Search

Background: Evidence on abatacept (ABA) utility for rheumatoid arthritis (RA) - associated interstitial lung disease (ILD) is growing. Clinical trials have shown equivalence in subcutaneous (SC) and intravenous (IV) administration of ABA for articular manifestations. However, this has not been studied in respiratory outcomes., Objective: To compare the effectiveness of ABA in RA-ILD patients according to the route of administration., Methods: National retrospective multicentre study of RA-ILD patients on treatment with ABA. They were divided into 2 groups: a) IV, and b) SC. The following outcomes were analysed from baseline to final follow-up using linear mixed models: a) forced vital capacity (FVC), b) diffusing capacity of the lungs for carbon monoxide (DLCO), c) chest high resolution computed tomography (HRCT), d) dyspnoea, e) RA activity, and f) sparing corticosteroids effect., Results: A total of 397 patients were included (94 IV-ABA and 303 SC-ABA), median follow-up of 24 [10-48] months. After adjustment for possible confounders, FVC and DLCO remained stable during the first 24 months without differences between IV-ABA and SC-ABA (p = 0.6304 and 0.5337). Improvement/ stability of lung lesions in HRCT was observed in 67 % of patients (75 % IV-ABA, 64 % SC-ABA; p = 0.07). Dyspnoea stabilized/ improved in 84 % of patients (90 % IV-ABA, 82 % SC-ABA; p = 0.09). RA - disease activity improved in both groups. No statistically significant differences regarding any of the variables studied between the two groups were found. ABA was withdrawn in 87 patients (21.9 %), 45 % IV-ABA and 37 % SC-ABA (p = 0.29). ILD worsening and articular inefficacy were the most common reasons for ABA discontinuation., Conclusion: In patients with RA-ILD, ABA seems to be equally effective regardless of the route of administration., Competing Interests: Declaration of competing interest Disclosures that may be interpreted as constituting of possible conflict(s) of interest for the study: B. A.-M. received grants/research supports from Abbvie and Roche and had consultation fees/participation in company-sponsored speaker´s bureau from Pfizer, Celgene, Novartis, Sanofi, Janssen, UCB and Lilly, outside the submitted work; N.V.-R. has received fees in company-sponsored speaker's bureau and research supports from AbbVie, Lilly, Celgene, Grünenthal, UCB Pharma, Nordic Pharma, MSD and Rubió; L.C.D.-C has received research supports and participation in company-sponsored speaker's bureau from Abbvie, Janssen, Lilly and Celgene; J.L.M has received fees in company-sponsored speaker's bureau from Boehringer Ingelheim, Bristol-Myers Squibb (BMS) and Galapagos and had consultation fees from Boehringer Ingelheim; G.B has received fees in company-sponsored speaker's bureau from Bristol-Myers Squibb (BMS); A.U.-A. has received grants/research supports from Abbvie, Galápagos, Novartis, GSK, Astrazeneca, Janssen, Pfizer and Amgen; C.F.-D. has received fees in company-sponsored speaker's bureau from: Janssen, Galápagos, Amgen, Bristol Myers Squibb (BMS); I. F.-A. has received grants/research supports from Abbott, MSD, Janssen, and Roche, as well as consultation fees from company sponsored speakers bureaus associated with Abbott, Pfizer, Roche, Sanofi, Celgene, and MSD; S.C. has received research supports from MSD and Pfizer and had consultation fees/participation in company-sponsored speaker's bureau from Amgen, BMS, Eli-Lilly, MSD, Roche, and UCB. S. C. is also assistant professor of the cátedra EPID-Future, funded by UAM-Roche, Universidad Autónoma de Madrid (UAM), Spain; R. B. received grants/research support from AbbVie, MSD, and Roche, and had consultation fees/participation in a company-sponsored speaker's bureau from AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, and MSD. The rest of the authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The macrophage migration inhibitory factor (MIF) plays a pivotal role in the development of rheumatoid arthritis (RA). Previous research indicates that MIF can trigger the expression of cytokine profiles associated with Th1, Th2, and Th17 responses in peripheral blood mononuclear cells (PBMC) from both RA patients and control subjects (CS). Despite these, few studies to date precisely elucidate the molecular mechanisms involved. The present study aimed to associate the