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1.
J Rheumatol ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007930

RESUMO

OBJECTIVE: To reach a consensus on the instruments to be used in clinical practice to evaluate the effectiveness of biological disease-modifying antirheumatic drugs (bDMARD) treatment in PsA patients in the short-medium term (3-6 months), and to establish the minimum health outcomes for treatment continuation. METHODS: A two-round Delphi questionnaire was developed based on both the information gathered in the literature review and four discussion groups. The suitability and feasibility of the proposed sets of instruments were assessed on a 7-point Likert scale. Consensus was established when at least 75% of healthcare professionals (HCPs) reached agreement. To define a minimum health outcome in order to continue treatment a combination of four disease activity states and three health-related quality of life states were defined for three hypothetical patient profiles. HCPs were given a dichotomous choice ("yes/no") in response to whether they would continue treatment in each case. RESULTS: 106 HCPs completed the second round. Consensus was reached on the use of: 1) Disease Activity in Psoriatic Arthritis (DAPSA) + Psoriatic Arthritis Impact of Disease (PsAID-12) or Minimal Disease Activity (MDA) + PsAID-12 + C-reactive protein, in peripheral PsA; and 2) Ankylosing Spondylitis Disease Activity Score (ASDAS) + PsAID-12, in axial PsA. Health outcomes considered sufficient to continue treatment were stricter for bDMARDs-naïve patients than for patients who failed several bDMARDs. CONCLUSION: To the best of our knowledge, this is the first multi-disciplinary consensus on a set of outcomes for the evaluation of bDMARDs effectiveness in PsA, in routine clinical practice.

2.
Arthritis Res Ther ; 22(1): 14, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964419

RESUMO

BACKGROUND: The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3). METHODS: Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events. RESULTS: Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6). CONCLUSIONS: The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis. TRIAL REGISTRATION: SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

3.
Autoimmun Rev ; 19(1): 102429, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31734402

RESUMO

Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.


Assuntos
Interleucina-17/imunologia , Artrite Psoriásica , Artrite Reumatoide , Humanos , Interleucina-17/antagonistas & inibidores , Psoríase , Espondilite Anquilosante
4.
Reumatol Clin ; 2019 Dec 16.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31859154

RESUMO

OBJECTIVE: We aimed to reach a consensus on the best instruments to monitor disease activity in patients with psoriatic arthritis (PsA) and to develop a consensus definition of remission. METHODS: A modified Delphi approach was used. A scientific committee provided statements addressing the definition of remission and the monitoring of PsA in clinical practice. The questionnaire was evaluated in 2 rounds by rheumatologists with experience in managing PsA patients. RESULTS: A panel of 77 rheumatologists reached agreement on 62 out of the 86 proposed items (72.0%). The most recommended index for monitoring disease activity was DAPSA (cut-off values: ≤4 for remission and >4-14 for low disease activity ([LDA]), MDA (at least 5/7 criteria). In cases with axial involvement, ASDAS was the preferred index (cut-off values: <1.3 for remission and <2.1 for LDA). BASDAI (cut-off values: ≤2 for remission and ≤4 for LDA) may be used as an alternative. PsAID was the preferred tool to assess disease impact. CONCLUSION: We propose a definition of remission in PsA as the absence of disease activity evaluated by DAPSA or MDA (ASDAS and/or BASDAI in patients with axial involvement), which would imply absence of signs or symptoms of inflammation, physical well-being, lack of disease impact, and absence of inflammation as measured by biological markers.

5.
Immun Ageing ; 16: 29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708994

RESUMO

Background: Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF). Results: The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors. The proportion of p16(+) senescent cells in normal ST from older donors was higher than from younger ones. Although older RA and OA ST showed proportions of senescent cells similar to older normal ST, senescence was increased in younger RA ST compared to age-matched normal ST. The percentage of senescent SA-ß-gal(+) SF after 14 days in culture positively correlated with donor's age. Initial exposure to H2O2 or TNFα enhanced SF senescence and increased mRNA expression of IL6, CXCL8, CCL2 and MMP3 and proteins secretion. Senescent SF show a heightened IL6, CXCL8 and MMP3 mRNA and IL-6 and IL-8 protein expression response upon further challenge with TNFα. Treatment of senescent SF with the senolytic drug fenofibrate normalized IL6, CXCL8 and CCL2 mRNA expression. Conclusions: Accumulation of senescent cells in ST increases in normal aging and prematurely in RA patients. Senescence of cultured SF is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31609525

