical area since clinical implications of ankle involvement appear to be continuously underestimated.
Objectives: To examine the ultrasonographic (US) features of the Achilles Tendon (AT), paratenon (AP) and enthesis in patients with RA and compare them to those of healthy athletes. To define the relationship between these findings and clinical and physical therapy parameters.
Methods: Consecutive patients aged ≥18 with RA according to ACR/EULAR 2010 criteria were included. We recorded socio-demographic data, disease duration, physical activity and Body Mass Index (BMI). Clinical evaluation relied on the Disease Activity Score 28 (DAS28), Health Assessment Questionnaire (HAQ), Routine Assessment of Patient Index Data 3 (RAPID 3), as well as on a visual analog scale (VAS), and entheseal pain. Separately, AT thickness, AP thickness, and echogenicity were examined bilaterally with US in 60 ankles from 30 RA patients and 36 from 18 controls. US examinations were performed by two experienced rheumatologists. To evaluate AT involvement, the Madrid Sonographic Enthesitis Index (MASEI) was used to assess elementary lesions: bursitis, calcification, erosion, Power Doppler (PD), thickening of tendon, and structural change. Statistical analysis: Standard descriptive results were expressed as means ± standard deviation (SD). Chi-square test and Fisher’s exact tests were used for categorical variables whereas T tests were used for continuous variables.
Results: For the 30 RA patients, their mean (±SD) age and disease duration were 58.3 ± 9.5 and 4.5 ± 5.9 years, respectively. 30% of the RA patients had foot and ankle pain at the intake visit. The mean (±SD) DAS28, HAQ and RAPID3 were 3.46 ± 0.9, 0.9 ± 0.6, and 11 ± 6.5, respectively. 26.7% of the patients were obese and 30% performed some physical activity. By US, at least 1 AT lesion was found in all RA patients. The most frequent US abnormality in these patients was tibialis posterior tenosynovitis followed by peroneus longus tenosynovitis. A statistically significant difference was found between RA patients and healthy controls in mean (±SD) MASEI (3.56 ± 2.4 vs. 2.33 ± 1.7, p = 0.01), and sub-item scores such as: structural changes (0.66 ± 0.4 vs. 0.2 ± 0.4, p = <0.01), erosion (0.8 ± 1.3 vs. 0.02 ± 0.16, p = <0,01) and PD (0.3 ± 0.9 vs. 0.02 ± 0.16, p = 0.03).
Conclusions: Achilles tendon involvement is rather frequent in RA patients. The MASEI score was significantly higher in patients with RA compared with those of the athletes.
TOBACCO EXPOSURE AND ITS RELATIONSHIP WITH SEVERE DAMAGE IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS
M.A. Cosatti1, S.A. Muñoz2, M. Natalia Tamborenea3, M. García4, A. Curti5, A. Cappuccio6, O. Rillo7, P.M. Imamura8, E. Schneeberger9, F. Dal Pra9, M. Ballent10, M.L. Cousseau11, J. Velasco Zamora12, V. Saurit13, S. Toloza14, M.C. Danielsen15, V.I. Bellomio16, C. Graf17, S. Paira18, J. Cavallasca19, B. Pons Estel20, J.L.C. Moreno21, M. Díaz22, P. Alba23, M. Verando24, G. Tate3, E. Mysler3, J. Sarano25, E.E. Civit26, F. Risueño27, P. Álvarez Sepúlveda28, M.S. Larroude6, M.F. Méndez29, A. Conforti30, D. Sohn31, C.A. Helling3, S. Roverano18, S. Malm-Green24, D. Medina Bornachera32, A. Alvarez32, A. Eimon1, G. Pendón33, M. Mayer34, J. Marin8, C. Catoggio1, and C.N. Pisoni1. 1CEMIC, Ciudad Autónoma de Buenos Aires; 2Hospital General de Agudos Juan A. Fernández, Ciudad Autónoma de Buenos Aires; 3Organización Médica de Investigaciones (OMI), Ciudad Autónoma de Buenos Aires; 4Hospital Interzonal General de Agudos “General José de San Martín”, Ciudad de La Plata, Provincia de Buenos Aires; 5Hospital de Clínicas “José de San Martín”, Ciudad Autónoma de Buenos Aires; 6Hospital Cesar Milstein, Ciudad Autónoma de Buenos Aires; 7Hospital General de Agudos “Dr. Ignacio Pirovano”, Ciudad Autónoma de Buenos Aires; 8Hospital Italiano, Ciudad Autónoma de Buenos Aires; 9Instituto de Rehabilitación Psicofísica (IREP), Ciudad Autónoma de Buenos Aires; 10Hospital Ramón Santamarina, Tandil, Provincia de Buenos Aires; 11Policlínica Privada Paz, Tandil, Provincia de Buenos Aires; 12Instituto Médico CER, Quilmes, Provincia de Buenos Aires; 13Hospital Privado Centro Médico de Córdoba, Córdoba, Provincia de Córdoba; 14Hospital Interzonal San Juan Bautista, Fernando del Valle de Catamarca, Provincia de Catamarca; 15Hospital Regional Ramón Carrillo, Santiago del Estero, Provincia de Santiago del Estero; 16Hospital A.C. Padilla, Tucumán, San Miguel de Tucumán, Provincia de Tucumán; 17Centro Médico Mitre, Paraná, Provincia de Entre Ríos; 18Hospital José MaríaCullen, Santa Fe, Provincia de Santa Fe; 19Hospital José Bernardo Iturraspe, Santa Fe, Provincia de Santa Fe; 20Sanatorio Parque, Rosario, Provincia de Santa Fe; 21Instituto Médico CER, San Juan, Provincia de San Juan; 22Centro Traumatológico Bariloche, San Carlos de Bariloche, Provincia de Río Negro; 23Hospital de Córdoba, Universidad Nacional de Córdoba, Provincia de Córdoba; 24Hospital General de Agudos Bernardino Rivadavia, Ciudad Autónoma de Buenos Aires; 25Instituto de Investigaciones Médicas “Dr. Alfredo Lanari”, Ciudad Autónoma de Buenos Aires; 26Hospital del Carmen, Godoy Cruz, Provincia de Mendoza; 27Itemédica, Bahía Blanca, Provincia de Buenos Aires; 28Hospital de San Isidro, San Isidro, Provincia de Buenos Aires; 29Consultorios Pilar, Puerto Madryn, Provincia de Chubut; 30OSEP Mendoza, Mendoza, Provincia de Mendoza; 31Consultorio privado de reumatología, Escobar, Provincia de Buenos Aires; 32Hospital Penna, Ciudad Autónoma de Buenos Aires; 33Hospital Ricardo Gutiérrez, La Plata, Provincia de Buenos Aires; 34Hospital Británico de Buenos Aires, Ciudad Autónoma de Buenos Aires. All centers are from Argentina.
Objective: To assess the relationship between smoking exposure and organ damage accrual measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) in consecutive Argentinean patients with systemic lupus erythematosus (SLE).
Methods: 623 SLE patients (fulfilling ≥4, 1997 ACR criteria) were included in this cross-sectional study. Sociodemographic and disease related variables, SDI score and smoking status were collected. Patients currently smoking were considered “smokers” and those who had never smoked or those who had previously smoked: “non-smokers”. The SDI was divided into 2 categories < 3 and ≥ 3 severe damage.
Results: Eighty-nine percent of the 623 patients were women, median age was 38 (IQR 30–46) years. Eighty-four percent were non-smokers and 16 % were smokers. Fifty- seven percent were white, and 43% were non-white (mestizo and Amerindian). Seventy-four percent had >12 years of formal education. The median disease duration was 9 years (IQR 4–13). The median number ACR criteria met were 6 (IQR 5–7); the mean SDI score was 1.16 (SD 1.75) for non-smokers and 1.43 (SD 1.89) for smokers (p = 0.915).
When the ACR criteria were compared between smokers and non-smokers only discoid lupus was significantly associated with smoking exposure.
Eighty-three percent of patients had SDI <3 and 17 % had ≥ 3. Twenty one percent of patients with SDI ≥ 3vs.15% of patients with <3 SLICC-SDI were smokers (p= 0.081).
Univariable analyses comparing demographical and clinical characteristics of both groups are depicted in Table 1.
In the multivariable regression analysis considering an SDI score ≥3 as the dependent variable (adjusting by smoking exposure, age, sex, race, disease duration, > 12 years of education, corticosteroids, CP, AZA and HCQ exposure), we found that smoking (OR 1. 90, CI 95% 1.04- 3.46, p 0.035), age (OR 1.33, CI 95% 1.00-1.75, p 0.044), and CP exposure (OR 2.64, CI 95% 1.41-4.97, p 0.002) were associated with an SDI ≥3.
Conclusion: Tobacco exposure, older age and cyclophosphamide use were associated with an SDI ≥3.
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT IN PRIMARY SJOGREN SYNDROME (pSS)
M. Bejarano1, A. Secco1, A. Catalán Pellet1, M. Mamani1, S. Papasidero2, J. Demarchi2, CA Asnal3, CE Crow3, A. Nitsche3, L. Encinas4, F. Caeiro4, C. Gobbi5, E. Albiero5, A. Gomez6, JC Barreira6, R. Aguila Maldonado7, M. Garcia7, M.A Gallardo8, E. Soriano8, L. Raiti9, G. Salvatierra10, and A. Eimon11. 1Hospital Rivadavia, Ciudad Autónoma de Buenos Aires, Argentina; 2Hospital Tornú, Ciudad Autónoma de Buenos Aires, Argentina; 3Hospital Alemán, Ciudad Autónoma de Buenos Aires, Argentina; 4Hospital Privado de Córdoba, Córdoba, Argentina; 5Hospital Córdoba, Córdoba, Argentina; 6Hospital Británico, Ciudad Autónoma de Buenos Aires, Argentina; 7Hospital San Martín de La Plata, La Plata, Argentina; 8Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; 9Clínica Bessone, Ciudad Autónoma de Buenos Aires, Argentina; 10IPRI, Santiago del Estero, Argentina; 11CEMIC, Ciudad Autónoma de Buenos Aires, Argentina.
Objectives: To describe the work productivity and activity impairment in adult patients diagnosed with pSS. To evaluate the potential association between activity impairment and clinical manifestations, depression and anxiety. To compare activity impairment according to educational level and site of care (public or private centers) as surrogates of socio-economic status.
Methods: We included patients with diagnosis of pSS according to the American-European criteria (2002) treated at 11 private and public Argentine rheumatologic centers between November 2013 and December 2016. All patients with another autoimmune rheumatic or chronic disease were excluded. The WPAI questionnaire was used.
Design: Observational, analytic, cross-sectional study. For the descriptive analysis, continuous variables were informed as means and SD. Categorical variables were reported in percentages. A multivariable linear regression model was performed, taking impaired activity due to health as the dependent variable, adjusted by potential confounders. The performance of the model was evaluated (assumptions, atypical observations, multicollinearity). If linearity and/or homoscedasticity was not fulfilled transformation of variables or robust regression was performed, as appropriate.