expression of Th differentiation TF (T-bet, GATA-3, RORγt) with MIF receptors (CD44, CD74, CXCR2, 4, 7) and Th1, Th2, and Th17 cytokines in PBMC from CS and RA patients., Method: PBMC from both groups was cultured for 24 h. The expression of the canonical and non-canonical MIF receptors and the TF was determined by flow cytometry. Additionally, multiplex bead analysis was employed to assess the levels of cytokines in the culture supernatants. The findings revealed that T CD4+ lymphocytes in the CS group exhibited a heightened expression of CD74 (p<0.05), whereas RA patients displayed an elevated expression of CXCR7 (p<0.001). Furthermore, T CD4+ lymphocytes from RA patients exhibited greater expression of GATA3, RORγt, and FOXP3, along with elevated levels of pro-inflammatory cytokines compared to the CS group (p<0.001)., Result: These results indicate that CD74 is more prominently expressed in PBMC from the CS group, whereas CXCR7 is more expressed in PBMC from RA patients., Conclusion: We also noted an increased secretion of Th17 profile cytokines in RA, potentially influenced by the activation of FOXP3 via CD74 and RORγt through CXCR7 using the endocytic pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: The aim of this study is to evaluate risk factors for severe coronavirus disease 2019 (COVID-19) in patients with immune-mediated rheumatic diseases, stratified by systemic autoimmune conditions and chronic inflammatory arthritis., Methods: An observational, cross-sectional multicentre study was performed. Patients from 10 rheumatology departments in Madrid who presented with severe acute respiratory syndrome coronavirus-2 infection between February 2020 and May 2021 were included. The main outcome was COVID-19 severity (hospital admission or mortality). Risk factors for severity were estimated, adjusting for covariates (socio-demographic, clinical, and treatments), using logistic regression analyses., Results: In total, 523 patients with COVID-19 were included, among whom 192 (35.6%) patients required hospital admission and 38 (7.3%) died. Male gender, older age, and comorbidities such as diabetes mellitus, hypertension, and obesity were associated with severe COVID-19. Corticosteroid doses >10 mg/day, rituximab, sulfasalazine, and mycophenolate use, were independently associated with worse outcomes. COVID-19 severity decreased over the different pandemic waves. Mortality was higher in the systemic autoimmune conditions (univariate analysis, P < .001), although there were no differences in the overall severity in the multivariate analysis., Conclusions: This study confirms and provides new insights regarding the harmful effects of corticosteroids, rituximab, and other therapies (mycophenolate and sulfasalazine) in COVID-19. Methotrexate and anti-tumour necrosis factor therapy were not associated with worse outcomes., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease which has shown positive correlations between negative psychological variables and disease activity in transversal studies and in the follow-up. However, the association of positive psychological variables with disease parameters including disease activity (DAS-28), functional disability (HAQ) and erythrocyte sedimentation rate (ESR) has not been investigated. Patients with RA attending the external consultation of a third level hospital were invited to participate and fill in a questionnaire with personal, disease and psychological variables; body mass index was also obtained as well as ESR. A total of 49 patients were included. The three dependent variables correlated among them, with the highest correlation for DAS-28 and HAQ (r=0.645, p<0.01), followed by somatization and HAQ (r=0.614, p<0.01) or DAS-28 (r=0.537, P<0.01). In addition, HAQ showed negative correlations with environmental mastery (r=- 0.366, p<0.01), personal growth (r=-0.292, p<0.05) and monthly extra money (r=-0.328, p<0.05), and borderline negative correlations with emotion perception (r=-0.279, p=0.053) and self-acceptance (r=-0.250, p=0.08). ESR showed a significant negative correlation with emotion perception (r=-0.475, p<0.01). In conclusion, we observed important correlations of positive psychological variables with disease activity, functional disability and ESR that could be addressed in order to prevent or treat these disease features.