RESUMO

OBJECTIVES: Gender differences may modify symptoms, disease expression, and treatment effects. The objective was to evaluate the link between life impact and gender in psoriatic arthritis (PsA). METHODS: ReFlaP (NCT03119805) was a study in 14 countries of consecutive adult patients with definite PsA. Participants underwent comprehensive PsA assessment: Disease Activity in PSoriatic Arthritis (DAPSA), Minimal Disease Activity (MDA), and Psoriatic Arthritis Impact of Disease (PsAID). Disease activity was compared by gender using t-tests or Wilcoxon tests. The association of PsAID with gender was analyzed using hierarchical generalized linear models. RESULTS: Of 458 participants 50.2% were male, mean age (SD) 53.1 (12.6) years, PsA duration 11 (8.2) years, and 51.5% taking bDMARDs. Women versus men had worse Leeds enthesitis index: 0.8 (1.7) / 0.3 (0.9), pain [numerical rating scale 0-10 (NRS)]: 4.7 (2.7) / 3.5 (2.7), HAQ-DI: 0.9 (0.7) / 0.5 (0.6), fatigue NRS: 5.2 (3) / 3.3 (2.8), PsAID: 4.1 (2.4) / 2.8 (2.3), p<0.001 for all, and were less frequently at treatment target (T2T): DAPSA (DAPSA cut-offs ≤4 remission, >4 and ≤14 low disease activity): 16.9 (14.9) / 12.6 (16.6), MDA: 25.7% / 50.0%, p<0.001 for all. High life impact (PsAID≥4) was associated with female gender [odds ratio (OR) 2.3], enthesitis (OR 1.34), tender joints (OR 1.10) p<0.001 for all, and comorbidities (OR 1.22, p=0.002). CONCLUSIONS: High life impact was independently associated with female gender, enthesitis, comorbidities, and tender joints. At T2T, women vs men had higher life impact. Life impact needs to become part of PsA T2T strategies.

7.
Ann Rheum Dis ; 78(11): 1505-1516, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31371305

RESUMO

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that mainly targets joints. Monocytes and macrophages are critical in RA pathogenesis and contribute to inflammatory lesions. These extremely plastic cells respond to extracellular signals which cause epigenomic changes that define their pathogenic phenotype. Here, we interrogated how DNA methylation alterations in RA monocytes are determined by extracellular signals. METHODS: High-throughput DNA methylation analyses of patients with RA and controls and in vitro cytokine stimulation were used to investigate the underlying mechanisms behind DNA methylation alterations in RA as well as their relationship with clinical parameters, including RA disease activity. RESULTS: The DNA methylomes of peripheral blood monocytes displayed significant changes and increased variability in patients with RA with respect to healthy controls. Changes in the monocyte methylome correlate with DAS28, in which high-activity patients are divergent from healthy controls in contrast to remission patients whose methylome is virtually identical to healthy controls. Indeed, the notion of a changing monocyte methylome is supported after comparing the profiles of same individuals at different stages of activity. We show how these changes are mediated by an increase in disease activity-associated cytokines, such as tumour necrosis factor alpha and interferons, as they recapitulate the DNA methylation changes observed in patients in vitro. CONCLUSION: We demonstrate a direct link between RA disease activity and the monocyte methylome through the action of inflammation-associated cytokines. Finally, we have obtained a DNA methylation-based mathematical formula that predicts inflammation-mediated disease activity for RA and other chronic immune-mediated inflammatory diseases.