Results: 252 patients were included, 98.38% were female, mean age of 52.64 years (+/−14.84). The mean percentage of working time lost due to health was 15.74% (+/−30.12. 95% CI: 9.58- 21.90); disability work due to health was 27.18% (+/−30.19. 95% CI:21.25-33.11), the total disability percentage due to health was 33.70% (+/−35.76. 95% CI: 26.39-41.01) and impaired activity due to health was 34.17% (+/−30.94. 95% CI:30.35-37.99). The following variables showed significantly and independent association in the multivariable analysis of robust regression: xerostomia (β coefficient: 0.25. 95%CI: 0.13-0.37), arthritis (β coefficient: 11.15. 95%CI:0.55-21.74), mild depression (β coefficient: 8.77. 95%CI: 1.43-16.12), moderate depression (β coefficient: 25.47. 95%CI: 13.84-37.10), moderately severe depression (β coefficient: 36.92. 95%CI: 26.91-46.93), severe depression (β coefficient: 32.12. 95%CI: 16.31- 48.10). The mean impaired activity due to health was 38.24% (+/− 30.67) in patients treated in public centers vs 28.04% (+/−30.61) on private centers, being this difference statistically significant. No statistically significant differences were found between patients with full or higher secondary education ((32.96% (+/− 31.03)) vs patients with lower educational level [(35.73% (+/−31.08)]
Conclusion: We found all WPAI scales to be compromised. Arthritis, xerostomia and depression were significantly and independently associated with impaired activity due to health. Patients treated in public centers presented a greater impaired activity. This could be an expression of the impact of the socio-economic status.
CLINICAL PREDICTORS OF REMISSION AND LOW DISEASE ACTIVITY IN LATIN AMERICAN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS: DATA FROM THE GLADAR COHORT
Rocio Gamboa-Cárdenas1, Manuel Ugarte-Gil1, Loreto Massardo2, Mónica Sacnun3, Verónica Saurit3, Mario Cardiel4, Enrique Soriano3, Cecilia N Pisoni3, Claudio Galarza5, Carlos Rios5, Sebastiao C Radominski6, Geraldo Castelar6, Rozana Coconelli Mezquita6, Inês Guimaraes da Silveira6, Cristiano A Zerbini de Freitas6, Carlo V Caballero7, Adriana Rojas-Villarraga7, Elías Forero Illera7, Marlene Guibert Toledano8, Francisco Ballesteros2, Rubén Montufar9, Vianna J Khoury10, Janitzia Vazquez-Mellado4, Jorge Esquivel4, Ignacio Garcia De La Torre4, Leonor A Barile-Fabris4, Lilia Andrade Ortega4, José F Díaz-Coto11, Raquel Teijeiro12, Angel Achurra-Castillo13, Maria H Esteva14, Graciela S Alarcón15, and Bernardo A Pons-Estel3. 1GLADAR Peru; 2GLADAR Chile; 3GLADAR Argentina; 4GLADAR Mexico; 5GLADAR Ecuador; 6GLADAR Brazil; 7GLADAR Colombia; 8GLADAR Cuba; 9GLADAR El Salvador; 10GLADAR Dominican Republic; 11GLADAR Costa Rica; 12GLADAR Uruguay; 13GLADAR Panama; 14GLADAR Venezuela; 15University of Alabama at Birmingham, USA.
Objectives: Achieving remission or low disease activity (LDA) are treatment goals in rheumatoid arthritis (RA) and identifying their predictors in early disease is relevant in our region. The objective of this study was to identify the baseline predictive factors of remission and LDA in patients from GLADAR, at one and two years from cohort entry.
Methods: The GLADAR cohort, initially constituted to describe the use of disease modifying antirheumatic drugs (DMARDS) in the region, includes consecutive RA patients with disease <1 year in duration from 46 centers in 14 Latin American countries. For these analyses, patients with complete clinical and laboratory assessments at the baseline, one- and two-year follow up visits were included. Remission and LDA were defined by the 28-joint disease activity score (DAS28-ESR) obtained at one and two years (<2.6 and ≤ 3.2, respectively). Gender, age at diagnosis, socioeconomic status (by the Graffar scale), ethnicity, rheumatoid factor (RF) positivity, disability (measured with the HAQ-DI), DMARDs and corticosteroid use were examined as potential predictive factors of these outcomes. Continuous variables were expressed as means and SDs, and categorical variables as percentages and 95% confidence intervals (95% CIs). Univariable and multivariable binary logistic regression models were examined in order to determine the predictors of remission and LDA/remission at 1- and 2-years after cohort entry.
Results: Five hundred and twenty-six patients were included, 451 (85.7%) patients were female; the mean (SD) age at diagnosis was 45.9 (13.7) years; 384/498 patients (77.1%) were RF positive, the mean baseline DAS28-ESR was 6.1 (1.6). Before the baseline visit, 346 (65.8%) patients have received glucocorticoids, 413 (78.5%) at least one DMARD [258 (49.0%) one DMARD and 155 (29.5%) two DMARDS] and 5 (1.0%) patients had received at least one biologic compound. Remission was met by 103 (19.6%) and LDA/remission by 175 patients (33.3%) at the 1-year follow up. Two hundred and ninety-four patients were followed for at least two years; remission and LDA/remission were met by 72 (24.5%) and 117 (39.8%) of these patients respectively. Predictors of remission and LDA/remission at 1 and 2-years of follow up are depicted in Table 1. A lower DAS28-ESR baseline score predicted remission and LDA/remission after one and two years of follow up.
Conclusions: We have now identified clinical predictors of remission and LDA/remission in Latin American patients with early RA from the GLADAR cohort. A lower disease activity at the baseline evaluation consistently predicted remission and remission/LDA. Our data suggest that an early diagnosis and a more aggressive treatment approach at disease onset is needed to prevent the deleterious effects of persistently active RA.
COST-EFFECTIVENESS OF SECUKINUMAB VERSUS OTHER BIOLOGICS IN THE TREATMENT OF PSORIATIC ARTHRITIS: AN ARGENTINEAN PERSPECTIVE
Eleonora Aiello1, Pablo Manuel Bianculli2, Devarshi Bhattacharyya3, Praveen Gunda3, and Gustavo Citera4. 1Independent Consultant, Buenos Aires, Argentina; 2Novartis Argentina S.A., Buenos Aires, Argentina; 3Novartis Healthcare Pvt. Ltd., Hyderabad, India; 4Instituto de Rehabilitación Psicofísica, Buenos Aires, Argentina.
Objective: Psoriatic Arthritis (PsA) is a chronic, systemic inflammatory disease which primarily affects the peripheral joints, connective tissues, and the axial skeleton. This study assessed the cost-effectiveness of secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, versus currently prescribed biologics in patients with PsA from the Argentinean social security perspective.
Methods: A semi-Markov decision analytic model was used to evaluate the cost-effectiveness of subcutaneous (SC) treatment secukinumab 150 mg and 300 mg against other SC treatments adalimumab, certolizumab pegol, etanercept, golimumab, ustekinumab, and intravenous (IV) treatment infliximab in biologic-naïve (with or without moderate to severe psoriasis) and biologic-experienced PsA patients over a life-time horizon (60 years). Response to treatments was evaluated after 12 weeks by PsA Response Criteria (PsARC) response rates. Non-responders or patients discontinuing initial-line of biologic were allowed to switch to subsequent-line biologics. Model input parameters (PsARC response, Psoriasis Area Severity Index [PASI], Health Assessment Questionnaire [HAQ], drug withdrawal rates, costs, resource use, utilities, and mortality inputs) were derived from PsA clinical trials, published literature, and other Argentinean sources. Model outcomes included quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained. An annual discount rate of 5% was applied to costs and benefits. Sensitivity analyses and an alternative scenario with higher cost option from the private payer perspective were conducted to test the robustness of the results.
Results: Among biologic-naïve PsA patients without psoriasis, secukinumab 150 mg provided highest QALYs (7.18) versus all SC biologics at lowest cost ($3,755,678 Argentine Peso), thus dominated all SC biologics. Infliximab provided slightly higher QALYs (7.31), but at greater costs ($6,543,069 Argentine Pesos), resulting into a very high ICER against Secukinumab 150 mg. Among biologic-naïve PsA patients with psoriasis and among biologic-experienced PsA patients, secukinumab 300 mg provided highest QALYs (6.99 and 7.53, respectively), dominated infliximab and was cost-effective versus other SC biologics. Deterministic sensitivity analyses indicated that the results were sensitive to variation in PsARC response rates, drug acquisition costs, change in HAQ, and utility values. Probabilistic sensitivity analysis showed that both secukinumab 150 mg and 300 mg had maximum net monetary benefits values. Results based on cost inputs from the private payer perspective were similar.
Conclusions: Secukinumab for the treatment of PsA in biologic-naïve and biologic-experienced patients is either a dominant or cost-effective treatment option compared to currently prescribed biologics in Argentina.
CLINICAL ASSOCIATIONS OF NOVEL ANTIPHOSPHOLIPID ANTIBODIES
Tomas Urrego1, Alejandro Hernández2, Sebastian Ruiz2, Sandra M. Osorno3, Carolina Rua4, Julieta Duque Botero2, Adriana L. Vanegas-García2, Carlos H. Muñoz5–6, Luis A. González5, Gloria Vásquez1–5, and Jose A. Gómez-Puerta3–7. 1Grupo de Inmunología Celular e Inmunogenética, Universidad de Antioquia, Medellín, Colombia; 2Departamento de Medicina Interna, Universidad de Antioquia, Medellín, Colombia; 3Dinámica IPS, Medellín, Colombia; 4Grupo de Investigación en Trombosis, Medellín, Colombia; 5Grupo de Reumatología, Universidad de Antioquia, Medellín, Colombia; 6Servicio de Reumatología, Hospital San Vicente Fundación, Medellín, Colombia; 7Servicio de Reumatología, Hospital Clínic, Barcelona, España.
Background: Novel antiphospholipid antibodies (aPL) have been described recently, including anti-phosphatidylserine/prothrombin (PS/PT) antibodies and anti-domain 1 against ß2 glycoprotein I (anti-D1-B2GP1). Clinical associations with “classic” aPL are well known (including anticardiolipin[aCL], lupus anticoagulant, [LA] and anti-B2GP1 antibodies); however, information about the relationship between clinical features of antiphospholipid syndrome (APS) and novel antibodies is more limited.
Objective: Our aim was to examine the clinical associations of 2 novel aPL (Anti PS/PT and anti-D1 B2GPI antibodies) in a cohort of Colombian patients with systemic lupus erythematosus (SLE) and primary APS.
Methods: In this cross-sectional study, anti-D1- B2GPI antibodies were tested using a chemiluminescent immunoassay (QUANTA Flash, Inova Diagnostics). In addition, anti-PS/PT (IgG and IgM), aCL (IgG and IgM) and anti-B2GP1 (IgG and IgM) were measured at the same time by ELISA techniques (QUANTA Lite, Inova Diagnostics). The LA was detected according to the guidelines of the International Society on Thrombosis and Hemostasis. Spearman's rank correlation was used to assess the association between antibodies.