Objective: To develop a joint proposal for screening criteria of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and vice versa, which serves as a guidelines in patient referral between the Rheumatology and Pneumology departments to early detection of these patients., Methods: A systematic literature review was carried out on the risk factors for the development of ILD in RA patients, and for the referral criteria to Rheumatology for suspected early RA. Based on the available evidence, screening criteria were agreed using the Delphi method by a panel of pneumologists and rheumatologists with expertise in these pathologies., Results: Screening criteria for ILD in patients with RA and for the early detection of RA in cases with ILD of unknown etiology have been developed. In both cases, a detection strategy was based on clinical risk factors. Recommendations also included the complementary tests to be carried out in the different clinical scenarios and on the periodicity that screening should be repeated., Conclusion: A selective screening strategy is recommended for the first time in the early diagnosis of patients with ILD-RA. This multidisciplinary proposal aims to solve some common clinical questions and help decision-making, although its usefulness to identify these patients with good sensitivity must be confirmed in a validation study., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Objective: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD)., Methods: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made., Results: Six PICO questions were selected, three of which analysed the safety and effectiveness of glucocorticoids, classical synthetic disease-modifying anti-rheumatic drugs (DMARDs) and other immunosuppressants, biological agents, targeted synthetic DMARDs, and antifibrotic therapies in the treatment of this complication. A total of 12 recommendations were formulated based on the evidence found and/or expert consensus., Conclusions: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions, reduce clinical healthcare variability, and facilitate decision-making for patients., (Copyright © 2022 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Objective: To develop multidisciplinary recommendations to improve the management of rheumatoid arthritis-related interstitial lung disease (RA-ILD)., Methods: Clinical research questions relevant to the objective of the document were identified by a panel of rheumatologists and pneumologists selected based on their experience in the field. Systematic reviews of the available evidence were conducted, and evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) criteria. Specific recommendations were made., Results: Six PICO questions were selected, three of which analysed the incidence and prevalence of RA-ILD, associated risk factors, and predictors of progression and mortality. A total of 6 specific recommendations on these topics, structured by question, were formulated based on the evidence found and/or expert consensus., Conclusions: We present the first official SER-SEPAR document with specific recommendations for RA-ILD management developed to resolve some common clinical questions and facilitate decision-making for patients., (Copyright © 2022 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Objective: To assess the efficacy and safety of abatacept (ABA) in monotherapy (ABAMONO) vs combined ABA [ABA plus MTX (ABAMTX) or ABA plus non-MTX conventional synthetic DMARDs (csDMARDs) (ABANON-MTX)] in RA patients with interstitial lung disease (ILD) (RA-ILD)., Methods: This was a restrospective multicentre study of RA-ILD Caucasian patients treated with ABA. We analysed in the three groups (ABAMONO, ABAMTX, ABANON-MTX) the following outcome variables: (i) dyspnoea; (ii) forced vital capacity (FVC) and diffusion capacity of the lung for the carbon monoxide (DLCO); (iii) chest high-resolution CT (HRCT); (iv) DAS28-ESR; (v) CS-sparing effect; and (vi) ABA retention and side-effects. Differences between basal and final follow-up were evaluated. Multivariable linear regression was used to assess the differences between the three groups., Results: We studied 263 RA-ILD patients (mean ± s.d. age 64.6 ± 10 years) [ABAMONO (n = 111), ABAMTX (n = 46) and ABANON-MTX (n = 106)]. At baseline, ABAMONO patients were older (67 ± 10 years) and took higher prednisone dose [10 (interquartile range 5-15) mg/day]. At that time, there were no statistically significant differences in sex, seropositivity, ILD patterns, FVC and DLCO, or disease duration. Following treatment, in all groups, most patients experienced stabilization or improvement in FVC, DLCO, dyspnoea and chest HRCT as well as improvement in DAS28-ESR. A statistically significant difference between basal and final follow-up was only found in CS-sparing effect in the group on combined ABA (ABAMTX or ABANON-MTX). However, in the multivariable analysis, there were no differences in any outcome variables between the three groups., Conclusion: In Caucasian individuals with RA-ILD, ABA in monotherapy or combined with MTX or with other conventional-DMARDs seems to be equally effective and safe. However, a CS-sparing effect is only observed with combined ABA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To determine cardiovascular (CV) mortality and incidence of the first CV event (CVE) in patients with chronic inflammatory rheumatic diseases (CIRD) after 5 years of follow-up., Methods: This is an analysis of the CARdiovascular in rheMAatology (CARMA) study after 5 years of follow-up. It includes patients with RA (n = 775), AS (n = 738) and PsA (n = 721), and individuals without CIRD (n = 677) attending outpatient rheumatology clinics from 67 public hospitals in Spain. Descriptive analyses were performed for the CV mortality at 5 years. The Systematic COronary Risk Evaluation (SCORE) function at 5 years was calculated to determine the expected risk of CV mortality. Poisson models were used to estimate the incidence rates of the first CVE. Hazard ratios of the risk factors involved in the development of the first CVE were evaluated using the Weibull proportional hazard model., Results: Overall, 2382 subjects completed the follow-up visit at 5 years. Fifteen patients died due to CVE. CV deaths observed in the CIRD cohort were lower than that predicted by SCORE risk charts. The highest incidence rate of CVE [7.39 cases per 1000 person-years (95% CI 4.63, 11.18)] was found in PsA patients. However, after adjusting for age, sex and CV risk factors, AS was the inflammatory disease more commonly associated with CVE at 5 years [hazard ratio 4.60 (P =0.02)], compared with those without CIRD., Conclusions: Cardiovascular mortality in patients with CIRD at 5 years of follow-up is lower than estimated. Patients with AS have a higher risk of developing a first CVE after 5 years of follow-up., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: TNF inhibitors (TNFis) are widely used for the treatment of rheumatoid arthritis (RA), although the response rates to this therapy in patients with RA remains heterogeneous and < 50% achieve remission (REM). Objective: To analyze baseline peripheral blood leukocytes profiles in order to search for biomarkers identifying patients who will most likely not achieve REM under TNFi treatment. Methods: A prospective bi-center pilot study including 98 RA patients treated with TNFis and followed-up during 6 months. Patients were classified according to DAS28 as follows: those who achieved REM (DAS28 ≤ 2.6) and those who did not (DAS28 > 2.6) at 6 months after starting TNFis. These rates were also assessed by simplified disease activity index (SDAI ≤ 3.3 and SDAI > 3.3, respectively). Peripheral blood immune cells were studied by flow cytometry before treatment initiation. Results: At 6 months, 61 or 80% of patients did not achieve REM by DAS28 or SDAI, respectively. Basal leukocyte profiles differed between REM vs. non-REM patients. Non-REM patients showed lower percentages of total and naïve B cells at baseline than REM subjects. A B lymphocyte/CD4+ lymphocyte ratio (BL/CD4 ratio) <0.2 clearly associated with a higher probability of non-REM status based on DAS28 at 6 months (OR = 9.2, p = 0.006). These data were confirmed when patient response was evaluated by SDAI index. Conclusion: Our results strongly suggest that BL/CD4 ratio could be considered as a useful biomarker for the early identification of non-remitters to TNFi in clinical practice., (Copyright © 2020 Rodríguez-Martín, Nieto-Gañán, Hernández-Breijo, Sobrino, García-Hoz, Bachiller, Martínez-Feito, Navarro-Compán, Lapuente-Suanzes, Bonilla, Pascual-Salcedo, Roy, Jurado, Nozal, Vázquez-Díaz, Balsa, Villar and Plasencia-Rodríguez.)