8.
J Rheumatol ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371648

RESUMO

OBJECTIVE: To analyze the prevalence of preexisting palindromic rheumatism (PR) in patients with established rheumatoid arthritis (RA) and to evaluate whether these patients have a distinctive clinical and serological phenotype. METHODS: Cross-sectional study in patients with established RA. Preexisting PR was determined using a structured protocol and confirmed by retrospective review of medical records. Demographic, clinical, radiological, immunological, and therapeutic features were compared in patients with and without PR. RESULTS: Included were 158 patients with established RA (78% female) with a mean disease duration since RA onset of 5.1 ± 2.7 years. Preexisting PR was recorded in 29 patients (18%). The median time from the onset of PR to progression to RA was 1.2 years. No between-group differences in demographic features, current disease activity, radiographic erosive disease, or disability were observed. Patients with PR had a higher prevalence of smoking (72% vs 40%). Positive rheumatoid factor, anticitrullinated peptide antibodies, and anticarbamylated protein antibodies were numerically higher in patients with PR. No differences in treatment were observed except for greater hydroxychloroquine (HCQ) use in patients with PR (38% vs 6%). Palindromic flares persisted in a significant proportion of patients during the RA course, including patients in clinical remission or receiving biological disease-modifying antirheumatic drugs. CONCLUSION: Eighteen percent of patients with RA had a history compatible with PR previous to RA onset. No specific clinical or serological phenotype was identified in these patients, although higher HCQ use and smoking prevalence were identified. Palindromic flares may persist during the RA disease course despite treatment.

9.
Clin Exp Rheumatol ; 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31376259

RESUMO

OBJECTIVES: The concept of axial disease in psoriatic arthritis (PsA) is not well established. It is also unclear how this disease domain should be evaluated. We aimed to test whether the remission is aligned with a low impact state of the disease in patients with axial PsA. METHODS: Post hoc analysis of a multicentre study conducted in 223 patients with PsA under treatment with systemic biological and non-biological therapies. To define axial disease, ASAS criteria were used. Remission corresponded to a BASDAI less than or equal to 2. The impact of the disease was evaluated according to the PsAID. The Cohen's kappa agreement between remission and patient-acceptable symptoms state (PASS) was analysed. RESULTS: Thirty-seven of the 223 patients (16.6%) met ASAS criteria for axial disease. Fifteen of the 122 (12.3%) patients in PASS situation had axial disease compared to 22 of 101 (21.8%) who did not reach this state, p<0.05. All items, as well as the total score of the BASDAI (4.48±2.03 vs. 1.14±1.02) were significantly higher in the patients who did not achieve a PASS, p<0.001. The kappa agreement between BASDAI remission and PASS was high [κ: 0.73 (95%CI: 0.64-0.83) p<0.0001]. CONCLUSIONS: BASDAI remission and a low impact of the disease show good clinimetric alignment. Both measures could be useful for a more comprehensive assessment of axial disease in PsA.

10.
Front Immunol ; 10: 1459, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312201

RESUMO

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041). Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.

11.
J Clin Invest ; 129(7): 2669-2684, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30990796

RESUMO

The polarization of macrophages is regulated by transcription factors such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1- or Fra-2-deficient macrophages revealed a central role of Fra-1, but not of Fra-2 in orchestrating the expression of genes related to wound response, toll-like receptor activation and interleukin signaling. Chromatin-immunoprecipitation (ChIP)-sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 down-regulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2- deficient mice, we observed an enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-L-arginine, while ʟ-arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1-deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active RA showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared to RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.

12.
PLoS One ; 14(2): e0213073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818333

RESUMO

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Etanercepte/uso terapêutico , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Variantes Farmacogenômicos , Adulto Jovem
13.
Reumatol Clin ; 2019 Jan 28.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30704919

RESUMO

OBJECTIVES: To describe the therapeutic management of Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS) in patients initiating treatment with biological agents. MATERIALS AND METHODS: Observational, retrospective, longitudinal study in 33 Spanish hospitals. Patients with RA, PsA and AS starting treatment with biological agents between September 2009 and August 2010 and a follow-up longer than 3 years were included. Clinical-demographic characteristics, drugs, biological therapy survival, and reasons for discontinuation or switching were analyzed. RESULTS: Four hundred and sixty-three patients were included (183 RA, 119 PsA and 161 AS), with a mean follow-up of 3.8 years. At the end of follow-up, a high proportion continued with the first biological prescribed (41.0% of RA, 59.7% of PsA and 51.6% of AS), 31.1%, 47.9% and 42.9% of RA, PsA and AS patients requiring dosage adjustments, respectively. There was temporary discontinuation in 8.2%, 8.4% and 15.5% of patients, and a switch of biologic agent was required in 37.7%, 26.1% and 24.2%. Definitive discontinuation occurred in 13.1%, 5.9% and 8.7% of RA, PsA and AS patients, respectively. Mean time to discontinuation or switching was 30.1 months for RA and 35.7 months for PsA and AS. CONCLUSIONS: Our results suggest that, in practice, half of patients with RA and two thirds with PsA or AS maintained the first biological, but with frequent dose adjustments.