Results: One-hundred and seventy-three patients were included, 87% of them were female with a mean age of 33 ± 12 years. 150 patients had SLE and 23 patients primary APS. Anti-PS/PT and anti-D1-B2GP1 had some strong association with several APS features (See Table). Noteworthy, is the association between anti-PS/PT IgG and obstetric morbidity. No other association were found with other non-criteria APS features. LA was associated with all the panel of aPL antibodies (p<0.05 for all). At the same time IgG anti PS/PT and IgM anti PS/PT had a moderate positive correlation (r ranging from 0.42 to 0.49) with IgG anti B2GP1 and aCL and IgM anti B2GP1 and aCL, respectively.
Conclusions: We found a strong association between 2 novel aPL (Anti PS/PT and anti-D1-B2GP1) antibodies with several clinical APS features including deep vein thrombosis, arterial thrombosis, thrombocytopenia and obstetric morbidity. A wider use of these 2 novel aPL in the future will bring us more information about their- clinical utility and potentially, differential management in APS patients.
Acknowledgements: Anti-D1-B2GPI antibodies were provided by Inova, Werfen, Colombia. ELISA determination of aCL and anti-B2GP1 were provided by Dinámica IPS.
INTEGRATED SAFETY SUMMARY OF TOFACITINIB IN PSORIATIC ARTHRITIS CLINICAL STUDIES
G.R. Burmester1, O. FitzGerald2, K. Winthrop3, V.F. Azevedo4, W.F.C. Rigby5, K.S. Kanik6, C. Wang6, P. Biswas7, T. Jones8, S. Menon6, N. Palmetto7, and R. Rojo6. 1Charité – University Medicine Berlin, Berlin, Germany; 2St Vincent’s University Hospital, Dublin, Ireland; 3Oregon Health and Science University, Portland, OR, USA; 4Universidade Federal do Paraná, Curitiba, Brazil; 5Geisel School of Medicine at Dartmouth, Lebanon, NH, USA; 6Pfizer Inc, Groton, CT, USA; 7Pfizer Inc, New York, NY, USA; 8Pfizer Inc, Collegeville, PA, USA.
Objective: To describe the safety profile of tofacitinib, an oral Janus kinase inhibitor under investigation for the treatment of psoriatic arthritis (PsA), from integrated Phase (P)3 and long-term extension (LTE) studies.
Methods: Data were analyzed for patients (pts) with active PsA who received ≥1 dose of tofacitinib 5 or 10 mg twice daily (BID) or placebo (PBO), integrated across 2 P3 studies (OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]) and an LTE study (OPAL Balance [ongoing, database not locked; NCT01976364]). Common adverse events (AEs; occurring in ≥2% of tofacitinib pts in any group) were analyzed in the PBO-controlled portion (Months 0–3) of the P3 studies (Cohort 1 [C1]). Serious AEs (SAEs) and discontinuations due to AEs were analyzed over 12 months in pts randomized to tofacitinib 5 or 10 mg BID in P3 studies (Cohort 2a [C2a]); pts randomized to PBO were excluded from this analysis. Cohort 3 (C3) consisted of all tofacitinib-treated pts in the P3 and LTE studies, and evaluated deaths and AEs of special interest (serious infections [SI], herpes zoster [HZ], opportunistic infections [OI] including HZ, major adverse cardiovascular events [MACE], malignancies excluding non-melanoma skin cancer [NMSC], and NMSC). Incidence rates (IR; pts with events/100 pt-years [PY] and 95% confidence intervals) are reported.
Results: C1 included 474 tofacitinib- and 236 PBO-treated pts; C2a included 474 tofacitinib-treated pts; and C3 included 783 tofacitinib-treated pts (exposure: 776 PY). Nasopharyngitis (5.9%) and headache (8.5%) were the most commonly reported AEs at Month 3 in pts receiving tofacitinib 5 and 10 mg BID, respectively. In pts randomized to tofacitinib 5 or 10 mg BID, over 12 months (C2a), the IRs for SAEs were 7.92 (4.09, 13.84) and 8.11 (4.19, 14.17), respectively. Discontinuation due to AEs occurred in 11 (4.6%) and 11 (4.7%) pts randomized to tofacitinib 5 and 10 mg BID, respectively, with IRs of 7.16 (3.58, 12.82) and 7.31 (3.65, 13.08), respectively, over 12 months (C2a). Across all tofacitinib-treated pts in the P3 and LTE studies (C3), SIs occurred in 11 pts (1.4%; IR 1.40 [0.70, 2.50]). HZ was reported in 16 pts (2.0%; IR 2.05 [1.17, 3.33]) receiving tofacitinib. All 3 cases of multidermatomal HZ were adjudicated as OIs; these were the only OIs (0.4%; IR 0.38 [0.08, 1.11]). In C3, 2 deaths occurred (0.3%; IR 0.25 [0.03, 0.91]); all were considered unrelated to the study drug. MACE were reported in 3 pts (0.4%; IR 0.38 [0.08, 1.11]), malignancies (excluding NMSC) in 5 pts (0.6%; IR 0.63 [0.21, 1.48]), and NMSC in 4 pts (0.5%; IR 0.51 [0.14, 1.30]) in C3.
Conclusions: In patients with active PsA, tofacitinib demonstrated a safety profile consistent with that seen with tofacitinib in rheumatoid arthritis; no new risks were identified. Longer-term follow-up and larger pt populations will provide further information on the safety profile of tofacitinib in pts with PsA.
RISK FACTORS FOR BONE LOSS IN JUVENILE-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS: A LONGITUDINAL STUDY
L. Sousa1, J. Paupitz1, N. Aikawa1, L. Takayama1, V. Caparbo1, and R. Pereira1. 1Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.
Objectives: Juvenile-onset systemic lupus erythematosus (JoSLE) is associated with low bone mass relative to the patients’ age and with fractures; nevertheless, risk factors and predictors of bone involvement are poorly understood in this condition. The aim of this study was to evaluate the risk factors for bone mass loss in patients with JoSLE examining clinical and laboratory data, besides bone microarchitecture parameters.
Methods: This study enrolled a sample of 49 female JoSLE patients, all of them diagnosed according to the ACR classification and 2012 SLICC criteria. All patients were evaluated at baseline and after 3.5 years of follow-up for clinical data associated with the disease, lifestyle habits, treatment, laboratory tests including bone turnover markers (N-terminal propeptide of type 1 collagen - P1NP; C-terminal telopeptide of type 1 collagen - CTX), areal bone mineral density (aBMD) by dual X-ray absorptiometry (DXA) at lumbar spine and hip and parameters of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) at distal tibia and radius. Vertebral fractures were examined using DXA (VFA, Genant’s method). aBMD changes above the least significant change were considered significant. Based on the difference between final and baseline aBMD value, the patients were divided into 3 groups: aBMD gain (BG), aBMD loss (BL) and aBMD no change (NC).
Results: The mean age of the patients was 18.7 ± 3.3 years and the mean disease duration was 6.0 ± 3.9 years. Sixty-one percent of patients presented aBMD gain, 18.4% aBMD loss and 22.4% remained stable over this period of follow-up. Comparing the BL and the BG groups, there was a higher frequency of alcohol consumption (33.3 vs. 0%, p=0.009), a higher frequency of inadequate calcium intake (66.7 vs. 26.7%, p=0.047) and lower serum levels of baseline P1NP (52.42 ± 33.56 vs. 119.72 ± 85.78 ng/mL, p=0.036) in the BL group. Moreover, a worse evolution of HR-pQCT bone parameters: trabecular volumetric density at tibia (−16.36 ± 15.71 vs. −1.55 ± 10.83 mg/cm3, p=0.003) and cortical thickness at tibia (−0.025 ± 0.09 vs. 0.054 ± 0.07 mm, p= 0.009) was observed in the BL group. In addition, a higher frequency of renal activity was observed when the BL and NC groups were examined together and compared to the BG group (52.6 vs. 23.3%, p=0.036). No significant differences were observed regarding other clinical, laboratorial and microarchitecture bone parameters and treatment.
Conclusions: This is the first longitudinal study in the literature that examines the risk factors for bone mass loss in JoSLE patients. The authors emphasize the importance of evaluating not only renal disease activity, but also lifestyle habits, mainly alcoholism and calcium intake in these young women. Furthermore, this study suggests that trabecular and cortical bone compartments were deteriorated in this disease and that low serum levels of P1NP may be a predictor of bone involvement in JoSLE.
DISCREPANT PERCEPTION OF LUPUS DISEASE ACTIVITY. A COMPARISON BETWEEN PATIENTS’ AND PHYSICIANS’ DISEASE ACTIVITY SCORES IN PERUVIAN PATIENTS
Claudia Elera-Fitzcarrald1,2, Karen Vega3,4, Rocío V. Gamboa-Cárdenas1, Katiuska Zúñiga3,4, Mariela Medina1, Victor Pimentel-Quiroz1, César Pastor-Asurza1, Risto Perich-Campos1, Zoila Rodríguez Bellido1, Graciela S. Alarcón4,5, Armando Calvo3,4, and Manuel F. Ugarte-Gil1,2. 1Servicio de Reumatología. Hospital Guillermo Almenara Irigoyen. EsSalud; 2Facultad de Medicina Universidad Científica del Sur; 3Servicio de Inmunología y Reumatología. Hospital Cayetano Heredia; 4Facultad de Medicina. Universidad Peruana Cayetano Heredia; 5School of Medicine, The University of Alabama at Birmingham, USA, United States.
Objectives: To compare patient’s and physician’s (MD’s) assessment of disease activity in Peruvian systemic lupus erythematosus (SLE) patients.
Methods: This is a cross sectional study of SLE patients conducted between August 2016 and December 2017 at two hospitals in Lima, Perú, one from the Social Security and the other from the Public Health Systems. Disease activity was assessed by the patient with either a Visual Analog Scale (VAS), 0–100 mm) or a Numerical Rating Scale (NRS, 0–4), before and after MD’s assessment. Disease activity was assessed by the MD with the Mex-SLEDAI (0–32) and damage with the SLICC/ACR Damage Index (SDI). Health-related quality of life (HRQoL) was ascertained with the LupusQoL. VAS and NRS scores obtained before and after the MD evaluation were compared using the Wilcoxon signed-rank test. The correlation between disease activity as assessed by the patient and the Mex-SLEDAI, SDI and LupusQoL was examined using Spearman Rank Correlation.