Peficitinib hydrobromide is a small Janus kinase inhibitor (JAK1, JAK2, JAK3 and TYK2) molecule for the treatment of rheumatoid arthritis (RA). Phase II and phase III clinical trials and extension studies with different doses have been conducted to assess the drug's efficacy and safety with substantially improved outcomes observed in RA. This JAK inhibitor oral drug demonstrated clinical response as once-daily monotherapy in patients with moderate to severe RA, also in combination with methotrexate (MTX), who had an inadequate response to MTX. The findings from studies of this new JAK inhibitor have shown that, both in monotherapy as well as in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), it has efficacy, safety and tolerability in RA patients., (Copyright 2020 Clarivate Analytics.)

PTPN22 represents an important non-HLA gene that has been strongly associated with rheumatoid arthritis (RA) pathogenesis. Several studies have reported a specific genetic variant for PTPN22 (+788 G>A; rs33996649) that might be associated with decreased RA risk in Caucasian population; nevertheless, its specific role in western Mexican population has not been yet described. A case-control study with 443 RA patients and 317 control subjects (CS) was conducted. The genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique and the PTPN22 mRNA expression was determined by SYBR Green-based real-time quantitative-PCR assay. No association between the PTPN22 +788 G>A polymorphism and RA susceptibility in western Mexican population was found when comparing genotype and allelic frequencies between RA patients and CS (G/G vs. G/A: OR 0.55, p = 0.14, 95% CI 0.22-1.32; G vs. A: OR 0.56, p = 0.14, 95% CI 0.23-1.36). The PTPN22 mRNA expression increased 4.6-fold more in RA patients than in CS, and RA patients, carriers of PTPN22 +788 G/A genotype, expressed 15.6-fold more than RA patients carrying the homozygous G/G genotype. Overall, these results showed that the PTPN22 +788 G>A polymorphism is not associated with RA susceptibility in western Mexican population, whereas the presence of G/A genotype is associated with increased PTPN22 mRNA expression in RA patients.