14.
Front Med (Lausanne) ; 6: 14, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805340

RESUMO

Psoriatic arthritis (PsA) is an immuno-inflammatory disease with a heterogeneous clinical presentation as affects musculoskeletal tissues (arthritis, enthesitis, spondylitis), skin (psoriasis) and, less frequently, eye (uveitis) and bowel (inflammatory bowel disease). It has been suggested that distinct affected tissues could exhibit different immune-inflammatory pathways so complicating the understanding of the physiopathology of psoriatic disease as well as its treatment. Despite of the key pathogenic and clinical relevance that enthesitis has in PsA, peripheral arthritis is more easily perceived. At the macroscopic level, PsA synovitis has predominantly tortuous, bushy vessels, whereas rheumatoid arthritis (RA) is characterized by mainly straight, branching vessels so reflecting prominent neo-angiogenesis in PsA. Synovial biopsies have demonstrated a similar cellular and molecular picture in PsA and RA, although some differences have been reported at the group level, as higher density of vessels, CD163+ macrophages, neutrophils and mast cells in PsA. In fact, synovial IL-17+ mast cells are significantly increased in PsA and produce more IL-17A compared with RA, and a proof of concept study supports its relevant role in the synovitis of SpA, included PsA. As firstly reported in RA, synovial lymphoid neogenesis is found also in the same proportion of PsA as in RA patients, despite the lack of autoantibodies in PsA. These lymphoid structures are associated with activation of the IL-23/Th17 pathway in RA and seemly in PsA, which could be useful to stratify RA patients. Immunohistochemical and transcriptomic methodologies have still not found synovial biomarkers useful to distinguish psoriatic from rheumatoid synovitis at the patient level. However, modern methodologies, as MALDI-Mass Spectrometry Imaging, applied to the study of synovial tissue have revealed metabolic and lipid signatures which could support clinical decision-making in the diagnosis of PsA and RA and to go further toward the personalized medicine.

15.
J Rheumatol ; 46(7): 710-715, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30709957

RESUMO

OBJECTIVE: To examine the grade of agreement between very low disease activity (VLDA) and Disease Activity Index for Psoriatic Arthritis (DAPSA) remission, as well as their association with the effect of the disease as assessed by the Psoriatic Arthritis Impact of Disease (PsAID) questionnaire in patients with psoriatic arthritis in routine clinical practice. METHODS: Posthoc analysis of data from a cross-sectional multicenter study. Patients were included who fulfilled the Classification for Psoriatic Arthritis (CASPAR) criteria with at least 1 year of disease duration and were treated with biological and/or conventional synthetic disease-modifying antirheumatic drugs according to routine clinical practice in Spain. Patients were considered in VLDA if they met 7/7 of the minimal disease activity criteria. DAPSA and clinical (c)DAPSA score ≤ 4 identified remissions. RESULTS: Of the 227 patients included in the original study, 26 (11.5%), 52 (22.9%), and 65 (28.6%) were in VLDA, DAPSA remission, and cDAPSA remission, respectively. There was a moderate agreement between VLDA and DAPSA remission (κ = 0.52) or cDAPSA remission (κ = 0.42). Patients with VLDA had less effect of the disease as measured by PsAID [mean total score (SD): VLDA 1.1 (1.2); DAPSA remission 1.3 (1.5); cDAPSA remission 1.7 (1.6)]. There was a moderate agreement between DAPSA remission or cDAPSA remission and PsAID < 4 (κ = 0.46 and κ = 0.58 respectively), while poor agreement (κ = 0.18) was found between VLDA and PsAID < 4. CONCLUSION: VLDA criteria seem to be more stringent for assessing a status of remission; however, DAPSA remission shows better correlation with a patient-acceptable symptoms state than VLDA does.