Results: Two hundred and forty patients were included. Their mean (SD) age at diagnosis was 34.9 (12.9) years; nearly all patients were Mestizo. Disease duration was 10.1 (7.0) years. The Mex-SLEDAI was 1.9 (2.7) and the SDI 1.2 (1.5). Disease activity as assessed by the patient, either by VAS [29.3 (26.5) and 26.5 (24.9) or NRS [1.5 (1.2) and 1.4 (1.1), before and after MD evaluation, respectively] did not correlate with the Mex-SLEDAI (MD assessment). Likewise, there was no correlation between either measure and the SDI. In contrast, disease activity as assessed by the patient, regardless of the scale or time obtained, correlated with several components of the LupusQoL (physical health, pain, planning, emotional health and fatigue). These data are shown in Table 1.
Conclusions: Physician and patient’s assessment of disease activity are discrepant with patients scoring, overall, higher than their MDs. Disease activity as perceived by patients correlates with how they perceive the disease is affecting them rather than with disease activity per se. Further studies are needed to assess how this discrepant perception between patients and their physicians may affect patients’ treatment adherence and outcomes.
SECUKINUMAB PROVIDES SUSTAINED REDUCTION IN FATIGUE IN PATIENTS WITH ANKYLOSING SPONDYLITIS THROUGH 3 YEARS: LONG-TERM RESULTS OF TWO RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 3 STUDIES
T.K. Kvien1, A. Deodhar2, L. Gossec3, P.G. Conaghan4, V. Strand5, M. Østergaard6, N. Williams7, B. Porter8, K. Gandhi8, and S. Jugl9. 1Diakonhjemmet Hospital, Oslo, Norway; 2Oregon Health & Science University, Portland, Oregon, United States; 3UPMC University Paris 06, Paris, France; 4University of Leeds, Leeds, United Kingdom; 5Stanford University School of Medicine, Palo Alto, CA, United States; 6Copenhagen Center for Arthritis Research (COPECARE), Glostrup, Denmark; 7RTI Health Solutions, Durham, NC; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; 9Novartis Pharma AG, Basel, Switzerland.
Objectives: In patients (pts) with ankylosing spondylitis (AS), fatigue is a common symptom negatively affecting health-related quality of life (HRQoL) and social functioning. Secukinumab (SEC), a fully human anti–IL-17A mAb, rapidly improved signs and symptoms, physical functioning, and HRQoL in pts with AS.1,2 Here, we present the long-term effects of SEC on fatigue in TNF inhibitor (TNF)-naïve and TNF inhibitor inadequate responder/intolerant (TNF-IR) AS pts in MEASURE 1 and MEASURE 2.
Methods: 371 and 219 pts were randomized to SEC or placebo (PBO) in MEASURE 1 (10 mg/kg IV followed by 150 or 75 mg SC) and MEASURE 2 (150 or 75 mg SC), respectively. At Week (Wk) 16, non-responder PBO pts were re-randomized to SEC 150 or 75 mg SC (in MEASURE 1, PBO pts achieving ASAS20 response at Wk 16 were switched to SEC at Wk 24). Fatigue was measured at baseline (BL) and Wks 4, 8, 12, 16, 24, 52, 104 and 156 using FACIT-F, which assesses fatigue in the previous 7 days using 13 questions graded on a 0–4 scale (higher scores = less fatigue). An increase from BL in FACIT-F score of ≥4 points (based on MCID) was used to define “response.” Approximately 69% of pts were TNF-naïve and 31% were TNF-IR across both trials. Analyses were based on the full analysis set and subgroups stratified by prior TNF therapy. Correlations between BL characteristics and improvements in fatigue were investigated using a logistical regression model. Only data from the approved dose (SEC 150 mg) are presented.
Results: FACIT-F was 24.5–25.6 and 22.6–24.3 at BL across groups in MEASURE 1 and 2, respectively. Improvements in FACIT-F with SEC at Wk 16 were sustained through Wk 156 in MEASURE 1 and Wk 104 in MEASURE 2 (Table). Rapid and sustained fatigue responses were also seen in subgroups stratified by prior TNF use. In the overall population, LS mean changes (±SEM) from BL in FACIT-F scores were significantly greater with SEC vs PBO at Wk 16 in both MEASURE 1 (7.60 ± 0.99 vs 3.34 ± 1.00, P = 0.002) and MEASURE 2 (8.10 ± 1.09 vs 3.27 ± 1.09, P = 0.018). Reductions in fatigue were sustained throughout the entire follow up period in both trials (MEASURE 1 Wk 156: 9.81 ± 0.95; MEASURE 2 Wk 104: 9.27 ± 1.13). Similar results were reported in both TNF-naïve and TNF-IR pts. Correlational analyses based on pooled data from both trials did not identify any BL factors that consistently predicted improvement in fatigue response at Wks 16, 52, and 104. A one-unit increase in BL BASDAI score (i.e., worsening based on MCID) was a significant factor impacting FACIT-F response at Wk 104 (P = 0.02).
Conclusions: SEC provided sustained improvements in fatigue for up to 156 wks in both TNF-naïve and TNF-IR pts with AS. Fatigue response was generally higher in TNF-naïve pts.
 Baeten. NEJM 2015;373:2534–48.
 Kvien. ARD 2016;75(Suppl2):823.
1. BASIC SCIENCE
SM04690, A WNT PATHWAY INHIBITOR: ANTI-INFLAMMATORY AND CARTILAGE PROTECTIVE EFFECTS IN PRECLINICAL OSTEOARTHRITIS MODELS
V. Deshmukh, T. Seo, M. Grifman, C. Swearingen, Y. Yazici. Samumed, LLC, San Diego, USA.
Objectives: Osteoarthritis (OA) is characterized by pain, swelling, and reduced function in the knee joint. Upregulated Wnt signaling drives OA through synovial inflammation, increased subchondral bone, and thinning cartilage. SM04690, a small molecule Wnt pathway inhibitor that demonstrated chondrogenic and anti-inflammatory properties preclinically1, was further evaluated to determine its potential to reduce inflammation, protect cartilage, improve joint health and modify pain in OA.
Methods: Cytokine secretion (IL-6 and TNF-α) from IL-1β-stimulated and SM04690-treated synovial fibroblasts was measured by ELISA. A single intra-articular injection of SM04690 or vehicle was evaluated in an in vivo rat knee monosodium iodoacetate (MIA) OA model. Joint inflammation was evaluated by H&E staining, inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α and IFN-γ) by qPCR, and cartilage protection by qPCR for matrix metalloproteinases (MMPs). Histological evaluation of cartilage health was performed using OARSI score and thickness by Safranin-O staining. Pain was measured as paw withdrawal threshold using Von Frey apparatus and weight distribution using incapacitance meter and analyzed using generalized estimating equation regression.
Results: SM04690 dose-dependently inhibited IL-1β-induced cytokine secretion in synovial fibroblasts (EC50 ~30nM; Fig.1). In the rat MIA OA model, compared to vehicle, SM04690 injection reduced visible knee swelling, inflammatory cells, proinflammatory cytokine and MMP production (p < 0.05). SM04690 increased (p < 0.01) paw withdrawal threshold from day 6 and improved weight distribution to the affected limb in treated rats, at multiple timepoints, compared to vehicle (Fig.2). SM04690 increased Safranin-O stained cartilage thickness and decreased OARSI score (p < 0.05) compared to vehicle.
Conclusion: In a rat MIA OA model, SM04690 injection reduced inflammation, protease production, and pain, with improved cartilage and joint health, compared to vehicle. Previously demonstrated regenerative effects in nonclinical studies1, along with anti-inflammatory properties, show SM04690 may improve symptoms and potentially provide disease modification in OA. Clinical studies are ongoing.
1Deshmukh et al. OAC 2017
HISTOMORPHOMETRIC ASSESSMENT OF THE TIBIAL METAPHYSIS AREA IN NOD MICE WITH SJÖGREN SYNDROME
B. Busamia B1, SJ Renou2, C. Gobbi1, S. Fontana1, E. Albiero1, P. Alba1, and M. Yorio1. 1Unidad de Reumatologìa, Hospital Córdoba, UNC; 2Cátedra de Anatomía Patológica FOUBA.
Background: Primary Sjögren syndrome (SSp) is a chronic, autoimmune, systemic disease characterized by lymphocytic infiltration of the exocrine glands with consequent drying of the mucosa, mainly oral (xerostomia) and ocular (xerophthalmia). Our group has previously described bone disorders in NOD mice with Sjögren Syndrome, both radiologically and histologically, compared with controls. Bone disorders related to SS have not been described accurately in the current literature.
Objective: To assess by histomorphometry of the tibial metaphysis area of NOD mice with SS, compared to controls NOD mice without SS.
Methods: We used 10 NOD female mice with SS (group SS) and 10 controls NOD without SS (group C, control). They were cared in the animal facilities of the Faculty of Chemistry of the UNC. At 4 months of age (weight 80 g ± 10) mice were anesthetized with ketamine-xylazine, both tibias were extracted, and then they were taken to euthanasia, respecting the ethical principles of animal experimentation. The bones were fixed in formalin buffer, decalcified with EDTA and processed for their inclusion in paraffin; cuts were oriented to eosin in order to perform the histological assessment. The histomorphometrically assessment of tibial metaphysis area and the length of trabecular bone were performed.
Results: The area of bone tissue and the length of trabecular bone were smaller in SS Group than in the C Group, with statistically significant difference: bone tissue área C group: 142079,3 ± 32250 μm2; SS Group: 103356,9 ± 19445 μm2. Trabecular lenght 557±31 μm; SS Group: 331±70 μm), p<0,05. The percentage of trabecular bone tissue in C group was: 16,5% - SS group: 9,6 %.
Conclusion: These results, in addition to our previous research, confirms that there is a bone disorder in this experimental model of SS. It is necessary to carry out immunostaining techniques of quality and activity of bone tissue, with the purpose of objectify the response in NOD mice with SS.
ASSESSMENT OF BONE MINERAL DENSITY OF THE LOWER JAW, SPINE AND TIBIAL BONE IN NOD MICE WITH SJÖGREN' SYNDROME
B. Busamia1, C. Gobbi1, K. Rhys1, M. Mariani2, S. Fontana2, S. Marchegiani S3, M Belletti3, E. Albiero1, P. Alba1, and M. Yorio1. 1Cátedra de Fisiología, Facultad de Odontología. UNC; 2Unidad de Reumatología, Hospital Córdoba. UNC; 3Servicio de Radiología, Sanatorio Allende, Córdoba.
Introduction: The model of NOD mice for experimental diabetes, concomitantly produces an alteration in the submandibular and lacrimal glands; histopathologically these changes are equivalent to Sjögren's syndrome (SS) that develops in humans. Only few data are found in the literature about bone diseases in SS.
Objective: To assess the bone mineral density in the lower jaw, spine and tibial bone in non-obese diabetic mice with Sjögren's syndrome (SS-NOD) compared to control mice C57, (C).