Objective: Interstitial lung disease (ILD) is one of the most serious complications of rheumatoid arthritis (RA). In the present study, we aimed to assess the efficacy of abatacept (ABA) in patients with ILD associated to RA., Methods: National multicenter, non-controlled, open-label registry study of RA patients with ILD treated with ABA., Results: 63 patients (36 women) with RA-associated ILD undergoing ABA therapy were studied. The mean ± standard deviation age at the time of the study was 63.2 ± 9.8 years. The median duration of RA and ILD from diagnosis were 6.8 and 1 year, respectively. RA was seropositive in 55 patients (87.3%). In 15 (23.8%) of 63 patients the development of ILD was closely related to the administration of synthetic or biologic disease modifying anti-rheumatic drugs. After a follow-up of 9.4 ± 3.2 months, two-thirds of patients remained stable whereas one-quarter experienced improvement in the Modified Medical Research Council scale. At that time forced vital capacity remained stable in almost two-thirds of patents and improved in one out of five patients assessed. Also, diffusing capacity of the lung for carbon monoxide remained stable in almost two-thirds and showed improvement in a quarter of the patients assessed. At 12 months, 50% of the 22 patients in whom chest HRCT scan was performed due persistence of respiratory symptoms showed stabilization, 8 (36.4%) improvement and 3 worsening of the HRCT scan pattern. Eleven of 63 patients had to discontinue ABA, mainly due to adverse events., Conclusion: ABA appears to be an effective in RA-associated ILD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and pro-inflammatory cytokines production. IL-1Ra is an anti-inflammatory cytokine codified by IL1RN gene that blocks IL-1 signalling. A VNTR polymorphism of 86 bp in IL1RN gene has been associated with RA risk and regulation of IL-1Ra expression. In this study, we determined mRNA and protein expression of IL-1Ra in RA patients and control subjects (CS). This study included 85 RA patients classified according to the ACR/EULAR 2010 criteria and 67 CS. Polymerase chain reaction was used to identify IL1RN VNTR polymorphism, the expression of sIL-1Ra (secreted isoform) mRNA was determined by SYBR Green-based real time quantitave-PCR assay, and IL-1Ra soluble levels quantification was evaluated by ELISA test. RA patients had higher soluble levels of IL-1Ra than CS (p < .01), sIL-1Ra mRNA expression was higher in RA patients compared to CS (p < .01). Carriers of IL1RN*2/2 homozygous genotype show increased IL-1Ra soluble levels compared to IL1RN*long/long and IL1RN*2/long genotypes (p < .05) in the CS group, whereas mRNA expression in carriers of IL1RN*2/2 genotype was 1.2 times higher compared to IL1RN*long/long genotypes in the same group. Regarding RA patients, high expression of sIL-1Ra mRNA on carriers of IL1RN*long/long genotype was observed. Nevertheless, in RA patients IL-1Ra soluble levels among genotypes did not show significant differences. High expression of IL-1Ra in RA patients under treatment or not with antirheumatic drugs was detected. Additionally, carriers of IL1RN*2/2 genotype had higher IL-1Ra expression than carriers of other genotypes.

Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions -1082, -819 and -592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. Several studies have reported a variable number of tandem repeat (VNTR) 86 bp (rs2234663) in the intron 2 of IL1RN gene with RA risk. The present study was designed to determine the frequencies of this polymorphism in patients with RA and control subjects (CS) and its association with RA in a western Mexican population. An analytical cross-sectional study was performed, in which 350 patients with RA and 307 CS were included. The identification of IL1RN VNTR polymorphism was carried out by polymerase chain reaction (PCR), and genotypes were associated with clinical variables (DAS28 and CRP). The presence of A1/A2 genotype was associated with RA risk (p = 0.03, OR = 1.45, 95% CI = 1.02-2.05). Also, results indicate that the presence of heterozygote genotypes which include A2 was associated with RA risk (p = 0.01, OR = 1.5, 95% CI = 1.07-2.11). Patients carrier of A2/A2 genotype have a higher score of DAS28 (5.64 [4.49-6.70]). A-/A- has higher level of CRP (2.30 [0.62-9.10]) in comparison with A2/A- (1.06 [0.37-2.82]). A1/A2 genotype was associated with susceptibility to RA in a western Mexican population. The presence of the A2/A2 genotype in RA is associated with increased disease activity.