16.
Rheumatology (Oxford) ; 58(4): 617-627, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30517745

RESUMO

OBJECTIVES: Synovial mast cells contain IL-17A, a key driver of tissue inflammation in SpA. A recent in vitro study showed that tissue-derived mast cells can capture and release exogenous IL-17A. The present study aimed to investigate if this mechanism could contribute to tissue inflammation in SpA. METHODS: Potential activation of mast cells by IL-17A was assessed by gene expression analysis of the Laboratory of Allergic Diseases 2 (LAD2) mast cell line. The presence of IL-17A-positive mast cells was assessed by immunohistochemistry in synovial tissue obtained before and after secukinumab treatment, as well as in skin and gut tissues from SpA-related conditions. RESULTS: IL-17A did not induce a pro-inflammatory response in human LAD2 mast cells according to the canonical IL-17A signalling pathway. In SpA synovial tissue, the percentage of IL-17A-positive mast cells increased upon treatment with secukinumab. IL-17A-positive mast cells were also readily detectable in non-inflamed barrier tissues such as skin and gut. In non-inflamed dermis and gut submucosa, IL-17A-positive mast cells are the most prevalent IL-17A-positive cells in situ. Compared with non-inflamed tissues, both total mast cells and IL-17A-positive mast cells were increased in psoriatic skin dermis and in submucosa from inflammatory bowel disease gut. In contrast, the proportion of IL-17A-positive mast cells was strikingly lower in the inflamed compared with non-inflamed gut lamina propria. CONCLUSION: IL-17A-positive mast cells are present across SpA target tissues and correlate inversely with inflammation, indicating that their IL-17A content can be regulated. Tissue-resident mast cells may act as IL-17A-loaded sentinel cells, which release IL-17A to amplify tissue inflammation.


Assuntos
Interleucina-17/metabolismo , Mastócitos/metabolismo , Espondilartrite/metabolismo , Sinoviócitos/metabolismo , Técnicas de Cultura de Células , Humanos , Inflamação
17.
Reumatol Clin ; 15(5): 252-257, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30522944

RESUMO

AIMS: To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2years of symptom evolution. METHODS: Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. CONCLUSIONS: The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis.

18.
Ann Rheum Dis ; 78(2): 201-208, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30442648

RESUMO

BACKGROUND: The objective was to compare different definitions of remission and low disease activity (LDA) in patients with psoriatic arthritis (PsA), based on both patients' and physicians' perspectives. METHODS: In ReFlap (Remission/Flare in PsA; NCT03119805), adults with physician-confirmed PsA and >2 years of disease duration in 14 countries were included. Remission was defined as very low disease activity (VLDA), Disease Activity index for PSoriatic Arthritis (DAPSA) ≤4, and physician-perceived and patient-perceived remission (specific question yes/no), and LDA as minimal disease activity (MDA), DAPSA <14, and physician-perceived and patient-perceived LDA. Frequencies of these definitions, their agreement (prevalence-adjusted kappa), and sensitivity and specificity versus patient-defined status were assessed cross-sectionally. RESULTS: Of 410 patients, the mean age (SD) was 53.9 (12.5) years, 50.7% were male, disease duration was 11.2 (8.2) years, 56.8% were on biologics, and remission/LDA was frequently attained: respectively, for remission from 12.4% (VLDA) to 36.1% (physician-perceived remission), and for LDA from 25.4% (MDA) to 43.9% (patient-perceived LDA). Thus, patient-perceived remission/LDA was frequent (65.4%). Agreement between patient-perceived remission/LDA and composite scores was moderate to good (kappa range, 0.12-0.65). When patient-perceived remission or LDA status is used as reference, DAPSA-defined remission/LDA and VLDA/MDA had a sensitivity of 73.1% and 51.5%, respectively, and a specificity of 76.8% and 88.0%, respectively. Physician-perceived remission/LDA using a single question was frequent (67.6%) but performed poorly against other definitions. CONCLUSION: In this unselected population, remission/LDA was frequently attained. VLDA/MDA was a more stringent definition than DAPSA-based remission/LDA. DAPSA-based remission/LDA performed better than VLDA/MDA to detect patient-defined remission or remission/LDA. Further studies of long-term outcomes are needed.