Methods: We used 10 female NOD mice and 10 C57 controls from animal facilities of the Faculty of Chemical Sciences at UNC. These animals were cared for under special conditions, free of specific pathogens. At 4 months of age (weight 80 g ± 10) animals were anesthetized with ketamine Xylazine. Bone Mineral Density (BMD) was measured with Densitometer Hologic QDR Discovery W 4500w; Scan Type: Lumbar Spine anteroposterior, jaw bones and tibia. We used Rx- dual-energy (DXA) with ionization chamber. Mice position: prone position, upper and lower limbs, and tail extended. A "bone map" of the bone area to study was performed and divided into into five sectors with "spinal lines": lower jaw (LJ), lumbar spine (LC), both tibial bones (TB), right and left epiphysis (RE and LE). Mineral density was expressed in grams of calcium/cm2. Statistical analysis was performed by ANOVA using, InfoStat 2015. BMD controls were: LJ 0.21, LC 0.11, LE 0.04, ED 0.03 and T 0.04 and in NODSS mice 0.19, 0.11, 0.01, 0.01, 0.01 g/cm2, respectively.
Results: The different bone regions within each group of mice and between both groups were compared. Variations between the bony regions in each experimental group were observed, a significant decrease in BMD values of the tibiae from NOD SS vs C57, was found; it was statistically significant for the left tibial epiphysis BMD (p <0.0001) in comparison to the other bones studied.
Conclusion: Tibial bone abnormalities were found in the NOD SS mice when compared with the controls, but not in the other skeletal sites studied. Pathologic correlation is necessary to determine and the significance of these findings.
IMMUNOSTIMULATORY CAPACITY OF MICROPARTICLES FROM PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS ON T LYMPHOCYTES
MA. Cardona-Carvajal1,2, K. Julio-Hoyos1,2, K. Álvarez2, L. Carmona2, M. Rojas2, and G. Vásquez2. 1Escuela de Microbiología y Bioanálisis. Universidad de Antioquia.2Grupo de Inmunología Celular e Inmunogenética. Facultad de Medicina. Universidad de Antioquia.
Objective: To evaluate the immunogenicity of microparticles (MPs) from healthy controls (HC) and patients with systemic lupus erythematosus (SLE), by the capacity to induce activation and proliferation of HC T-lymphocytes, suggesting a specific recognition, event that should explain the role of these cellular fragments in the pathogenesis of SLE.
Materials and Methods: To establish the proliferation, mononuclear cells from human peripheral blood isolated by density gradient were staining with CFSE (carboxyfluorescein succinimidyl ester) and stimulated during 96 hours with phytohaemagglutinin (PHA), anti-CD3/CD28 and two different concentrations of isolated MPs from five SLE patients and HC. The expression of CD25 and CD28 in T cells was established by flow cytometry.
Results: Although, PHA and anti-CD3/CD28 induced CD25 and CD28 expression and T cell proliferation, it was not changed by the treatment with 50 ug/ml and 150 ug/ml MPs derivatives from controls and patients. Proliferation and division indexes do not differ between the MPs concentrations, source or PHA and anti-CD3/CD28 combination either.
Conclusions: SLE patients and controls’ MPs, neither induce healthy controls T lymphocytes activation, nor proliferation. In addition, this work showed that MPs do not promote T lymphocytes activation or proliferation induced by PHA and anti CD3/CD28. The observed effects are not dependent on the dose or MPs isolation source.
POLYMORPHISMS OF DICKKOPF 1 IN EARLY RHEUMATOID ARTHRITIS COULD MODULATE THE PRESENTATION OF RADIOLOGICAL DAMAGE
Alex Darío Cardona-Rincón1,2, Mónica Acevedo-Godoy3, Ángela Arias-Arias4, Lorena Chila-Moreno3, Sandra J Perdomo-Lara3, Philippe Chalem Ch5, Wilson Bautista-Molano2,3, Rafael Valle-Oñate1, Juan Manuel Bello G1,2, and Consuelo Romero-Sánchez1,2,3. 1Hospital Militar Central, Bogotá, Colombia; 2Universidad Militar Nueva Granada, Bogotá-Colombia; 3Universidad El Bosque, Bogotá-Colombia; 4Universidad Colegio Mayor de Cundinamarca, Bogotá-Colombia; 5Fundación Instituto de Reumatología Fernando Chalem.
Background: Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovitis, joint destruction and excessive bone loss. Recent evidence suggests that Dickkopf-1 (DKK-1) may have an active role in the regulation of bone biology. In addition, those patients with RA that carry genetic variants of DKK-1 have higher serum levels and greater bone damage. The objective of this study was to investigate the bone resorption marker DKK-1 and its polymorphisms in patients with early RA (eRA) and its association with rheumatic indexes and radiological score.
Methods: A cross-sectional study was conducted to explore the association of bone marker DKK-1 and its polymorphisms with radiological and rheumatic outcomes in patients with eRA according to the criteria of the American College of Rheumatology/EULAR 2010. Patients selected were over 18 and less than 65 years of age, had early disease, and treatment with conventional DMARDS (Disease Modifying AntiRheumatic Drugs). Disease activity was assessed by scales DAS 28 and SDAI. Radiographs of hands and feet were obtained and scored using the Sharp-van der Heijde score (SHS) and the Simple Erosion Narrowing Score (SENS). DKK-1 polymorphisms rs1896368, rs1896367 and rs1528873 were determined using the High Resolution Melting technique (Bio-Rad®) and serum levels by ELISA- MyBiosource®). A bivariate analysis was performed to determine the variables associated to the presence of radiological, and a penalized regression model was performed to confirm these associations. This study was approved by the Ethics Committee of the Institution.
Results: 63 patients with eRA were included, with a mean age of 48.5 years (SD = 11.5 years).79.4% of the patients were female, 6.3% were current smokers and 61.7% and 43.3% had positive RF (Rheumatoid Factor, Spinreact®) and ACPAs IgG/IgA (Innova, Diagnosis®) (Anti Citrullinated Peptides Antibodies) respectively. No association was found between DKK-1 levels and disease activity indexes or radiological damage scores. Patients heterozygous for the rs1896367 polymorphism more frequently had erosions (p = 0.026), JSN (Joint Space Narrowing) in the feet (p = 0.005), higher SHS score (p = 0.016) and higher frequency score > 6 (p = 0.001) by SENS. As for the polymorphism rs1896368, those with homozygous expression had a lower frequency of JSN (p = 0.026) and homozygosity was negatively associated with JSN in the feet (p = 0.002); these patients did not present scores of SENS > 6 (p = 0.001). In a penalized regression model, patients homozygous for the rs1896368 polymorphism of DKK-1 have a lower risk of presenting radiological damage, (OR: 0.04 CI: 0.01-0.93, p = 0.05).
Conclusions: Serum levels of DKK-1 may have a preponderant role as a marker in bone or joint damage in more advanced stages than in eRA, however, the presence of polymorphisms of DKK-1, specifically of rs1896368 in eRA could modulate the presentation of radiological damage.
129- ASSOCIATION BETWEEN ANTIBODIES TO CARBAMYLATED PROTEINS AND SPECIFIC PEPTIDES OF THE HUMAN FIBRINOGEN B-CHAIN IN EARLY RHEUMATOID ARTHRITIS
L. Chila-Moreno3,4, L.S. Rodríguez4, J. De Avila3, W. Bautista-Molano2,3, J.M. Bello-Gualtero1,2, and C. Romero-Sánchez1,2,3. 1Hospital Militar Central, Bogotá- Colombia; 2Universidad Militar Nueva Granada, Bogotá-Colombia; 3Universidad El Bosque, Bogotá-Colombia; 4Pontificia Universidad Javeriana, Bogotá-Colombia.
Background: The presence of autoantibodies is one of the hallmarks of rheumatoid arthritis (RA). Anti-carbamylated protein(anti-CarP) antibodies are new autoantibodies present in RA and which are detected before the onset of RA and have been associated with disease severity; however, the precise target antigen of anti-CarP antibodies has not been elucidated. The objective of this study was to associate the anti-carbamylated protein and peptides antibodies with genetic and activity clinical indexes in patients with early RA(eRA).
Methods: A cross-sectional study of 51 RA patients with the diagnosis of eRA according to the ACR/EULAR 2010 criteria Bogota-Colombia was carried out. Anti-CarP antibodies were measured for the presence of anti-carbamylated-fetal calf serum (anti-CarP-FCS) by chemiluminescence by Inova-Diagnostics and antibodies directed to specific epitopes of the human Fibrinogen β-Chain peptide(anti-CarP-Fib), two peptides with specific homocitrulline were synthesized and one with lysine as negative control by in-house ELISA method. Disease activity was assessed by DAS28 and SDAI. Radiographs of hands and feet were obtained and scored using the Sharp-van der Heijde score (SVdH) and the Simple Erosion Narrowing Score-SENS. HLA-DRB1 typing was carried out by Luminex 200 TM technique. The association was examined by Chi-square and Fisher tests and the comparison using kappa concordance coefficient.
Results: Fifty-one patients were evaluated. 19.6% were male and 80.4% were female. 29.4% were positive for RF and 45.1% positive for ACPA. The positivity of Anti-Carp -FCS antibodies was 47.1% and the positivity of the antibodies against carbamylated peptides was: Anti-CarP-Fib2 47.1% and anti-CarP-Fib3 31.4%. Twenty-eight patients (54.9%) showed the shared epitope. A negative association was found between the presence of anti-CarP-FCS antibodies passive exposure to tobacco (p = 0.037). Interestingly, anti-Carp-Fib2 antibodies resulted associated with the presence of positive RF (79.2%) (p = 0.022) and higher level of ACPA(p = 0.032). Additionally, the anti-CarP-Fib2 antibodies were associated with joint space narrowing in the feet by the SVdH whereas 83.3% were positive for both (p = 0.043), and space narrowing in feet by SENS score (p = 0.043). No associations were found with the HLADR B1, serological and clinical markers related with RA. In addition, a concordance analysis was performed between the results of anti-CarP-FSC protein and specific anti-peptides anti-CarP-Fib with the following results: 21/24 patients were positive for anti-CarP-FCS and anti-CarP-Fib2 (p =0.00001 and Kappa = 0.685) and anti-CarP-FCS and anti-CarP-Fib3 (p =0.007 and kappa = 0.36)
Conclusions: Anti-CarP-Fib2 appear to target regions of the human fibrinogen β-chain that contain homocitrulline in a specific place and could be in the future be considered good biomarkers for the presence of joint damage in era. The evaluation of antibodies against carbamylated peptides showed a substantial concordance with the anti-carbamylated protein
URINE BIOMARKERS IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITH OR WITHOUT LUPUS NEPHRITIS: AN EXPLORATORY STUDY IN COLOMBIAN PATIENTS
Y.P. Trujillo1, A. Kerguelen2, S. Amado1,2, D.G. Fernández-Ávila1,2, A. Barreto-Prieto1, and L.S. Rodríguez1*. 1Pontificia Universidad Javeriana, Bogotá, Colombia; 2Hospital Universitario San Ignacio, Bogotá, Colombia.
Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the production of autoantibodies directed against intracellular antigens; clinical variability makes it difficult to predict damage to specific organs caused by the disease; consequently, new treatments in order to mitigate the pathology of this disease are neccessary This is an important reason to improve the panel of biomarkers. Although the cause of the disease is still unknown, however, the lack of removal of apoptotic cells has been postulated as a possible induction mechanism. It has also been shown that urine is a reliable source of biomarkers allowing an observation window of what may be happening to the patient.
Objective: The objective of this work was to determine if there are differences between the urine levels of molecules related to the removal of apoptotic cells and triggering of the inflammatory process, as well as of cytokines involved in the disease, in patients with SLE with or without lupus nephritis (LN) in comparison to healthy controls.
Material and Methods: To explore this, the study population was divided into three groups: healthy controls (n = 6), SLE patients without LN (n = 5), and SLE patients with LN (n = 4). This population was recruited at the Hospital Universitario San Ignacio, in Bogota Colombia. The urine samples were collected and concentrated by ultrafiltration. We evaluated by Western Blot the following molecules: HMGB1, HISTONE H3, CALRETICULIN (CRT), ANEXIN A1 and CD46, CX3CL1 by ELISA and cytokines IL-8, IL-6, IL-12p70, TNF-α and IL-1β by Cytometric Bead Array.
Results: We detected histone H3 levels in only one SLE patient with LN. The band detected for this patient suggests a posttranslational modification of this molecule. No histone H3 was detected in the age-sex matched healthy controls. There was no difference for HMGB1 and CX3CL1 levels in all groups examined. CD46, ANEXIN A1 and CRT were not detected in our samples. Finally, when we evaluated the cytokines, an increase of IL-8 levels was observed in SLE patients with or without LN in comparison to the healthy controls. For IL-6, an increase was found between patients with SLE without LN in comparison to patients with LN, but no differences were found in the levels of the other cytokines.
Conclusion: Urine levels of IL-8 and histone H3 could be interesting in studying renal damage in SLE. HMGB1 as “danger signal”, CX3CL1 as “find-me signal” do not seem to be useful to predict renal involvement in SLE patients. More patients must be recruited to confirm these findings.
CHARACTERIZATION OF EXPRESSION PROFILES OF IKAROS TRANSCRIPTION FACTOR IN AUTOIMMUNE DISEASES
L.K Duque Suárez1, G. Quintana López2, P. Coral Alvarado2, P. Méndez Patarroyo2, H. Groot de Restrepo1, and V. López Segura1. 1Human Genetics Laboratory, Universidad de Los Andes, Bogotá, Colombia; 2EAI-Reumavance Research Group, Hospital Fundación Santa Fe de Bogotá, Bogotá, Colombia.
Background: Autoimmune diseases are syndromes characterized by an immune response against self-antigens. They are complex pathologies associated with a variety of genes, but these do not fully explain all disorders. Ikaros is a transcription factor involves in lymphopoiesis and its involvement in development of hematologic tumors is well known. Ikaros has a high level of alternative splicing, therefore at least 10 isoforms are known. Among these, isoforms arising from non-canonical splicing due to insertions and deletions and dominant negative isoforms, that lack 2 to 4 zinc fingers of their DNA binding domain, theoretically lose their function.
Objective: In this study, we characterized the isoforms expression profile of Ikaros through of the interexonic regions quantification in patients diagnosed with Sjögren Syndrome, systemic lupus erythematosus, systemic sclerosis and rheumatoid arthritis.
Methods: Peripheral blood samples were obtained and RNA was extracted. A novel qRT-PCR design was carried out, where each interexonic region of Ikaros was amplified and non-canonical splicing was detected by melting dissociation curve analysis. REST 2009 2.0.13 software was used for relative quantification and statistical analysis was based on the Kruskal-Wallis, Dunn and Wilcoxon tests. The hierarchical clustering analysis was performed using Cluster 3.0 and Java Treeview 1.1.6r2 programs.
Results: The expression pattern of all Ikaros interexons in the control group has similar proportions, reflecting mainly the presence of complete functional isoforms. Patients with rheumatoid arthritis and Sjögren syndrome have a higher overall expression with an elevated quantity of dominant negative isoforms. Systemic lupus erythematosus patients have the least expression of functional isoforms present, proving the lack of Ikaros expression as a possible cause of the disease and not the imbalance of isoforms. Additionally, non-canonical splicing variants detected affect exons with DNA binding and dimerization domains. Patients and controls were clustered by the expression level of each interexonic region and the presence or absence of non-canonical splicing. Three groups could be distinguished: Rheumatoid arthritis like samples with the greater expression of Ikaros, control characterized by a homogeneous expression and systemic lupus erythematosus like samples with the least expression.
Conclusions: This is the first study conducted in Latin America that sought to determine the relationship between Ikaros and autoimmune diseases and the first description of Ikaros in patients with rheumatoid arthritis, Sjögren syndrome and systemic sclerosis. We also confirmed the alteration of Ikaros expression in systemic lupus erythematosus. The different patterns of expression in arthritis and lupus indicated that Ikaros could be considered a diagnosis biomarker.
COLLAGEN V/C57BL6 MOUSE MODEL: A NOVEL PRECLINICAL MODEL TO STUDY PATHOPHYSIOLOGY AND THERAPEUTIC APPROACHES IN SYSTEMIC SCLEROSIS
W. R. Teodoro1, A. P. P. Velosa2, Z. A. de J. Queiroz1, L. A. dos Santos1, S. Catanozi2, A. dos Santos Filho1, C. Bueno1, M. Vendramini1, S. M Fernezlian3, E. M. Eher3, F. D. T. Q. S. Lopes4, P. D. Sampaio-Barros1, and V. L. Capelozzi3. 1Division of Rheumatology; 2Division of Endocrinology; 3Department of Pathology; 4Laboratory of Experimental Therapeutics, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brasil.
Introduction: Experimental models are important instruments for a better understanding of the pathogenesis of systemic sclerosis (SSc) and can also propose new therapies for the disease.
Objective: In the present work, we aimed to characterize functional, serological and histopathological features of skin and pulmonary parenchyma in SSc patients and in type V collagen (COL V) immunized C57BL6 mice.
Methods: The histopathological patterns in skin and lung biopsies of 23 patients with SSc and five controls were assessed and compared to those of female C57BL/6 mice immunized with human COL V in Freund´s adjuvant. Mice were euthanized after 120 days and skin and lungs were examined by histology, immunofluorescence, immunohistochemistry, histomorphometry, qRT-PCR, ELISA and pulmonary mechanics.
Results: The serum of immunized mice presented antinuclear antibodies (ANA) and anti-collagen type III and IV autoantibodies, while the skin of immunized mice showed increase number of inflammatory cells and deposition of collagen type III and V (p<0.01) coincident with the increase of COL3A1, COL5A1 and COL5A2 gene expression. Skin biopsies of SSc patients showed fibrosis with abnormal dermal histoarchitecture and increased markers of α1(V) and α2(V) chains in the dermis and vessels (p<0.01). Interestingly, the lungs presented a high pulmonary resistance (p<0.01) and elasticy (p<0.01) by mechanic lung evaluation. Characteristic histologic features of lungs 120 days following COLV immunization were a non-specific interstitial pneumonia (NSIP) pattern combined with thickening of small and medium intrapulmonary arteries. Lungs from immunized mice also presented an increase of total collagen and type I collagen fibers (p<0.01), 4-hydroxyproline (p<0.01), CD4+ T lymphocytes (p<0.01), transforming growth factor beta (TGF-β) (p<0.01) and connective tissue growth factor (CTGF) (p<0.01). A significant increase sign of endothelial cell activity by vascular endothelial growth factor (p<0.01) and endothelin-1 (p=0.03) protein and genic expression was detected in thickened arteries, which also revealed elevated signs of endothelial apoptosis by caspase-3 expression (p<0.01). Lung biopsies of SSc patients without clinically evident pulmonary hypertension mimicked all features of IMU-COLV-NSIP, cutaneous and vascular histologic pattern and so demonstrated comparable vascular, inflammatory and fibrotic manifestations.
Conclusion: This experimental model demonstrated that all typical manifestations of SSc-related pulmonary and skin remodeling are mimicked by COLV immunized C57BL6 mice, which constitutes an appropriate preclinical model to study the mechanisms and therapeutic approaches of pulmonary and skin involvement in SSc.
METHOTREXATE-LOADED LIPID-CORE NANOCAPSULES PREVENTS JOINT SPACE NARROWING AND SYNOVITIS IN EXPERIMENTAL ARTHRITIS
A.L. Boechat1, C.P. Oliveira2, A.R.C. Barbosa1, R.M. Santos1, S.S. Guterres2, A.R. Pohlmann2, and O.T.F. Costa1. 1Universidade Federal do Amazonas, Manaus, Brasil; 2Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.
Background and Objective: Methotrexate-loaded lipid-core nanocapsules (MTX-LNC) is a new drug delivery formulation that is capable to concentrate the drug at inflamed sites, increasing its therapeutic effect and reducing collateral damage. The objective of this research was to evaluate this new MTX drug delivery formulation for reducing joint space narrowing and synovitis in experimental arthritis compared with conventional methotrexate (MTX).
Methods: The nanocapsules formulation was prepared by self-assembling methodology. The two lipid nanocapules formulations (LNC) were named (1) MTX-LNC, containing 0.250 mg/mL−1 of MTX, and (2) LNC, without MTX. The volume distribution for the nanocapsules formulations was MTX-LNC D [4,3] 264 and LNC D [4,3] 243. Adjuvant Arthritis was induced in Lewis rats. At experimental day 28th, the animals were sacrificed and the hind paws histologically processed to obtain serial sections. The tissue samples were analysed using quantitative morphometry methodology (stereology). For this purpose, the counting points method was applied for Cavalliere’s volume determination and the relative volume of joint components (Delesse). The evaluated structures were synovial space (volume) and synovial membrane (superficial area).
Results: The experimental results showed that MTX-LNC had a greater effect on arthritis than conventional MTX (p < 0.0001). The effect on reducing arthritis was observed earlier for MTX-LNC compared to MTX (p < 0.0001). When the hind paw structures were evaluated by quantitative morphometry, the arthritis group treated with MTX-LNC had a greater synovial space volume compared to the MTX- treated and arthritis groups (0.09 mm3, 0.04 mm3, 0.24 mm3, respectively; p < 0.0001). We also observed that MTX-LNC was able to reduce the synovial membrane superficial area compared with the arthritis and MTX-treated groups (22.61 mm2, 35.8 mm2, 29.35 mm2, respectively; p < 0.0001).
Conclusion: Taken together these data demonstrate that MTX-LNC not only reduces paw edema formation but also reduces synovitis and joint space narrowing more efficiently than conventional MTX.
KYNURENINE AS A NEW MOLECULAR MARKER FOR HIGH CARDIOVASCULAR RISK IN RHEUMATOID ARTHRITIS
A.L. Boechat1, N.O. Boechat1, M. Tavares1, V.C. Harraquian1, A.G. da Costa2, A.M. Tarragô1, R.O. dos Santos1, E.S. Lima1, A. Sadahiro1, and Pritesh Lalwani3. 1Universidade Federal do Amazonas, Manaus, Brasil; 2Universidade do Estado do Amazonas, Manaus, Brasil; 3Fundação Oswaldo Cruz, Manaus, Manaus, Brasil.