Objectives: The aim of this study is to compare clinical outcomes, incidence of flares and administered drug reduction between rheumatoid arthritis (RA) patients under TNF inhibitors (TNFi) tapering strategy and RA patients on standard regimen., Methods: Two groups of RA patients on TNFi with DAS28<3.2 were compared: the tapering group (TG: 67 pts from Spain) and the control group with standard therapy regimen (CG: 77 pts from the Netherlands). DAS28 was measured at different time points: visit 0 (prior starting TNFi), visit 1 (prior to start tapering in TG and with DAS28<3.2 in TG and CG), visit 2 (6 months after visit 1), visit 3 (1 year after visit 1), visit 4 (the last visit available after visit 1) and visit-flare (visit with the worst flare between visit 1 and visit 4)., Results: Despite the reduction of administered drug at visit 4 in the TG (interval elongation of 32.8% in infliximab, 52.9% in adalimumab and 52.6% in etanercept), the DAS28 remained similar between groups at the end of the study (DAS28: 2.7±0.9 in TG vs. 2.5±1 in CG, p=0.1). No differences were seen in the number of patients with flares [26/67 (38.9%) in the TG vs. 30/77 (39%) in the CG, p=0.324] and only nineteen out of 136 patients (14%) had anti-drug antibodies at the end of the study., Conclusions: The tapering strategy of TNFi in RA patients result in a reduction of the drug administered, while the disease control is not worse than patients on the standard regimen.

Antibodies against cyclic citrullinated peptides (anti-CCP) are widely used for diagnosis of rheumatoid arthritis (RA). We performed a comparative analysis of antibodies targeting the citrullinating enzyme peptidylarginine deiminase type 4 (anti-PAD4) and mutated citrullinated vimentin (anti-MCV) with anti-CCP autoantibodies in RA patients and examined their relationships with clinical parameters, cytokine profiles and the PADI4 gene. Autoantibodies were examined by enzyme-linked immunosorbent assay (ELISA) in sera of 170 RA patients and 103 controls. Cytokine profiles were measured using a multiplex system. PADI4 polymorphisms (89 G > A, 90 T > C and 92 G > C) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Anti-PAD4, anti-MCV and anti-CCP autoantibodies were detected in 24, 61 and 74% of RA patients, respectively. Positive correlations were observed between anti-PAD4 and disease duration; anti-CCP and erythrocyte sedimentation rate (ESR); anti-MCV and ESR and C-reactive protein. Anti-MCV antibodies were associated with high disease activity score 28 (DAS-28) in early RA. Concentrations of T helper type 1 (Th1) [tumour necrosis factor (TNF)-α, interleukin (IL)-12, IL-2, IL-1β], Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-17) cytokines were higher in RA than in controls. Th2 and, to a lesser extent, Th1-related cytokines, showed positive correlations with anti-MCV and anti-CCP. The GTG haplotype in PADI4 was associated with anti-CCP and anti-MCV, but not anti-PAD4 antibodies. In conclusion, anti-PAD4 antibodies are detected mainly in established RA, which is in contrast to the early detection of antibodies against citrullinated peptide/proteins (ACPAs). Among autoantibodies, anti-MCV appear to perform better as markers of disease activity. Furthermore, anti-CCP and anti-MCV are associated genetically with the citrullinating enzyme PAD4 and are related strongly to Th1 and Th2 cytokines, suggesting a feed-forward loop between cytokines and ACPA production., (© 2015 British Society for Immunology.)

Objective: To analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time., Methods: Clinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.4-10.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years)., Results: Antibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (P = 0.05 at 6 months, P = 0.02 at 1 year, P = 0.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (P = 0.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (P = 0.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (P = 0.073) and longer survival (P = 0.015) on treatment., Conclusion: The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.

Background: Rheumatoid arthritis (RA) is characterized by a progressive joint damage mediated mainly by tumor necrosis factor alpha (TNFalpha). We investigated the relationship of TNFalpha-308 and -238 polymorphisms with messenger RNA (mRNA) expression and soluble TNFalpha (sTNFalpha) in 50 RA and 100 healthy subjects (HS)., Methods: Clinical and laboratory assessments were performed. Spanish Health Assessment Questionnaire Disability Index, Spanish version of Arthritis Impact Measurement Scales and Disease Activity Score using 28 joint count indices were applied to RA patients. The TNFalpha-308 and -238 polymorphisms were performed by polymerase chain reaction and restriction fragment length polymorphism techniques. The mRNA expression of TNFalpha was quantified by real-time polymerase chain reaction. The sTNFalpha levels were measured by enzyme-linked immunosorbent assay., Results: The TNFalpha-308 polymorphism showed an increased frequency of guanine (G)/adenine (A) genotype in RA versus HS (P = 0.03; 95% confidence interval, 1.05-8.08; odds ratio, 2.9) and also the A allele was more frequent in RA patients versus HS (P = 0.04; 95% confidence interval, 1.01-7.29; odds ratio, 2.7). The G/G genotype and also the G allele were more frequent in HS. No significant difference was observed in TNFalpha-238 polymorphism. Rheumatoid arthritis patients showed high TNFalpha mRNA expression (1.33-fold). The G/G genotype was associated with high mRNA and sTNFalpha levels in both TNFalpha polymorphisms. The correlation of sTNFalpha levels with C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, Spanish Health Assessment Questionnaire Disability Index, and Spanish version of Arthritis Impact Measurement Scales, was observed., Conclusion: The TNFalpha-308 polymorphism is a susceptibility marker to RA. The G/G genotype is associated with a high mRNA and soluble TNFalpha expression.