Assuntos
Artrite Psoriásica/psicologia , Autoavaliação Diagnóstica , Médicos/psicologia , Índice de Gravidade de Doença , Adulto , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Reprodutibilidade dos Testes , Resultado do Tratamento
19.
Ann Rheum Dis ; 78(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552173

RESUMO

OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA. METHODS: We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA. RESULTS: We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs. CONCLUSION: These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.


Assuntos
Artrite Psoriásica/genética , Glicosaminoglicanos/genética , N-Acetilglucosaminiltransferases/genética , Psoríase/genética , Transdução de Sinais/genética , Adulto , Artrite Psoriásica/epidemiologia , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , América do Norte/epidemiologia , Polimorfismo de Nucleotídeo Único , Psoríase/epidemiologia , Espanha/epidemiologia
20.
Arthritis Res Ther ; 20(1): 275, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545393

RESUMO

BACKGROUND: Calprotectin is a biomarker of disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) and predicts relapse in juvenile idiopathic arthritis. Higher drug trough serum levels are associated with a good response in patients treated with tumor necrosis factor inhibitors (TNFi). Power Doppler ultrasound synovitis is predictive of relapse and structural damage progression in patients in clinical remission. The purpose of this study was to analyze the accuracy of serum calprotectin levels, drug trough serum levels (TSL), and power Doppler (PD) activity as predictors of relapse in RA and PsA patients in remission or with low disease activity receiving TNFi. METHODS: This was a longitudinal, prospective, 1-year single-center study of 103 patients (47 RA, 56 PsA) receiving TNFi in remission or with low disease activity (28-joint Disease Activity Score (DAS28) ≤ 3.2). The predictive value of serum calprotectin, TNFi TSL, and PD were assessed using receiver operating characteristic (ROC) analyses. To illustrate the predictive performance of calprotectin, TNFi TSL, and PD score, Kaplan-Meier curves were constructed from baseline to relapse. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates and to fully adjust the association between calprotectin, TNFi TSL, and PD score with relapse. A generalized estimating equation model with an identity link for longitudinal continuous outcomes was used to assess the effect of covariates on TNFi TSL. RESULTS: Ninety-five patients completed 1 year of follow-up, of whom 12 experienced a relapse. At baseline, relapsers had higher calprotectin levels, lower TNFi TSL, and higher PD activity than nonrelapsers. ROC analysis showed calprotectin fully predicted relapse (area under the curve (AUC) = 1.00). TNFi TSL and PD had an AUC of 0.790 (95% confidence interval (CI) 0.691-0.889) and 0.877 (95% CI 0.772-0.981), respectively. Survival analyses and log rank tests showed significant differences between groups according to calprotectin serum levels (p < 0.001), TNFi TSL (p = 0.004), and PD score (p < 0.001). Univariate Cox regression models showed that time-to-remission/low disease activity (hazard ratio (HR) = 1.17, p < 0.001), calprotectin levels (HR = 2.38, p < 0.001), TNFi TSL (HR = 0.47, p = 0.018), and PD score (HR = 1.31, p < 0.001) were significantly associated with disease relapse. In the multivariate analysis, only baseline calprotectin levels independently predicted disease relapse (HR = 2.41, p = 0.002). The generalized estimating equation analysis showed that only disease activity by DAS28-erythrocyte sedimentation rate (ESR) was significantly associated with longitudinal changes in TNFi TSL (regression coefficient 0.26 (0.0676 to 0.0036), p = 0.001). CONCLUSION: Time-to-remission/low disease activity, calprotectin serum levels, TNFi TSL, and PD score were significantly associated with disease relapse. However, only baseline calprotectin serum levels independently predicted disease relapse in RA and PsA patients under TNFi therapy.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Complexo Antígeno L1 Leucocitário/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Artrite Psoriásica/sangue , Artrite Psoriásica/diagnóstico , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Recidiva , Indução de Remissão , Fator de Necrose Tumoral alfa/metabolismo
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