Objective: To evaluate the role of kynurenine (KYN) and inflammation markers in atherogenesis in RA patients.
Methods: Twenty-five RA patients were consecutively evaluated regarding their clinical variables and common carotid intima-media thickness (cIMT) and common carotid intima-media thickness (cIMT). In addition, KYN, tryptophan (TRP), Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Total Thiols, pro- and anti-inflammatory cytokines were quantified in patients’ serum. RA patients were then divided into cIMT < 0.9 mm or low- cardiovascular risk (CVR) and cIMT > 0.9 mm or high-CVR and compared with the above clinical and serological parameters.
Results: We observed an increased DAS28-CRP and HAQ score in high-CVR group compared to the low risk group. KYN (p = 0.0194) and KYN/TRP ratio (p = 0.0147) serum levels were significantly elevated in the high-risk patients. Furthermore, KYN and KYN/TRP ratios were significantly positively correlated with cIMT increase and KYN efficiently classified RA patients with high-risk profile (AUC = 0.81, p = 0.022), using ROC analysis. Additionally, distinct cytokine profile was observed for those patients with low cardiovascular risk (cIMT < 0.9 mm), showing a low proinflammatory cytokine levels and a high mean levels of T regulatory cell cytokines IL-10 and TGF-β1 (p = 0.004 and p = 0.019) indicating that they have a fully Treg response with a low inflammatory profile. On the other hand, high cardiovascular risk patients show a proinflammatory cytokine profile with high mean level of TNF-α (p = 0.015) and IL-6 (p = 0.015 and p = 0.031) with Th1/Th17 signature cytokines INF-γ (p = 0.024), IL-2 (p = 0.001), IL-17A (p = 0.034) and IL-23 (p = 0.031). No significant differences were founded for TOS and TAS or total serum thiols.
Conclusions: Increased inflammation is associated with increase in KYN and changes in the arterial walls, which subsequently increases cardiovascular disease risk in RA patients. Further studies are needed to understand the importance of these findings; however, we have demonstrated an immunological rationale for stratifying RA patients based on their cIMT measures as high or low cardiovascular risk.
RELATIVE EXPRESSION OF IFN-alpha BIOSYNTHETIC PATHWAY GENES IN PERIPHERAL BLOOD CELLS OF PATIENS WITH IgG4-RELATED DISEASE
C. Attallah1, H. Casafú2, L. Costa2, M. Oggero1, E. Fernández2, and S. Paira3. 1School of Biochemistry and Biological Sciences, UNL, CONICET. Santa Fe, Argentina; 2School of Medical Science, UNL. Santa Fe, Argentina; 3Rheumatology Section, JM Cullen Hospital. Santa Fe. Argentina.
Objectives: IgG4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition with characteristic histopathological findings in the organs involved. Although previous data have provided strong evidence that plasmacytoid dendritic cells (pDCs) activation and IFN-alpha production are prominent features of IgG4-related Type 1 Autoimmune Pancreatitis, IgG4-RD immunopathogenesis is scarcely known. The aim of this study was to evaluate the relative expression of IFN-alpha biosynthetic pathway genes in patients with different manifestations of IgG4-RD.
Methods: The study was conducted on 9 diagnosed IgG4-RD patients aged between 23-75 years (median 59.0 [IQR, interquartile range: 42.0, 61.50]), and 8 healthy subjects aged 27-70 years (median 46.5 [IQR 34.25, 60.25]). Patients were diagnosed according to the comprehensive diagnostic criteria for IgG4-RD (2011), resulting as definite (n = 7) and probable (n = 2). Written informed consent was obtained from all subjects. Patients were further sub-divided into two groups: group I included patients with mono-organic involvement (n = 1) and group II included patients with multi-organic involvement (n = 8). The treatment profiles of patients at the moment of blood sampling were as follows: non-treated (n = 2) and under treatment with: steroids (n = 1), steroids and methotrexate (n = 5), and steroids and azathioprine (n = 1).
TLR7, TLR9, IRF5, IRF7, Foxp3 and Fas gene expression were examined using the real-time reverse transcriptase polymerase chain reaction (RT-PCR). From total RNA of peripheral blood mononuclear cells the expression level was quantitated by real-time quantitative PCR (qPCR) and normalized with the values of the housekeeping control of the ?-actin gene. Relative gene expression was calculated using the comparative 2-??Ct method. A melting curve was done to increase the sensibility and specificity of the test.
Statistical analyses were performed using the nonparametric Mann-Whitney U test. Results were considered significant when the p value was less than 0.05. Statistical analyses were carried out using the Graph-Pad software (Prism).
Results: Neither the genes involved in IFN-alpha biosynthetic pathway (IRF5, IRF7, TLR7 and TLR9) nor the Fas or transcription factor Foxp3 showed differences in the relative expression of their transcripts between patients and healthy donors.
Conclusions: Although these results are preliminary due to the small number of patients studied, no differences were found in the gene expression of IFN-alpha biosynthetic pathway members. It is interesting to continue this study since innate immunity has been considered by other investigators as having a central role in the development of the disease.
ASSOCIATION BETWEEN URIC ACID TRANSPORTASOME POLYMORPHISMS AND GOUT RISK IN MEXICAN POPULATION
A. Francisco-Balderas1,2, J. F. Peralta-Aguilar1, E. O. Méndez-Salazar1, G. A. Martínez-Nava1, J. Fernández-Torres1,3, A. López-Reyes1, D. Garrido-Rodríguez4, C. F. Pérez-Beltrán5, L. Silveira-Torre5, and D. Clavijo-Cornejo1. 1Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, México City, México; 2Instituto Politécnico Nacional, México City, México; 3Universidad Autónoma Metropolitana, México City, México; 4Instituto Nacional de Enfermedades Respiratorias, México City, México; 5Instituto Nacional de Cardiología Ignacio Chávez, México City, México.
Background and Objective: Gout is a disorder characterized by arthritis caused by the deposition of monosodium urate crystals; its prevalence in Mexico is estimated to be of 0.3%. It is preceded by chronic hyperuricemia (UA) in serum (over 6.8 mg/dl). The renal urate excretion is carried out by a transport system named the UA transportasome; it is known that single nucleotide polymorphisms (SNP) in this system are related to the development of gout. Therefore, this study aimed at evaluating the association between transportasome gene polymorphisms and gout susceptibility in the Mexican population.
Methods: A total of 41 SNP of transportasome and 11 ancestry-informative markers were genotyped using TaqMan probes in a Quant Studio 12 k Flex instrument (Applied Biosystems). We examined 62 gout cases diagnosed according to the ACR/EULAR criteria, 23 individuals with asymptomatic hyperuricemia (AH) and 165 healthy individuals. The allelic discrimination and ancestry analysis were carried out using the TaqMan genotyper and STRUCTURE1.2.1 software, respectively. To assess the associations between the genetic variants and gout as well as AH state, we calculated odds ratios (ORs) with 95% confidence intervals by multinomial logistic regression models. To assess the association between SNP and UA serum levels and gout, we performed lineal regression models, both analyses adjusted by clinical parameters (age, body mass index, gender and ancestry) in STATA v.14 software.
Results: Seven SNPs of six different genes were associated with gout. ABCG2 rs2231142 (T) and BCAS3 rs2079742 (C) minor alleles were associated positively (OR = 3.48, p < 0.01 and OR = 3.02, p < 0.01; respectively). A significantly declined risk for gout was found in the carriers of the minor allele of ATXN2 rs653178 (C allele OR = 0.44 p = 0.047) and SFMBT1 rs6770152 (G allele OR = 0.42 p < 0.01) SNP. Despite that, we did not observe a significant association between the diagnosis of gout and the minor allele of GCKR rs780094 and rs1260326, OVOL rs642803 and PRKG2 rs10033237 SNP; these showed a significant association when examined by genotype in a co-dominant inheritance model. SNPs related to glomerular filtration process, UBE2Q2 rs1394125 and INHBC rs3741414, presented a positive association with AH state (A allele OR = 4.25, p = 0.005; T allele OR = 2.45, p = 0.04; respectively); however, they were not significantly associated with gout. The intergenic variant rs17786744 (OR = 0.312 p = 0.005) minor allele (G) was negatively associated with AH. The lineal regression shows that ABCG2 rs2231142 SNP had a significantly estimated average difference in UA serum levels.
Conclusions: These data suggest that SNPs in the transportasoma are genetic risk factors for gout and AH state. In this Mexican population, ABCG2 rs2231142 SNP showed the most consistent results and could prove to be a useful genetic susceptibility marker for gout and to identify individuals at high risk of developing it. Larger sample size studies are required before drawing definitive conclusions.
PARTICIPATION OF ANTIMICROBIAL PEPTIDES (AMPS) IN THE PHYSIOPATHOGENESIS OF JOINT DAMAGE MEDIATED BY METALLOPROTEINASES (MMPS) IN ARTHRITIS INDUCED BY TYPE II COLLAGEN
G. Méndez1, S. Godina2, R. González3, D.P. Portales4, J.A. Enciso1, and M.H. García1. 1Unit of Biomedical Research of Zacatecas, IMSS, Zacatecas, México; 2Autonomus University of Zacatecas, UAZ, Zacatecas, México; 3Center of Applied Research in Health and Biomedicine, San Luis Potosí, México; 4Autonomus University of San Luís Potosí, UASLP, San Luis Potosí, México.
Introduction: Antimicrobial peptides (AMPs) are molecules with antimicrobial activity; however, they are also able to modulate different cellular activities such as secretion of metalloproteinases (MMPs), cytokines and different processes like T cell chemotaxis and monocytes. It has been reported that AMPs may have inflammatory or anti-inflammatory activity depending on the type of receptor with which they interact, the type of cell, and the inflammatory environment in which they are found. In chronic inflammatory diseases such as rheumatoid arthritis (RA), increased levels of AMPs have been observed and have been positively associated with the presence of bone erosions. Moreover, in type II collagen-induced arthritis (CIA) different phases have been described, in which different cytokines and receptors are present. In this study we determined the expression of AMPs, rCRAMP, mBD-3, mBD-4 and MMP-3 during the progression of CIA, with the purpose of associating their expression levels with the histopathological changes of the different phases of CIA.
Objective: The aim of this study was to evaluate the expression of AMPs, rCRAMP, mBD-3, mBD-4 as well as MMP-3 during the development and progression of CIA and examine the association of these with parameters of cellular infiltration and cartilage loss.
Methodology: CIA was induced by type II collagen and complete Freund's adjuvant in DBA1/J mice. Clinical severity was assessed using a scoring system, according to this score the joints were classified as onset, peak and remission CIA phases. After the animals were sacrificed, the joints were dissected, and histological sections were prepared, stained with hematoxylin-eosin (H & E) and safranin O, respectively. Detection of the peptides rCRAMP, mBD-3, mBD-4 as well as MMP-3, was carried out by immunohistochemistry.