We investigate the clinical association of tumor necrosis factor receptor 2 (TNFR2) M196R polymorphism with rheumatoid arthritis (RA) and knee osteoarthritis (OA). Acute phase reactants, lipid profile, sTNFR2 levels, disease activity-disability indexes, and TNFR2 M196R polymorphism were analyzed in 50 RA, 50 knee OA patients, and 120 healthy subjects (HS). The M/M genotype frequency was 0.74 (RA), 0.80 (OA), and 0.64 (HS). The M/R genotype frequency was RA (0.26), OA (0.20), and HS (0.29). The R/R genotype was observed only in HS (0.07). The M allele was associated with OA (P = 0.0137, OR = 2.43). Total cholesterol, triglyceride levels, apolipoprotein A-I and B showed significant differences (P < 0.05). The highest sTNFR2 levels were observed in RA and OA (P = 0.001), however M/M and M/R carriers do not correlate with sTNFR2 production. Our findings suggest an association of the M allele with knee OA. In addition, high sTNFR2 levels in RA and OA were found.

Objective: To investigate the validity of reduced joint counts for ultrasonographic (US) assessment of joint inflammatory activity in patients with rheumatoid arthritis (RA)., Methods: Ninety-four patients with RA were included. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels were recorded for each patient. The presence of tenderness, swelling and a subjective swelling score from 0 to 3 were assessed by two rheumatologists who reached consensus in 60 joints examined in each patient. All patients underwent an US examination by a third blinded rheumatologist, using power Doppler (PD). US joint effusion, synovitis and PD signal were graded from 0 to 3 in the 60 joints. A 60-joint count and index for effusion, synovitis and PD signal were recorded. A 6-, 10-, 16-, 18-, and two 12-joint counts and indices for US parameters that included the most frequently US involved joints were calculated for each patient., Results: A 12-joint assessment for effusion, synovitis and PD signal, including bilateral wrist, second and third MCP, second and third PIP of hands and knee joints highly correlated with corresponding 60-joint US counts and indices. This reduced-joint US evaluation showed a similar correlation with clinical and laboratory parameters of disease activity to corresponding 60-joint assessment., Conclusion: We propose that a 12-joint evaluation may be a useful tool for US assessment of overall joint inflammatory activity in RA.

Objective: To compare the clinical assessment of overall inflammatory activity in patients with rheumatoid arthritis (RA) with grey scale and power Doppler (PD) ultrasonography (US)., Methods: Ninety four consecutive patients with RA were included. Demographic and clinical data, C reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were recorded for each patient. The presence of tenderness, swelling, and a subjective swelling score from 1 to 3 were independently assessed by two rheumatologists, who reached a consensus in 60 joints examined in each patient. All patients underwent a US examination by a third blinded rheumatologist, using PD. US joint effusion, synovitis, and PD signal were graded from 1 to 3 in the 60 joints. Joint count and joint index for effusion, synovitis, and PD signal were recorded. A 28 joint count for clinical and US variables was calculated. Interobserver reliability of the US examination was evaluated by a fourth blinded rheumatologist., Results: US showed significantly more joints with effusion (mean 15.2) and synovitis (mean 14.6) than clinical examination (mean 11.5, p<0.05). A significant correlation was found between joint count and joint index for swelling, US effusion, synovitis, and PD signal. The 28 joint count for effusion, synovitis, and PD signal correlated highly with the corresponding 60 joint counts. US findings correlated better with CRP and ESR than clinical measures. Interobserver reliability was better for US findings than for clinical assessment., Conclusion: US is a sensitive method for assessing joint inflammatory activity in RA, complementary to clinical evaluation.

Objective: To determine whether major histocompatibility complex (MHC) polymorphisms are associated with a good or poor response to infliximab therapy in patients with rheumatoid arthritis (RA)., Methods: Seventy-eight infliximab-treated patients with RA were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, MHC class I chain-related gene A (MICA) transmembrane polymorphism alleles, and tumor necrosis factor a (TNFa), TNFb, TNFc, TNFd, TNFe, D6S273, HLA-B-associated transcript 2 (BAT2), and D6S2223 microsatellites. Chi-square tests were performed to compare allele proportions between responder and nonresponder patients. A control sample of 342 healthy individuals was also included to detect linkage disequilibrium between pairs of markers., Results: Among responders, the frequency of the TNFa11;b4 minihaplotype was increased (41% versus 16% in nonresponders; P = 0.01) and that of the D6S273&#95;3 allele was decreased (32% versus 56% in nonresponders; P = 0.04). The D6S273&#95;4/BAT2&#95;2 pair was much more frequently observed among responders (46% versus 11% in nonresponders; P = 0.001). When compared with controls, this pair of alleles was found to be associated only with the group of responder patients (46% in responders versus 17% in controls; P = 0.00002). Most of the time, these markers are present in a DRB1*0404/D6S273&#95;4/BAT2&#95;2/TNFa11;b4 context. No statistically significant differences were observed for MICA and D6S2223 polymorphisms and for shared epitope status., Conclusion: The data suggest that genetic determinants of response to infliximab therapy exist in the HLA complex.

We investigated the effect of beta 3-adrenergic receptor (beta(3)AR) polymorphism on lipid profiles in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) treated with chloroquine. One hundred sixty-eight subjects were classified into three groups: 61 RA patients, 57 SLE patients, and 50 healthy subjects. All patients fulfilled the 1987 and 1982 classification criteria for RA and SLE, respectively, of the American College of Rheumatology. Demographic data and clinical characteristics of the patients were registered. Fasting lipid profile determination and leukocyte genomic DNA isolation from peripheral blood was performed in all the participants. Screening of the beta(3)-AR gene polymorphic region (exon 1) was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Quantitative and qualitative variables were analyzed using analysis of variance (ANOVA) with the LSD and chi(2) tests, respectively. An association between the arg64/arg64 beta(3)-AR genotype and high levels of triglycerides (TG) and very low-density lipoprotein cholesterol (VLDL-c) was found in three RA patients ( P=0.01), two of them taking chloroquine. Arg64/arg64 beta(3)-AR polymorphism may contribute to increased TG and VLDL-c in RA patients, independently of chloroquine treatment.

During the course of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), several immune and neuroendocrine changes associated with pregnancy may exert positive (amelioration) or negative (exacerbation) effects on the clinical outcome. In order to shed light on the mechanisms underlying these responses, we performed a prospective longitudinal study in RA and SLE pregnant women, including healthy pregnant women as a control group. Cytokine messenger RNA (mRNA) expression assessed by quantitative competitive polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC), cytokine levels and lymphocyte proliferation responses (LPR) following phytohaemagglutinin (PHA) stimulation of PBMC, plasma metalloprotease-9 activity (MMP-9) and hormonal status during pregnancy were determined. TNFa was the most abundant cytokine mRNA expressed in PBMC in all groups studied (healthy pregnant women, RA and SLE pregnant patients). However, a general TH2 response reflected by high IL-10 levels was found in RA, as well as SLE, patients. A significant change in IFN-gamma was observed in RA patients but only during the first trimester of pregnancy. This compared with a major TH1 response in healthy pregnant women. Interestingly, our study showed a homogeneous hormonal pattern in RA and SLE patients. Although decreased cortisol levels were observed in all patients studied, this is possibly related to the remission of disease activity status brought about by steroid treatment before and during pregnancy. In summary, we suggest that complex immune and hormonal networks are involved in pregnancy and that rheumatic diseases are very dynamic immune processes that cannot be described with a clear-cut cytokine profile. Furthermore, the observations in this study may reflect treatment-related immune effects more than those associated with disease.

Objective: To investigate the effect of APO E gene polymorphism over lipid profile, macular toxicity and clinical manifestations in RA and SLE patients treated with chloroquine., Materials and Methods: We studied 45 RA and 29 SLE patients treated with chloroquine who were classified based on the therapeutic regime of chloroquine into three groups: A) Cumulative dose of 100-300 g, B) >300 g and C) Never received chloroquine. Clinical evaluation, fasting lipid profile, visual field testing and stereoscopic photos of the retina were performed. APO E genotype was determined by PCR-RFLP., Results: Reduced apo B levels in RA and SLE according to the cumulative dose of chloroquine 2/3 APO E genotype in a subset of SLE patients were observed. Macular toxicity was independent of both APO E genotype and cumulative chloroquine dose., Conclusions: Reduced apo B levels were observed associated to chloroquine treatment and 2/3 APO E genotype.