Results: Cell infiltration was found to be increased in the peak and remission phases, as was the degradation of cartilage. MMP-3 expression increased in the peak phase and was localized in infiltrated cells. CRAMP expression is constitutively present and increased in the peak and remission phases; in addition, it was associated with cellular infiltration, cartilage degradation and MMP-3 expression. The expression of mBD4 showed a tendency to increase in infiltrated cells and synovial membrane in the peak phase, this showed a positive association with cellular infiltration. AMP mBD3 showed low expression in all phases.
Conclusions: These results suggest that the antimicrobial peptide CRAMP is associated with the development and progression of CIA.
LEVELS OF TRANSFORMING GROWTH FACTOR BETA ISOFORMS (TGF-B1, TGF-B2, TGF-B3) IN SYSTEMIC SCLEROSIS
R.A. Carranza- Muleiro1,2, L. Manuel-Apolinar3, I.M. Arciniega Martínez1, A.A. Reséndiz-Albor1, E.J. Rodríguez-Rodríguez1, M.A. Martínez-Bencomo4, M.P. Jimenez-Arellano6, J. Martínez-Varillas6, T. Pérez-Capistran1, D. Martínez-Rodríguez1, G. García-Collinot1, G. Medina2, J. Jara-Quezada2, and M.P. Cruz-Domínguez2. 1Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional IPN). México City; 2Hospital de Especialidades Centro Medico la Raza, Instituto Mexicano del Seguro Social. México City; 3UMAE Unidad de Enfermedades endocrinológicas y metabólicas, HECM Siglo XXI Instituto Mexicano del Seguro Social, México City; 4Universidad Nacional Autónoma de México (UNAM), México, México; 6. Universida Veracruzana (UV), Xalapa, Veracruz.
Background and Objectives: Systemic sclerosis (SSc) or scleroderma is a chronic, progressive, autoimmune and rheumatologic disease which has three hallmarks: fibrosis, small vessel vasculopathy and aberrant immune responses. Transforming growth factor beta (TGF-β) is a pleiotropic and essential cytokine of human survival with both autocrine and paracrine effects. TGF-β1 is a cytokine that orchestrates the fibrotic changes in systemic sclerosis (SSc), but the role of TGF-β2 and TGF-β3 has not been well studied.
The aim of our study was to compare levels of TGF-β1, TGF-β2 and TGF-β3 between SSc and healthy controls (HC), and the possible correlation between clinical and biochemical parameters in these patients.
Methods: We performed a cross-sectional study in fifty-eight patients out of a cohort of 126 individuals with SSc, at the Hospital de Especialidades Centro Médico Nacional La Raza, México City, according to the criteria of ACR/EULAR 2013 of SSc, and 24 apparently healthy volunteers. The study was approved by the ethics local committee. Written informed consent was obtained from each subject. TGF-β isoforms (TGF-β1, TGF-β2 and TGF-β3) concentrations in serum were determined by specific ELISA kits. Statistical analysis was performed using the software Statistical Package for the Social Sciences (SPSS) version 21.0 (SPSS Inc., Chicago, IL, USA), and Graph Pad Prism 6.0 (GraphPad Software Inc., San Diego, CA) statistical program. To compare HC vs SSc, HC vs lSSc, HC vs dSSc, and lSSc vs dSSc TGF-β isoforms serum levels, the Mann-Withney U tests was used. To analyze the relationship between TGF-β isoforms and serum biomarkers or clinical findings we use Spearman’s correlation coefficients. A p value ≤ 0.05 was considered statistically significant.
Results: We studied 56 females of 52 ± 11 years of age, and 2 males of 39 and 55 years of age. Twenty-two female volunteers of 51 ± 7 years of age, and 2 males 39 and 46 years of age were also studied. Level of TGF-β1 was 36.95 ± 15.28 ng/mL (0.015-67.67), TGF-β2 was 98.65 (0.015-40.01 ng/mL), TGF-β3 was 0.015 (0.015-14.069 ng/mL). We found the mean levels of TGF-β1 to be higher in the SSc patients than in the HC (37.45 vs 17.91 ng/mL, p = 0.0001**); by subtype the levels were also higher in the lSSc vs the HC (37.62 vs 17.91 ng/mL, p = 0.0001**) and in the dSSc vs the HC (17.91 vs 36.28 ng/mL, p = 0.0001**). For TGF-β2, the levels were also higher in the SSc patients than in the HC (9.86 vs 1.87 ng/mL, p = 0.0058*), independently of subtype lSSc vs. HC (9.89 vs 1.87 ng/mL, p = 0.0025*) and dSSc vs HC (9.83 vs 1.87 ng/mL, p = 0.0052*). However, TGF-β3 was similar between groups HC vs SSc (0.0015 vs 0.0025 ng/mL). TGF-β2 showed correlation with nitric oxide (r-0.360; p = 0.046*) and TGF-β3 with osteonectin (r 0.421; p = 0.044*) but not with other biochemical parameters.
Discussion: Fibrosis is a major player in SSc pathogenesis. We found TGF-β1 to be increased in SSc similar to other studies, recognizing their regulatory role in this disease but not as a biomarker of clinical disease. We found also TGF-β2 elevation in SSc in inverse correlation with nitric oxide that suggest the possibility to be regulatory of vascular reactivity and fibrosis opening the field for future studies. TGF-β3 levels seems to be of a minor relevance in SSc.
Conclusion: TGF-β1 and TGF-β2 superfamily proteins isoforms are significantly increased in SSc confirming the findings of other authors; we also found isoform TGF-β2 increased in inverse relationship with nitric oxide suggesting its possibly role on vascular dysfunction that need to be investigated.
NON-PROTOCOLIZED RE-BIOPSY IN PATIENTS WITH ANCA-ASSOCIATED GLOMERULONEPHRITIS: IS IT NECESSARY?
V. Scaglioni1, M. Scolnik1, FS. Pierini1, L.J. Catoggio1, S.B. Christiansen1, C.F. Varela1, G. Greloni1, G. Rosa-Diez1, and E.R. Soriano1. 1Hospital Italiano de Buenos Aires. Buenos Aires. Argentina.
Background/Objective: Non-protocolized repeat renal biopsies are rarely performed in ANCA glomerulonephritis (GN). Their role in predicting long term renal outcomes and aiding in clinical decisions have not been examined in detail. The aim of this study was to evaluate the usefulness of renal re-biopsy in patients with ANCA GN in treatment decisions.
Methods: We included all patients with biopsy-proven ANCA GN: granulomatosis with polyangiitis (GPA), granulomatosis with polyangiitis and eosinophilia (GPAE), microscopic polyangiitis (MPA) and renal-limited vasculitis (RLV) between January 2002 and May 2017. We examined patient’s baseline characteristics, induction and maintenance treatments, renal response after induction and time to renal relapse/rebiopsy. The histology of re-biopsies was reviewed and correlation with clinical findings (hematuria) and first biopsy histology was examined. Histological classification was made according to 2010 classification criteria for ANCA glomerulonephritis. Data of physicians' decisions after re-biopsy were collected.
Results: 60 patients (77% females) were included. Of those, 15 (25%) underwent renal re-biopsy during the follow up based on clinical manifestations. Mean time until re-biopsy was 38.4 months (SD 20.4). In the re-biopsy group, 73% of patients had new onset hematuria vs. 7.5% in the no-rebiopsy group. New onset or worsening proteinuria was present in 73% of patients in the re-biopsy group (40% and 33%, respectively) vs. only 2.5% in the no-rebiopsy group. Decline in the GFR was present in 60% of patients in the re-biopsy group vs. 2.5% in the other. When examining the histological changes in the repeat biopsy we did not find a correlation between active lesions (crescents, necrosis etc.) and hematuria. All patients that underwent repeat biopsy were considered to be active but renal histology showed progression in terms of chronicity and rare active histological lesions (Table 1). Despite this lower percentage of active lesions, in 67% of patients, physicians made a treatment change, initiating a new induction therapy regimen and achieving renal response in 85% of patients.
Conclusions: Renal histology in repeat biopsies did not show active lesions justifying clinical renal manifestations that lead to re-biopsy. Despite this, physicians made a change in treatment in the majority of cases after re-biopsy. Patients who presented with new onset hematuria, proteinuria and worsening in the GFR had a good response to this new induction treatment achieving renal laboratory remission in 85% of patients. Role of histological findings in rebiopsies needs to be further examined.
AUTOIMMUNE INTERSTITIAL LUNG DISEASE IN LATIN AMERICA. RESULTS OF THE EPIMAR COHORT STUDY
F. Vivero1, F. Campins1, S. Babini1, P Malfante1, D. Lancellotti1, E. Gandara1, J. Sebastiani1, V. Basso1, and J. Enghelmayer2. 1Hospital Privado de Comunidad, Mar del Plata, Argentina; 2Hospital de Clinicas, Buenos Aires, Argentina.
Objectives: Autoimmune (Ai) interstitial lung diseases (ILD) represents a specific subgroup of ILD, for which information about prognosis and natural history is lacking. The objective of this study was to evaluate the characteristics and course of patients treated for AI-ILD.
Methods: We conducted a multicenter cohort study in 39 centers from Argentina, Colombia and Uruguay between January 2015 and July 2017. Patients were included if they were diagnosed with AI-ILD by a multidisciplinary team as suggested by current reviews. Patients were classified in the following sub-groups: ILD associated tissue connective disease (ILD-CTD), interstitial pneumonia with autoimmune features (IPAF) and ANCA-associated ILD (ILD-ANCA). All images were reviewed by a blinded board-certified radiologist.
Results: Among the 223 patients included during the study period, 166 (74%) were women. Mean age was 60 years (SD 14). One-hundred and eighty-nine (85%) patients were classified as ILD-CTD (rheumatoid arthritis 32%, systemic sclerosis 27%, dermatomyositis 14%). Sixteen patients were classified as IPAF and 8 as ILD-ANCA. The mean time between the diagnosis of CTD and ILD was 3.3 years. Antinuclear antibodies (52%) were the most frequent autoantibodies followed as rheumatoid factor (36%), anti-Ro (21%) and anti-cyclic citrullinated peptide (21%). Fifty-three percent of patients showed slight restriction at moment of diagnosis. The most common treatment strategy was the combination of steroids and cyclophosphamide (23%) or azathioprine (16%).
Conclusions: To the best of our knowledge, this is the first study to evaluate the characteristics and treatment strategies used in patients affected by AI-ILD in Latin-America. Future studies should evaluate the impact of current treatment strategies in the outcome of AI-ILD.
PREVALENCE OF HYPOVITAMINOSIS D IN ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOUS AND ITS RELATIONSHIP WITH SLEDAI-2K COMPONENTS IN PATIENTS TREATED IN TWO RHEUMATOLOGY SERVICES, BOGOTA 2017
R.A. Guzman1, L.G. Piñeros2, J. Ga